阅读说明：本技术 用图卡替尼治疗乳腺癌的方法 (Method of treating breast cancer with ceratinib ) 是由 L·沃克 C·J·恩德斯 A·J·李 H·孙 A·R·托佩茨-埃里克森 于 2020-01-24 设计创作，主要内容包括：本发明提供了图卡替尼及其在治疗癌症如乳腺癌的方法中的用途。本发明还提供了用于在治疗癌症如乳腺癌中使用的包含图卡替尼的组合物和试剂盒。(The present invention provides Tucanitinib and its use in a method of treating cancer, such as breast cancer. The invention also provides compositions and kits comprising picatinib for use in the treatment of cancer, such as breast cancer.)

1. A method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaininib or a salt or solvate thereof, wherein the subject is not being concurrently treated with a therapeutically effective amount of a substrate of a multidrug and toxin efflux (MATE) protein.

2. The method of claim 1, wherein the subject has not received treatment with the substrate of the MATE protein within the past 7 days.

3. The method of claim 1, wherein the subject has not received treatment with the substrate of the MATE protein within the past 3 months.

4. The method of claim 1 wherein the subject has not received treatment with the substrate of the MATE protein within the past 12 months.

5. The method of claim 1, wherein the subject has not previously been treated with the substrate of the MATE protein.

6. The method of any one of claims 1-5, wherein the MATE protein is MATE 1.

7. The method of any one of claims 1-5, wherein the MATE protein is MATE 2K.

8. The method of any one of claims 1-7, wherein the substrate of the MATE protein is selected from the group consisting of metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin, and pyrimethamine.

9. The method of claim 8, wherein the substrate is metformin.

10. A method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaserod or a salt or solvate thereof, wherein the subject is not being treated simultaneously with a therapeutically effective amount of a substrate for Organic Cation Transporter (OCT).

11. The method of claim 10, wherein the subject has not received treatment with the substrate of the OCT within the past 7 days.

12. The method of claim 10, wherein the subject has not received treatment with the substrate of the OCT within the past 3 months.

13. The method of claim 10, wherein the subject has not received treatment with the substrate of the OCT protein within the past 12 months.

14. The method of claim 10, wherein the subject has not previously been treated with the substrate of the OCT.

15. The method of any of claims 10-14, wherein the OCT is OCT 1.

16. The method of any of claims 10-14, wherein the OCT is OCT 2.

17. The method of any one of claims 10-16, wherein the substrate of the OCT is selected from metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin, and pyrimethamine.

18. The method of claim 17, wherein the substrate is metformin.

19. The method of any one of claims 10-18 wherein the subject is not being concurrently treated with a therapeutically effective amount of a substrate for MATE protein.

20. The method of claim 19, wherein the subject has not received treatment with the substrate of the MATE protein within the past 7 days.

21. The method of claim 19 wherein the subject has not received treatment with the substrate of the MATE protein within the past 3 months.

22. The method of claim 19 wherein the subject has not received treatment with the substrate of the MATE protein within the past 12 months.

23. The method of claim 19, wherein the subject has not previously been treated with the substrate of the MATE protein.

24. The method of any one of claims 19-23, wherein the MATE protein is MATE 1.

25. The method of any one of claims 19-23, wherein the MATE protein is MATE 2K.

26. A method for treating breast cancer in a subject, comprising administering to the subject a therapeutically effective amount of tegaininib or a salt or solvate thereof, wherein the subject has no impaired renal function.

27. A method according to claim 26, wherein the subject has not suffered from impaired renal function within the past 12 months.

28. The method of any one of claims 1-25, wherein the subject has not had impaired renal function.

29. A method according to claim 28, wherein the subject has not suffered from impaired renal function within the past 12 months.

30. A method according to one of claims 26-29, wherein impaired renal function is determined based on serum creatinine levels in the subject.

31. The method of claim 30, wherein a) the subject is male and the subject has a serum creatinine level less than 1.5mg/dL, or b) the subject is female and has a serum creatinine level less than to 1.4 mg/dL.

32. A method according to one of claims 26-29, wherein impaired renal function is determined based on the subject having an abnormal creatinine clearance rate.

33. The method of any one of claims 26-29, wherein impaired renal function is determined based on the subject's glomerular filtration rate.

34. The method of any one of claims 1-33, wherein the subject is not being concurrently treated with a therapeutically effective amount of a compound that modulates the activity of a cytochrome p450 protein.

35. The method of claim 34, wherein the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the past 7 days.

36. The method of claim 34, wherein the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the past 3 months.

37. The method of claim 34, wherein the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the past 12 months.

38. The method of claim 34, wherein the subject has not previously been treated with a compound that modulates the activity of the cytochrome p450 protein.

39. The method of any one of claims 34-38, wherein the compound that modulates the activity of the cytochrome p450 protein is an inhibitor of the activity of the cytochrome p450 protein.

40. The method of claim 39, wherein the compound that modulates the activity of the cytochrome p450 protein is a strong inhibitor of the activity of the cytochrome p450 protein.

41. The method of claim 39 or 40, wherein the cytochrome p450 protein is CYP3A 4.

42. The method of claim 41, wherein the compound that inhibits the activity of CYP3A4 is itraconazole.

43. The method of claim 39 or 40, wherein the cytochrome p450 protein is CYP2C 8.

44. The method of claim 43, wherein the compound that inhibits the activity of CYP2C8 is gemfibrozil.

45. The method of any one of claims 34-38, wherein the compound that modulates the activity of the cytochrome p450 protein is an inducer of the activity of the cytochrome p450 protein.

46. The method of claim 45, wherein the compound that modulates the activity of the cytochrome p450 protein is a strong inducer of the activity of the cytochrome p450 protein.

47. The method of claim 45 or 46, wherein the cytochrome p450 protein is CYP3A 4.

48. The method of claim 47, wherein the cytochrome p450 protein is CYP2C 8.

49. The method of any one of claims 45-48, wherein said compound that induces the activity of said cytochrome p450 protein is rifampicin.

50. A method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaserod, or a salt or solvate thereof, wherein the subject is not being treated simultaneously with a therapeutically effective amount of a compound that modulates the activity of a cytochrome p450 protein.

51. The method of claim 50, wherein the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the past 7 days.

52. The method of claim 50, wherein the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the past 3 months.

53. The method of claim 50, wherein the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the past 12 months.

54. The method of claim 50, wherein the subject has not previously been treated with a compound that modulates the activity of the cytochrome p450 protein.

55. The method of any one of claims 50-54, wherein the compound that modulates the activity of the cytochrome p450 protein is an inhibitor of the activity of the cytochrome p450 protein.

56. The method of claim 55, wherein the compound that modulates the activity of the cytochrome p450 protein is a strong inhibitor of the activity of the cytochrome p450 protein.

57. The method of claim 55 or 56, wherein the cytochrome p450 protein is CYP3A 4.

58. The method of claim 57, wherein the compound that inhibits the activity of CYP3A4 is itraconazole.

59. The method of claim 55 or 56, wherein the cytochrome p450 protein is CYP2C 8.

60. The method of claim 59, wherein the compound that inhibits the activity of CYP2C8 is gemfibrozil.

61. The method of any one of claims 50-54, wherein the compound that modulates the activity of the cytochrome p450 protein is an inducer of the activity of the cytochrome p450 protein.

62. The method of claim 61, wherein the compound that modulates the activity of the cytochrome p450 protein is a strong inducer of the activity of the cytochrome p450 protein.

63. The method of claim 61 or 62, wherein the cytochrome p450 protein is CYP3A 4.

64. The method of claim 61 or 62, wherein the cytochrome p450 protein is CYP2C 8.

65. The method of any one of claims 61-64, wherein the compound that induces the activity of the cytochrome p450 protein is rifampicin.

66. A method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaserod, or a salt or solvate thereof, wherein the subject is not being treated simultaneously with a therapeutically effective amount of a substrate for a cytochrome p450 protein.

67. The method of claim 66, wherein the subject has not received treatment with the substrate of the cytochrome p450 protein within the last 7 days.

68. The method of claim 66, wherein the subject has not received treatment with the substrate for the cytochrome p450 protein within the last 3 months.

69. The method of claim 66, wherein the subject has not received treatment with the substrate for the cytochrome p450 protein within the past 12 months.

70. The method of claim 66, wherein the subject has not previously been treated with a substrate for the cytochrome p450 protein.

71. The method according to any one of claims 66-70, wherein the cytochrome p450 protein is CYP3A 4.

72. The method of any one of claims 66-71, wherein the substrate of the cytochrome p450 protein is a sensitive CYP3A substrate.

73. The method according to any one of claims 66-70, wherein the cytochrome p450 protein is CYP2C 8.

74. The method of any one of claims 66-73, wherein the substrate of the cytochrome p450 protein is selected from the group consisting of budesonide, buspirone, eplerenone, eletriptan, felodipine, fluticasone, lovastatin, midazolam, saquinavir, sildenafil, simvastatin, triazolam, and vardenafil.

75. The method of claim 74, wherein the substrate for the cytochrome p450 protein is midazolam.

76. A method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaserod, or a salt or solvate thereof, wherein the subject is not being treated simultaneously with a therapeutically effective amount of a substrate for P-glycoprotein (P-gp).

77. The method of claim 76, wherein the subject has not received treatment with the substrate of P-gp within the past 7 days.

78. The method of claim 76, wherein the subject has not received treatment with the substrate of P-gp within the past 3 months.

79. The method of claim 76, wherein the subject has not received treatment with the substrate of P-gp within the past 12 months.

80. The method of claim 76, wherein the subject has not previously been treated with a substrate for P-gp.

81. The method of any one of claims 76-80, wherein the substrate of P-gp is a substrate with a narrow therapeutic index.

82. The method of any one of claims 76-81, wherein the substrate of P-gp is selected from amitriptyline, carbamazepine, clonidine, cyclosporine, digoxigenin, digoxin, imipramine, phenobarbital, phenytoin, quinidine, rifampin, sirolimus, tacrolimus, temsirolimus, trimipramine, vincristine, paclitaxel, and dabigatran etexilate.

83. The method of claim 82, wherein the substrate of P-gp is digoxin.

84. The method of any one of claims 1-83, wherein the subject is administered cartinib at a dose of about 150mg to about 650 mg.

85. The method of claim 84, wherein the procatinib is administered to the subject at a dose of about 300 mg.

86. The method of claim 84 or 85, wherein the cartinib is administered once or twice daily.

87. The method of claim 86, wherein the subject is administered cartinib at a dose of about 300mg twice daily.

88. The method of any one of claims 1-87, wherein the icaritinib is orally administered to the subject.

89. The method of any one of claims 1-88, wherein the breast cancer is HER2 positive breast cancer.

90. The method of claim 89, wherein the cancer is HER2 positive as determined using in situ hybridization, fluorescence in situ hybridization, or immunohistochemistry.

91. The method of any one of claims 1-90, wherein the breast cancer is metastatic.

92. The method of claim 91, wherein the breast cancer has metastasized to the brain.

93. The method of any one of claims 1-92, wherein the breast cancer is locally advanced.

94. The method of any one of claims 1-93, wherein the breast cancer is unresectable.

95. The method of any one of claims 1-94, further comprising administering to the subject one or more additional therapeutic agents to treat the breast cancer.

96. The method of claim 95, wherein the one or more additional therapeutic agents are selected from capecitabine and an anti-HER 2 antibody.

97. The method of claim 95, wherein the one or more additional therapeutic agents is capecitabine.

98. The method of claim 95, wherein the one or more additional therapeutic agents is trastuzumab.

99. The method of claim 95, wherein the one or more additional therapeutic agents are capecitabine and trastuzumab.

100. The method of claim 97 or 99, wherein capecitabine is administered at about 500mg/m²To about 1500mg/m²Is administered to the subject.

101. The method of claim 100, wherein capecitabine is administered at about 1000mg/m ²Is administered to the subject.

102. The method of claim 100 or 101, wherein capecitabine is administered orally to the subject.

103. The method of any one of claims 99-102, wherein capecitabine is administered to the subject twice daily.

104. The method of claim 98 or 99, wherein trastuzumab is administered to the subject at a dose of about 400mg to about 800 mg.

105. The method of claim 104, wherein trastuzumab is administered to the subject at a dose of about 600 mg.

106. The method of claim 104 or 105, wherein trastuzumab is administered subcutaneously to the subject.

107. The method of claim 98 or 99, wherein trastuzumab is administered to the subject at a dose of about 4mg/kg to about 10 mg/kg.

108. The method of claim 107, wherein trastuzumab is administered to the subject at a dose of about 6 mg/kg.

109. The method of claim 107, wherein trastuzumab is administered to the subject at a dose of about 8 mg/kg.

110. The method of claim 107, wherein trastuzumab is administered to the subject at an initial dose of about 8mg/kg followed by a subsequent dose of about 6 mg/kg.

111. The method of any one of claims 107-110, wherein trastuzumab is administered intravenously.

112. The method of any one of claims 104-111, wherein trastuzumab is administered about once every 1 week, about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks.

113. The method of claim 112, wherein trastuzumab is administered about once every 3 weeks.

114. The method of claim 99, wherein the uncicotinib, capecitabine, and trastuzumab are administered to the subject in a 21 day treatment cycle.

115. The method of claim 114, wherein on each day of the 21-day treatment cycle, procatinib is administered to the subject twice daily.

116. The method of claim 114 or 115, wherein capecitabine is administered to the subject twice daily on each of days 1-14 of the 21-day treatment cycle.

117. The method of any one of claims 114-116, wherein trastuzumab is administered to the subject once every 21 days of the treatment cycle.

118. The method of claim 117, wherein the dose of trastuzumab during the first 21-day treatment cycle is 8mg/kg and the dose of trastuzumab during the subsequent 21-day treatment cycle is 6 mg/kg.

119. The method of any one of claims 1-118, wherein the subject has been previously treated with one or more additional therapeutic agents for the breast cancer.

120. The method of claim 119, wherein the one or more additional therapeutic agents is an anti-HER 2 antibody or an anti-HER 2 antibody-drug conjugate.

121. The method of claim 120, wherein the one or more additional therapeutic agents is trastuzumab, pertuzumab, and/or T-DM 1.

122. The method of any one of claims 1-121, wherein the subject has not been treated with another therapeutic agent for the breast cancer within the past 12 months.

123. The method of any one of claims 1-118, wherein the subject has not been previously treated with another therapeutic agent for the breast cancer.

124. The method of any one of claims 1-123, wherein the subject has not been previously treated with lapatinib, neratinib, afatinib, or capecitabine.

125. The method of any one of claims 1-124, wherein treating the subject results in a Tumor Growth Inhibition (TGI) index of at least about 85%.

126. The method of any one of claims 1-124, wherein treating the subject results in a TGI index of about 100%.

127. The method of any one of claims 1-126, wherein one or more therapeutic effects in the subject are improved relative to baseline following administration of cartinib to the subject.

128. The method of claim 127, wherein the one or more therapeutic effects are selected from the group consisting of: size, objective response rate, duration of response, time to response, progression-free survival and overall survival of tumors derived from the breast cancer.

129. The method of any one of claims 1-128, wherein the size of the tumor derived from the breast cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from the breast cancer prior to administration of cartilaginib to the subject.

130. The method according to any one of claims 1-129, wherein the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%.

131. The method of any one of claims 1-130, wherein the subject exhibits progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of cartinib to the subject.

132. The method of any one of claims 1-131, wherein the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of cartinib to the subject.

133. The method of any one of claims 1-132, wherein the duration of response to tucatinib is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of tucatinib to the subject.

134. The method of any one of claims 1-133, wherein the subject is a human.

Technical Field

The present invention relates to methods of treating breast cancer (such as HER2 positive breast cancer) with tucatinib or a salt or solvate thereof.

Background

To date, breast cancer is the most common cancer in women. Each year, more than 180,000 and 100 million women, respectively, in the united states and worldwide are diagnosed with breast cancer. Breast cancer is the leading cause of death in women between the ages of 50-55 years and is the most common unpredictable malignancy in western hemisphere women. It is estimated that 2,167,000 women currently suffer from the disease in the united states. Based on the incidence of Cancer from 1995 to 1997, a report from the National Cancer Institute (NCI) estimates that about 1 out of 8 women in the united states (about 12.8%) will develop breast Cancer during their lifetime (NCI monitoring, Epidemiology and End result Program, SEER publication SEER Cancer static's Review 1973 1997). In american women, breast cancer is second to skin cancer the second most common form of cancer. An estimated 250,100 new cases of breast cancer are expected to be diagnosed in the united states in 2001. Among them, 192,200 new more advanced (aggressive) breast Cancer cases (5% increase over last year) are expected to occur in women, 46,400 new early (in situ) breast Cancer cases (9% increase over last year) are expected to occur in women, and about 1,500 new breast Cancer cases (Cancer Facts & FIG. 2001American Cancer Society) are expected to be diagnosed in men. An estimated 40,600 deaths due to breast cancer were expected in 2001 (40,300 women, 400 men). Among female causes of cancer death, breast cancer is ranked second only to lung cancer. Nearly 86% of women diagnosed with breast cancer may still survive five years later, but 24% of them will die of breast cancer 10 years later, and nearly half (47%) will die of breast cancer 20 years later.

Each woman is at risk for breast cancer. More than 70% of breast cancers occur in women with no other identifiable risk factors than age (U.S. general Accounting office. Breast Cancer, 1971: Prevention, Treatment and research. GAO/PEMD-92-12; 1991). Only 5% to 10% of Breast cancers have been associated with a family history of Breast Cancer (Henderson I C, Breast Cancer. in: Murphy G P, Lawrence W L, Lenhard R E (eds.). Clinical Oncology. Atlanta, Ga.: American Cancer Society; 1995: 198-.

Cancer is often the result of mutations that may occur in many genes that play a role in a wide range of cellular processes. In many cases, cancer cells carry mutations in genes that control processes such as cell growth, division, differentiation, or interaction with the extracellular environment. For example, mutations that increase the activity of HER2, a cell surface receptor that promotes cell growth and division, have been implicated in many cancers.

In many cases, tumors are resistant to a particular cancer therapy, or are initially sensitive to a particular therapy but later become resistant. Resistance development is often the result of mutations that alter the activity of cellular components (e.g., mutations that make signaling molecules constitutively active) or mutations that result in altered gene expression (e.g., mutations that result in increased expression of a cellular signaling receptor such as HER 2). In some cases, resistance occurs simultaneously with or results from the occurrence of a mutation that converts the cancer to a more aggressive (e.g., metastatic) form. Metastatic cancer is often associated with a worse prognosis compared to non-metastatic cancer.

Cancers characterized by overexpression of HER2 (referred to as HER2 positive cancers) are often associated with poor prognosis and/or are resistant to many standard therapies. Thus, there is a need for new therapies effective for the treatment of cancers (such as HER2 positive cancers and/or metastatic HER2 positive cancers). The present invention fulfills this need, and provides other advantages as well.

All references, including patent applications, patent publications, and scientific literature, cited herein are hereby incorporated by reference in their entirety as if each individual reference were specifically and individually indicated to be incorporated by reference.

Disclosure of Invention

Provided herein is a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaininib or a salt or solvate thereof, wherein the subject is not being concurrently treated with a therapeutically effective amount of a substrate of a multidrug and toxin efflux (MATE) protein. In some embodiments, the subject has not received treatment with the substrate of the MATE protein within the last 7 days. In some embodiments, the subject has not received treatment with the substrate of the MATE protein within the last 3 months. In some embodiments, the subject has not received treatment with the substrate of the MATE protein within the past 12 months. In some embodiments, the subject has not previously received treatment with the substrate of the MATE protein. In some of any of the embodiments herein, the MATE protein is MATE 1. In some of any of the embodiments herein, the MATE protein is MATE 2K. In some of any of the embodiments herein, the substrate of the MATE protein is selected from the group consisting of metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin, and pyrimethamine.

Also provided herein is a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of picatinib, or a salt or solvate thereof, wherein the subject is not being concurrently treated with a therapeutically effective amount of a substrate of Organic Cation Transporter (OCT). In some embodiments, the subject has not received treatment with the substrate of the OCT within the last 7 days. In some embodiments, the subject has not received treatment with the substrate of the OCT within the last 3 months. In some embodiments, the subject has not received treatment with the substrate of the OCT protein within the past 12 months. In some embodiments, the subject has not previously been treated with the substrate of the OCT. In some of any of the embodiments herein, the OCT is OCT 1. In some of any of the embodiments herein, the OCT is OCT 2. In some of any of the embodiments herein, selected from the group consisting of metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin, and pyrimethamine.

Also provided herein is a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of picatinib, or a salt or solvate thereof, wherein the subject has no impaired renal function. In some embodiments, the subject has not experienced impaired renal function within the past 12 months. In some of any of the embodiments herein, impaired renal function is determined based on serum creatinine levels in the subject. In some of any of the embodiments herein, impaired renal function is determined based on serum creatinine levels in the subject. In some embodiments, the subject is male and the subject has a serum creatinine level less than 1.5mg/dL, or the subject is female and has a serum creatinine level less than to 1.4 mg/dL. In some of any of the embodiments herein, impaired renal function is determined based on the subject having an abnormal creatinine clearance rate. In some of any of the embodiments herein, impaired renal function is determined based on the glomerular filtration rate of the subject.

Also provided herein is a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaserod, or a salt or solvate thereof, wherein the subject is not being treated simultaneously with a therapeutically effective amount of a compound that modulates the activity of a cytochrome p450 protein. In some embodiments, the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the last 7 days. In some embodiments, the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the last 3 months. In some embodiments, the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the past 12 months. In some embodiments, the subject has not previously been treated with a compound that modulates the activity of the cytochrome p450 protein. In some of any of the embodiments herein, the compound that modulates the activity of the cytochrome p450 protein is an inhibitor of the activity of the cytochrome p450 protein. In some of any of the embodiments herein, the compound that modulates the activity of the cytochrome p450 protein is a strong inhibitor of the activity of the cytochrome p450 protein. In some of any of the embodiments herein, the compound that modulates the activity of the cytochrome p450 protein is an inducer of the activity of the cytochrome p450 protein. In some of any of the embodiments herein, the compound that modulates the activity of the cytochrome p450 protein is a strong inducer of the activity of the cytochrome p450 protein.

Also provided herein is a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaserod, or a salt or solvate thereof, wherein the subject is not being treated simultaneously with a therapeutically effective amount of a substrate for a cytochrome p450 protein. In some embodiments, the subject has not received treatment with the substrate of the cytochrome p450 protein within the last 7 days. In some embodiments, the subject has not received treatment with the substrate of the cytochrome p450 protein within the last 3 months. In some embodiments, the subject has not received treatment with the substrate of the cytochrome p450 protein within the past 12 months. In some embodiments, the subject has not previously received treatment with the substrate of the cytochrome p450 protein. In some of any of the embodiments herein, the substrate of the cytochrome p450 protein is a sensitive CYP3A substrate.

Also provided herein is a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaserod, or a salt or solvate thereof, wherein the subject is not being concurrently treated with a therapeutically effective amount of a substrate for P-glycoprotein (P-gp). In some embodiments, the subject has not received treatment with the substrate of P-gp within the last 7 days. In some embodiments, the subject has not received treatment with the substrate of P-gp within the last 3 months. In some embodiments, the subject has not received treatment with the substrate of P-gp within the past 12 months. In some embodiments, the subject has not previously received treatment with a substrate for P-gp. In some of any of the embodiments herein, the substrate of P-gp is a substrate with a narrow therapeutic index.

In some of any of the embodiments herein, the method further comprises administering to the subject an amount of about 150mg to about 650mg of the icaritinib. In some of any of the embodiments herein, the method further comprises administering to the subject the icaritinib at a dose of about 300 mg. In some of any of the embodiments herein, the cartinib is administered once or twice daily. In some of any of the embodiments herein, the subject is administered cartinib at a dose of about 300mg twice daily. In some of any of the embodiments herein, the method further comprises administering to the subject the oral administration of icaritinib.

In some of any of the embodiments herein, the breast cancer is HER2 positive breast cancer. In some embodiments, the cancer is HER2 positive as determined using in situ hybridization, fluorescence in situ hybridization, or immunohistochemistry. In some of any of the embodiments herein, the breast cancer is metastatic. In some embodiments, the breast cancer has metastasized to the brain. In some of any of the embodiments herein, the breast cancer is locally advanced. In some of any of the embodiments herein, the breast cancer is unresectable.

In some of any of the embodiments herein, the method further comprises administering to the subject one or more additional therapeutic agents to treat the breast cancer. In some embodiments, the one or more additional therapeutic agents are selected from capecitabine and an anti-HER 2 antibody (e.g., trastuzumab). In some embodiments, capecitabine is administered orally to the subject. In some of any of the embodiments herein, capecitabine is administered to the subject twice daily. In some embodiments, trastuzumab is administered subcutaneously or intravenously. In some embodiments, trastuzumab is administered about once every 3 weeks.

In some of any of the embodiments herein, the subject has been previously treated with one or more additional therapeutic agents for the breast cancer. In some embodiments, the one or more additional therapeutic agents is an anti-HER 2 antibody or an anti-HER 2 antibody-drug conjugate. In some of any of the embodiments herein, the subject has not been treated with another therapeutic agent for the breast cancer within the past 12 months. In some of any of the embodiments herein, the subject has not been previously treated with another therapeutic agent for the breast cancer.

In some of any of the embodiments herein, treating the subject results in a Tumor Growth Inhibition (TGI) index of at least about 85% (such as about 100%). In some of any of the embodiments herein, one or more therapeutic effects in the subject are improved relative to baseline following administration of cartinib to the subject. In some embodiments, the one or more therapeutic effects are selected from: size, objective response rate, duration of response, time to response (time to response), progression free survival and overall survival of tumors derived from the breast cancer. In some of any of the embodiments herein, the subject is a human.

Drawings

Figure 1 shows a treatment and assessment schedule for the phase I clinical study described in example 1.

Figure 2 is a graph showing mean (± SD) plasma metformin concentration versus time curves for subjects treated with metformin alone or metformin in combination with ticatinib.

Figure 3 is a graph showing mean (± SD) plasma iohexol concentration versus time curves for subjects treated with metformin alone or a combination of metformin and vectinib.

Figure 4 is a graph showing mean (± SD) plasma cartilaginib trough concentrations versus time.

Figure 5 shows a treatment and assessment schedule for part a of the phase I clinical study described in example 2.

Figure 6 shows a treatment and assessment schedule for part B of the phase I clinical study described in example 2.

Figure 7 shows a treatment and assessment schedule for section C of the phase I clinical study described in example 2.

Figure 8 shows a treatment and assessment schedule for section D of the phase I clinical study described in example 2.

Figure 9 shows a treatment and assessment schedule for section E of the phase I clinical study described in example 2.

Detailed Description

I. Definition of

In order that the disclosure may be more readily understood, certain terms are first defined. As used herein, each of the following terms shall have the meaning set forth below, unless the context clearly provides otherwise. Additional definitions are set forth throughout this application.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure relates. For example, circumcise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2 nd edition, 2002, CRC Press; the Dictionary of Cell and Molecular Biology, 3 rd edition, 1999, academic Press; and Oxford Dictionary Of Biochemistry And Molecular Biology, revised edition, 2000, Oxford university Press provided the skilled artisan with a general Dictionary Of many Of the terms used in this disclosure. For the purposes of the present invention, the following terms are defined.

Units, prefixes, and symbols are denoted in their international system of units (SI) approved form. Numerical ranges include the numbers defining the range. The headings provided herein are not limitations of the various aspects of the disclosure which can be had by reference to the specification as a whole. Accordingly, the terms defined immediately below may be more fully defined by reference to the specification as a whole.

The terms "a", "an" or "the" as used herein include not only aspects having one member, but also aspects having more than one member. For example, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells, and reference to "the agent" includes reference to one or more agents known to those skilled in the art, and so forth.

The term "or" as used herein should generally be interpreted non-exclusively. For example, a claim to "a composition comprising a or B" will generally present aspects with respect to compositions comprising both a and B. However, "or" should be construed to exclude those presented aspects that cannot be combined without contradiction (e.g., a composition pH between 9 and 10 or between 7 and 8).

Group "A or B" is generally equivalent to a group "selected from A and B".

The term "and/or" as used herein is to be taken as a specific disclosure of each of the two specified features or components, with or without the other. Thus, the term "and/or" as used herein with phrases such as "a and/or B" is intended to include "a and B", "a or B", "a" (alone) and "B" (alone). Likewise, the term "and/or" as used with phrases such as "A, B and/or C" is intended to encompass each of the following: A. b and C; A. b or C; a or C; a or B; b or C; a and C; a and B; b and C; a (alone); b (alone); and C (alone).

It is to be understood that the aspects and embodiments of the invention described herein include "comprising," "consisting of," and "consisting essentially of" the various aspects and embodiments.

The terms "about" and "approximately" as used herein shall generally mean an acceptable degree of error in the measured quantity given the nature or accuracy of the measurement. Typical exemplary degrees of error are within 20% (%) of a given value or range of values, preferably within 10%, more preferably within 5%. Any reference to "about X" explicitly indicates at least the values X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" is intended to teach and provide written descriptive support for claim limitations such as "0.98X". In particular, the terms "about" and "approximately" in reference to a given quantity encompass and describe the given quantity per se.

Alternatively, in biological systems, the terms "about" and "approximately" may mean a value within one order of magnitude, preferably within 5-fold, more preferably within 2-fold, of a given value. Unless otherwise indicated, numerical quantities given herein are approximate, meaning that the terms "about" and "approximately" may be inferred without explicit recitation.

When "about" is applied to the beginning of a range of values, it applies to both ends of the range. Thus, "from about 5% to 20%" is equivalent to "from about 5% to about 20%". When "about" is applied to a first value of a set of values, it applies to all values in the set. Thus, "about 7, 9, or 11 mg/kg" is equivalent to "about 7, about 9, or about 11 mg/kg".

The term "comprising" as used herein should generally be interpreted as not excluding further ingredients. For example, a claim to "a composition comprising a" is intended to cover both a and B; A. b and C; A. b, C and D; A. b, C, D and E, etc.

As used herein, the term "co-administration" includes the sequential or simultaneous administration of two or more structurally different compounds. For example, two or more structurally different pharmaceutically active compounds may be co-administered by: administering a pharmaceutical composition suitable for oral administration comprising two or more structurally distinct active pharmaceutically active compounds. As another example, two or more structurally different compounds may be co-administered by: one compound is administered followed by the other compound. The two or more structurally distinct compounds may include an anti-HER 2 antibody and ceratinib. In some cases, the co-administered compounds are administered by the same route. In other cases, the co-administered compounds are administered via different routes. For example, one compound may be administered orally and the other compound may be administered via intravenous, intramuscular, subcutaneous or intraperitoneal injection, e.g., sequentially or simultaneously. The compounds or compositions administered simultaneously or sequentially may be administered such that the anti-HER 2 antibody and the charcotinib are present simultaneously in the subject or in the cell at effective concentrations.

"cancer" refers to a broad group of diseases characterized by uncontrolled growth of abnormal cells in the body. "cancer" or "cancerous tissue" may include tumors. Unregulated cell division and growth results in the formation of malignant tumors that invade adjacent tissues and may also metastasize to remote sites in the body through the lymphatic system or blood stream. After metastasis, the distal tumor can be said to be "derived" from the pre-metastatic tumor. For example, "a tumor derived from breast cancer" refers to a tumor that is the result of metastatic breast cancer.

In the context of cancer, the term "staging" refers to the classification of the extent of cancer. Factors considered in staging cancer include, but are not limited to, tumor size, invasion of nearby tissues by the tumor, and whether the tumor has metastasized to other sites. The particular criteria and parameters that distinguish one stage from another may vary depending on the type of cancer. For example, cancer staging is used to help determine prognosis or to identify the most appropriate treatment option or options.

One non-limiting example of a cancer staging system is known as the "TNM" system. In the TNM system, "T" refers to the size and extent of the major tumor, "N" refers to the number of nearby lymph nodes to which the cancer has spread, and "M" refers to whether the cancer has metastasized. "TX" indicates that the primary tumor cannot be measured, "T0" indicates that the primary tumor cannot be found, and "T1", "T2", "T3", and "T4" indicate the size or extent of the primary tumor, with larger numbers corresponding to larger tumors or tumors that grow into nearby tissues. "NX" indicates that cancer in the nearby lymph nodes cannot be measured, "N0" indicates that there is no cancer in the nearby lymph nodes, and "N1", "N2", "N3", and "N4" indicate the number and location of lymph nodes to which the cancer has spread, with larger numbers corresponding to larger numbers of lymph nodes containing cancer. "MX" indicates that metastasis cannot be measured, "M0" indicates that metastasis has not occurred, and "M1" indicates that the cancer has metastasized to other parts of the body.

As another non-limiting example of a cancer staging system, a cancer is classified or graded as having one of the following five stages: "stage 0", "stage I", "stage II", "stage III" or "stage IV". Phase 0 indicates the presence of abnormal cells, but has not spread to nearby tissues. This is also commonly referred to as Carcinoma In Situ (CIS). CIS is not cancer, but may subsequently develop into cancer. Stage I, II and III indicate the presence of cancer. Higher numbers correspond to larger tumor sizes or tumors that have spread to nearby tissues. Stage IV indicates that the cancer has metastasized. The person skilled in the art will be familiar with different cancer staging systems and will be able to apply or interpret them easily.

The term "HER 2" (also known as HER2/Neu, ERBB2, CD340, receptor tyrosine protein kinase ERBB-2, proto-oncogene Neu, and human epidermal growth factor receptor 2) refers to a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family of receptor tyrosine kinases. Amplification or overexpression of HER2 plays an important role in the development and progression of certain aggressive types of cancer, including colorectal, gastric, lung (e.g., non-small cell lung cancer (NSCLC)), biliary (e.g., cholangiocarcinoma, gallbladder), bladder, esophageal, melanoma, ovarian, liver, prostate, pancreatic, small bowel, head and neck, uterine, cervical, and breast cancer. Non-limiting examples of HER2 nucleotide sequences are shown with GenBank reference numbers NP _001005862, NP _001289936, NP _001289937, NP _001289938, and NP _ 004448. Non-limiting examples of HER2 peptide sequences are shown with GenBank reference numbers NP _001005862, NP _001276865, NP _001276866, NP _001276867, and NP _ 004439.

When HER2 is amplified or overexpressed in or on a cell, the cell is said to be "HER 2 positive". The level of HER2 amplification or overexpression in HER2 positive cells is typically expressed as a score ranging from 0 to 3 (i.e., HER 20, HER 21 +, HER 22 +, or HER 23 +), with higher scores corresponding to greater degrees of expression.

The term "Tucaninib" (also known as ONT-380 and ARRY-380) refers to a small molecule tyrosine kinase inhibitor that inhibits or blocks the activation of HER 2. The cartinib has the following structure:

the term "anti-HER 2 antibody" refers to an antibody that binds to HER2 protein. anti-HER 2 antibodies for use in the treatment of cancer are typically monoclonal, but the term does not exclude polyclonal antibodies. anti-HER 2 antibodies inhibit HER2 activation or downstream signaling by various mechanisms. As non-limiting examples, an anti-HER 2 antibody may prevent ligand binding, receptor activation, or receptor signaling, result in reduced expression or localization of HER2 to the cell surface, inhibit HER2 lysis, or induce antibody-mediated cytotoxicity. Non-limiting examples of anti-HER 2 antibodies suitable for use in the methods and compositions of the present invention include trastuzumab, pertuzumab, adotrastuzumab-maytansine (also known as T-DM1), magerituximab (margetuximab), and combinations thereof.

The term "Tumor Growth Inhibition (TGI) index" refers to a value used to indicate the degree to which an agent (e.g., vecatinib, capecitabine, an anti-HER 2 antibody, or a combination thereof) inhibits tumor growth when compared to an untreated control. The TGI index for a particular time point (e.g., a particular number of days into an experiment or clinical trial) is calculated according to the following formula:

where "Tx day 0" represents the first day of treatment administration (i.e., the first day of administration of experimental or control therapy (e.g., vehicle only)) and "Tx day X" represents day X after day 0. Typically, the average volume of the treatment group and the control group is used. As a non-limiting example, in experiments where study day 0 corresponds to "Tx day 0" and the TGI index is calculated on study day 28 (i.e., "Tx day 28"), if the mean tumor volume of both groups is 250mm on study day 0, both groups are considered to be³And the mean tumor volumes of the experimental group and the control group were 125mm, respectively³And 750mm³Then the TGI index at day 28 is 125%.

As used herein, the term "synergistic" or "synergy" refers to a result observed when a combination of components or agents (e.g., a combination of cartilaginous and an anti-HER 2 antibody) is administered that produces an effect (e.g., inhibition of tumor growth, prolongation of survival) that is greater than would be expected based on the additive characteristics or effects of the individual components. In some embodiments, synergy is determined by performing a Bliss analysis (see, e.g., Foucquier et al Pharmacol. Res. Perspect. (2015)3(3): e 00149; incorporated herein by reference in its entirety for all purposes). The Bliss independence model assumes that drug effects are the result of a probabilistic process, and that drugs act completely independently (i.e., drugs do not interfere with each other (e.g., drugs have different sites of action), but each contribute to a common outcome). The predicted effect of the combination of the two drugs was calculated according to the Bliss independence model using the following formula:

E_AB＝E_A+E_B-E_A×E_B，

Wherein E_AAnd E_BRespectively show the effects of drugs A and B, and E_ABIndicating the effect of the combination of drugs a and B. When the observed combined effect is greater than the predicted effect E_ABWhen the two drugs are combined, the combination of the two drugs is considered to beAnd (4) synergistic. When the observed combined effect is equal to E_ABThe effect of the combination of the two drugs is considered additive. Alternatively, when the observed effect of the combination is less than E_ABThe combination of the two drugs is considered antagonistic.

The observed effect of the drug combination can be based on, for example, TGI index, tumor size (e.g., volume, mass), absolute change in tumor size (e.g., volume, mass) between two or more time points (e.g., between the first day of treatment administration and a particular day after the first administration of treatment), rate of change in tumor size (e.g., volume, mass) between two or more time points (e.g., between the first day of treatment administration and a particular day after the first administration of treatment), or time to live of the subject or population of subjects. When the TGI index is taken as a measure of the observed effect of a drug combination, the TGI index may be determined at one or more time points. When the TGI index is determined at two or more time points, in some cases, the mean or median value of the multiple TGI indices may be used as a measure of the observed effect. In addition, the TGI index may be determined in a single subject or a population of subjects. When determining the TGI index in a population, the mean or median TGI index in the population (e.g., at one or more time points) can be used as a measure of the observed effect. When tumor size or tumor growth rate is used as a measure of the observed effect, tumor size or tumor growth rate can be measured in a subject or population of subjects. In some cases, the mean or median tumor size or tumor growth rate is determined for the subject at two or more time points, or at one or more time points in a population of subjects. When measuring time to live in a population, the average or median time to live can be used as a measure of the effect observed.

Predicted combined effect E_ABSingle or multiple doses of the drugs (e.g., cartilaginib and anti-HER 2 antibody) that make up the combination may be used for calculation. In some embodiments, the predicted combined effect E_ABUsing only each drug A and B (e.g. Tucaninib and anti-HER 2 antibody)Calculated for a single dose, and the value E_AAnd E_BBased on the effect of each drug observed when administered as a single agent. When E is_AAnd E_BBased on the observed effect of administering drugs A and B as a single agent, E_AAnd E_BCan be based on, for example, the TGI index, the tumor size (e.g., volume, mass) measured at one or more time points, the absolute change in tumor size (e.g., volume, mass) between two or more time points (e.g., between the first day of treatment administration and a particular number of days after the first administration of treatment), the rate of change in tumor size (e.g., volume, mass) between two or more time points (e.g., between the first day of treatment administration and a particular number of days after the first administration of treatment), or the time to live of the subject or population of subjects in each treatment group.

When considering the TGI index as a measure of the observed effect, the TGI index may be determined at one or more time points. When the TGI index is determined at two or more time points, in some cases, the mean or median value may be used as a measure of the observed effect. In addition, TGI index can be determined in a single subject or population of subjects in each treatment group. When determining the TGI index in a population of subjects, the mean or median TGI index (e.g., at one or more time points) in each population can be used as a measure of the observed effect. When tumor size or tumor growth rate is used as a measure of the observed effect, tumor size or tumor growth rate can be measured in the subjects or population of subjects in each treatment group. In some cases, the mean or median tumor size or tumor growth rate is determined for the subject at two or more time points, or at one or more time points in a population of subjects. When measuring time to live in a population, the average or median time to live can be used as a measure of the effect observed.

In some embodiments, the predicted combined effect E_ABCalculated using a range of doses (i.e., when administered as a single agent, the effect of each drug is observed at multiple doses and used inObserved effects at multiple doses to determine the predicted combined effect at a particular dose). As a non-limiting example, E, calculated according to the following formula, may be used_AAnd E_BTo calculate E_AB：

Wherein E_AmaxAnd E_BmaxMaximum effect of drugs A and B, respectively, A₅₀And B₅₀Is the half-maximal effective dose for drugs a and B, respectively, a and B are the administered doses for drugs a and B, respectively, and p and q are coefficients derived from the shape of the dose-response curves for drugs a and B, respectively (see, e.g., foucquer et al pharmacol.res.perspect. (2015)3(3): e 00149).

In some embodiments, a combination of two or more drugs is considered synergistic when the observed TGI index produced by the combination is greater than the predicted TGI index of the drug combination (e.g., when the predicted TGI index is based on the assumption that the drugs produce additive combined effects). In some cases, a combination is considered synergistic when the observed TGI index is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% greater than the predicted TGI index of the drug combination.

In some embodiments, the rate of tumor growth (e.g., rate of change in size (e.g., volume, mass) of the tumor) is used to determine whether the drug combination is synergistic (e.g., the drug combination is synergistic when the rate of tumor growth is slower than expected when the drug combination produces additive effects). In other embodiments, the time-to-live is used to determine whether the drug combination is synergistic (e.g., the drug combination is synergistic when the time-to-live of the subject or population of subjects is longer than expected when the drug combination produces an additive effect).

By "treatment" or "therapy" of a subject is meant any type of intervention or treatment performed on the subject, or administration of an active agent to the subject, with the purpose of reversing, alleviating, ameliorating, inhibiting, slowing, or preventing the onset, progression, severity, or recurrence of the symptoms, complications, conditions, or biochemical indicators associated with the disease. In some embodiments, the disease is cancer.

"subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates, such as non-human primates, sheep, dogs, and rodents (e.g., mice, rats, and guinea pigs). In some embodiments, the subject is a human. The terms "subject" and "patient" and "individual" are used interchangeably herein.

An "effective amount" or a "therapeutically effective dose" of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of a disease or promotes disease regression as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or prevention of injury or disability due to disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using various methods known to skilled practitioners, such as in human subjects during clinical trials, in animal model systems that predict efficacy in humans, or by assaying the activity of the agent in an in vitro assay.

For example, for treatment of a tumor, a therapeutically effective amount of an anti-cancer agent inhibits cell growth or tumor growth in a treated subject (e.g., one or more treated subjects) by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% relative to an untreated subject (e.g., one or more untreated subjects). In some embodiments, a therapeutically effective amount of an anti-cancer agent inhibits cell growth or tumor growth by 100% in a treated subject (e.g., one or more treated subjects) relative to an untreated subject (e.g., one or more untreated subjects).

In other embodiments of the present disclosure, tumor regression may be observed and persist for a period of at least about 20 days, at least about 30 days, at least about 40 days, at least about 50 days, or at least about 60 days.

A therapeutically effective amount of a drug (e.g., cartinib) includes a "prophylactically effective amount," which is any amount of a drug that inhibits the occurrence or recurrence of cancer when administered alone or in combination with an anti-cancer agent to a subject having a risk of developing cancer (e.g., a subject having a pre-cancerous condition) or suffering from cancer recurrence. In some embodiments, the prophylactically effective amount completely prevents the occurrence or recurrence of cancer. By "inhibiting" the occurrence or recurrence of cancer is meant reducing the likelihood of occurrence or recurrence of cancer, or preventing the occurrence or recurrence of cancer altogether.

As used herein, "sub-therapeutic dose" means a dose of a therapeutic compound (e.g., cartinib) that is lower than the usual or typical dose of the therapeutic compound when administered alone to treat a hyperproliferative disease (e.g., cancer).

For example, an "anti-cancer agent" promotes cancer regression in a subject. In some embodiments, the therapeutically effective amount of the drug promotes regression of the cancer to the extent that the cancer is eliminated. By "promoting cancer regression" is meant that administration of an effective amount of a drug, alone or in combination with an anti-cancer agent, results in a reduction in tumor growth or size, tumor necrosis, a reduction in the severity of at least one disease symptom, an increase in the frequency and duration of disease symptom-free periods, or prevention of injury or disability due to disease affliction. Furthermore, the terms "effective" and "effectiveness" with respect to treatment include both pharmacological effectiveness and physiological safety. Pharmacological efficacy refers to the ability of a drug to promote cancer regression in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) caused by administration of a drug.

By "sustained response" is meant a sustained effect on the reduction of tumor growth after cessation of treatment. For example, the tumor size may remain the same or smaller than the size at the beginning of the administration period. In some embodiments, the duration of the sustained response is at least the same as the duration of treatment, or at least 1.5 times, 2.0 times, 2.5 times, or 3 times as long as the duration of treatment.

As used herein, "complete response" or "CR" refers to the disappearance of all target lesions; "partial response" or "PR" means that the sum of the longest diameters (SLD) of the target lesions is reduced by at least 30%, relative to the baseline SLD; and "disease stable" or "SD" means that the target lesion is neither sufficiently narrowed to fit PR nor sufficiently increased to fit PD, with reference to the minimum SLD since the start of treatment.

As used herein, "progression-free survival" or "PFS" refers to the length of time during and after treatment during which the treated disease (e.g., breast cancer) is not worsening. Progression-free survival can include the amount of time a patient experiences a complete response or a partial response and the amount of time a patient experiences stable disease.

As used herein, "total reaction rate" or "ORR" refers to the sum of the rate of Complete Reaction (CR) and the rate of Partial Reaction (PR).

As used herein, "overall survival" or "OS" refers to the percentage of individuals in a group that are likely to survive after a particular duration.

As referred to herein, the term "weight-based dose" means that the dose administered to a subject is calculated based on the weight of the subject. For example, when a subject weighing 60kg requires 6.0mg/kg of an agent (e.g., trastuzumab), an appropriate amount of the agent (i.e., 360mg) can be calculated and used for administration to the subject.

The use of the term "fixed dose" in reference to the methods of the present disclosure means that two or more different agents (e.g., cartinib and anti-HER 2 antibody) are administered to a subject at a particular (fixed) ratio to each other. In some embodiments, the fixed dose is based on the amount of the agent (e.g., mg). In certain embodiments, the fixed dose is based on the concentration of the agent (e.g., mg/ml). For example, a 1:2 ratio of tucaninib to anti-HER 2 antibody administered to a subject can mean that about 300mg of tucaninib and about 600mg of anti-HER 2 antibody or about 3mg/ml of tucaninib and about 6mg/ml of anti-HER 2 antibody are administered to the subject.

The use of the term "flat dose" with respect to the methods and dosages of the present disclosure means a dose that is administered to a subject without regard to the subject's weight or Body Surface Area (BSA). Thus, a flat dose is not provided at a mg/kg dose, but rather in the absolute amount of the agent (e.g., cartilaginous or anti-HER 2 antibody). For example, a subject weighing 60kg and a subject weighing 100kg will receive the same dose of cartilaginib (e.g., 300 mg).

The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal being treated therewith.

As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that facilitates administration of an active agent to a cell, organism, or subject. By "pharmaceutically acceptable carrier" is meant a carrier or excipient that can be included in the compositions of the present invention and that does not cause significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers include water, NaCl, physiological saline solution, lactated ringer's solution, physiological sucrose, physiological glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring and coloring agents, liposomes, dispersion media, microcapsules, cationic lipid carriers, isotonic and absorption delaying agents, and the like. The carrier can also be a substance used to provide stability, sterility, and isotonicity to the formulation (e.g., antimicrobial preservatives, antioxidants, chelating agents, and buffers), a substance used to prevent the action of microorganisms (e.g., antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and the like), a substance used to provide edible flavoring to the formulation, and the like. In some cases, the carrier is an agent that facilitates the delivery of the small molecule drug or antibody to a target cell or tissue. Those skilled in the art will recognize that other pharmaceutical carriers may be used in the present invention.

As used herein, the phrase "pharmaceutically acceptable salt" refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, gluconate, formate, benzoate, glutamate, methanesulfonate, "methanesulfonate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoic acid (i.e., 4, 4' -methylene-bis- (2-hydroxy-3-naphthoic acid)) salt, alkali metal (e.g., sodium and potassium) salt, alkaline earth metal (e.g., magnesium) salt, and ammonium salt. Pharmaceutically acceptable salts may be contemplated to include another molecule, such as an acetate, succinate, or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. The plurality of charged atoms can have a plurality of counterions where the plurality of charged atoms are part of a pharmaceutically acceptable salt. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.

"administering" or "administration" refers to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Exemplary routes of administration include oral, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, such as by injection or infusion (e.g., intravenous infusion). The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, and in vivo electroporation. The therapeutic agent may be administered via a non-parenteral route or orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, such as intranasal, vaginal, rectal, sublingual or topical. Administration may also be performed, for example, once, multiple times, and/or over one or more extended periods of time.

The terms "baseline" or "baseline value" used interchangeably herein may refer to a measurement or characterization of symptoms prior to or at the beginning of administration of therapy. The baseline value can be compared to a reference value in order to determine a reduction or improvement in the symptoms of a disease contemplated herein (e.g., breast cancer). The terms "reference" or "reference value" used interchangeably herein may refer to a measurement or characterization of a symptom after administration of a therapy. The reference value may be measured one or more times during or at the completion of the dosage regimen or treatment cycle. The "reference value" may be an absolute value; a relative value; a value having an upper limit and/or a lower limit; a range of values; average value; a median value; mean value; or a value compared to a baseline value.

Similarly, the "baseline value" may be an absolute value; a relative value; a value having an upper limit and/or a lower limit; a range of values; average value; a median value; mean value; or a value compared to a reference value. The reference value and/or baseline value may be obtained from one individual, two different individuals, or a group of individuals (e.g., a group of two, three, four, five, or more individuals).

The term "monotherapy" as used herein means that tucatinib, or a salt or solvate thereof, is the only anticancer agent administered to a subject during a treatment cycle. However, other therapeutic agents may be administered to the subject. For example, anti-inflammatory or other agents administered to a subject with cancer to treat symptoms associated with the cancer, including, for example, inflammation, pain, weight loss, and systemic discomfort, but not the underlying cancer itself, may be administered during a monotherapy period.

As used herein, an "adverse event" (AE) is any adverse and often unintentional or undesirable sign (including abnormal laboratory findings), symptom, or disease associated with treatment with a drug. Drug treatment may have one or more related AEs, and each AE may have the same or a different level of severity. Reference to a method that is capable of "altering an adverse event" means a treatment regimen that reduces the incidence and/or severity of one or more AEs associated with the use of a different treatment regimen.

As used herein, a "severe adverse event" or "SAE" is an adverse event that meets one of the following criteria:

fatal or life-threatening (as used in the definition of serious adverse event, "life-threatening" refers to an event in which a patient is at risk of death when the event occurs; it does not refer to an event that is assumed to be fatal when more serious.

Cause persistent or significant disability/disability

Constitute congenital abnormality/birth defect

Medically significant, i.e. defined as an event that endangers the patient or may require medical or surgical intervention to prevent one of the outcomes listed above. In deciding whether an AE is "medically significant", medical and scientific judgments must be made

Hospitalization is required or existing hospitalization is extended, not including the following: 1) conventional treatment or monitoring of the underlying disease, independent of any worsening of the condition; 2) selective or preplanned treatment of pre-existing conditions unrelated to the indication in the study and not exacerbated since self-endorsement of informed consent; and 3) social reasons and temporary care without any deterioration in the overall condition of the patient.

As used herein, the terms "about once per week", "about once per two weeks" or any other similar dosing interval term means an approximate number. "about once per week" may include every seven days ± one day, i.e. every six days to every eight days. "about once every two weeks" may include every fourteen days ± two days, i.e., every twelve days to every sixteen days. "about once every three weeks" may include every twenty-one days ± three days, i.e. every eighteen days to every twenty-four days. Similar approximations apply to, for example, about once every four weeks, about once every five weeks, about once every six weeks, and about once every twelve weeks. In some embodiments, a dosing interval of about once every six weeks or about once every twelve weeks, respectively, means that a first dose may be administered on any day of the first week, and then the next dose may be administered on any day of the sixth or twelfth week. In other embodiments, a dosing interval of about once every six weeks or about once every twelve weeks means that a first dose is administered on a particular day of the first week (e.g., monday) and then the next dose is administered on the same day of the sixth or twelfth week (i.e., monday), respectively.

As used herein, any concentration range, percentage range, ratio range, or integer range is understood to include the value of any integer within the range, and where appropriate, their fraction (e.g., tenth and hundredth of an integer), unless otherwise indicated.

Various aspects of the disclosure are described in further detail in the following subsections.

Description of the embodiments

A. Method of treating breast cancer with ceratinib

In one aspect, the invention provides a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaserod, or a salt or solvate thereof, wherein the subject is not being treated simultaneously with a therapeutically effective amount of a substrate for a multidrug and toxin efflux (MATE) protein. In some embodiments, the MATE protein is MATE 1. In some embodiments, the MATE protein is MATE 2K. When a subject is concurrently receiving treatment with a substrate of MATE protein, this means that the subject has received treatment with the substrate of the MATE protein within less than 7 days (e.g., within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, or within 6 days) of administering the therapeutically effective amount of the tegaintinib, or a salt or solvate thereof.

In another aspect, the present invention provides a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tucaninib, or a salt or solvate thereof, wherein the subject has not received treatment with a therapeutically effective amount of a substrate of MATE protein for a period of time during which the therapeutically effective amount of tucaninib, or a salt or solvate thereof, is administered. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for MATE protein within the past 7 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years prior to administration of the therapeutically effective amount of tucaninib, or a salt or solvate thereof. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for MATE protein within the last 7 days. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for MATE protein within the last 3 months. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for MATE protein within the past 12 months. In some embodiments, the subject has not previously received treatment with the substrate of the MATE protein. In some embodiments, the MATE protein is MATE 1. In some embodiments, the MATE protein is MATE 2K.

In some embodiments, the substrate of the MATE protein is selected from the group consisting of metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin, and pyrimethamine. In some embodiments, the substrate of the MATE protein is metformin.

In one aspect, the invention provides a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaserod, or a salt or solvate thereof, wherein the subject is not being concurrently treated with a therapeutically effective amount of a substrate for Organic Cation Transporter (OCT). In some embodiments, the OCT is OCT 1. In some embodiments, the OCT protein is OCT 2. When a subject is concurrently receiving treatment with a substrate for OCT, this means that the subject has received treatment with the substrate for OCT within less than 7 days (e.g., within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, or within 6 days) of administering the therapeutically effective amount of the tocainib, or a salt or solvate thereof.

In another aspect, the invention provides a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of picatinib, or a salt or solvate thereof, wherein the subject has not received treatment with a therapeutically effective amount of a substrate of OCT for a period of time in which the therapeutically effective amount of picatinib, or a salt or solvate thereof, is administered. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for OCT within the past 7 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years prior to administration of the therapeutically effective amount of the tocainib, or a salt or solvate thereof. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate of OCT within the last 7 days. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate of OCT within the last 3 months. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for an OCT protein within the past 12 months. In some embodiments, the subject has not previously been treated with the substrate of the OCT. In some embodiments, the OCT protein is OCT 1. In some embodiments, the OCT protein is OCT 2.

In some embodiments, the substrate of the OCT protein is selected from the group consisting of metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin, and pyrimethamine. In some embodiments, the substrate of the OCT protein is metformin.

In another aspect, the invention provides a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaserod, or a salt or solvate thereof, wherein the subject is not being treated simultaneously with a therapeutically effective amount of a substrate of OCT or a substrate of MATE protein. In some embodiments, the MATE protein is MATE 1. In some embodiments, the MATE protein is MATE 2K. In some embodiments, the substrate of the MATE protein is selected from the group consisting of metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin, and pyrimethamine. In some embodiments, the substrate of the MATE protein is metformin. In some embodiments, the OCT is OCT 1. In some embodiments, the OCT protein is OCT 2. In some embodiments, the substrate of the OCT protein is selected from the group consisting of metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin, and pyrimethamine. In some embodiments, the substrate of the OCT protein is metformin. When a subject is concurrently receiving treatment with a substrate of MATE protein or a substrate of OCT, this means that the subject has received treatment with the substrate of the MATE protein or the substrate of OCT within less than 7 days (e.g., within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, or within 6 days) of administering the therapeutically effective amount of the tocaintinib, or a salt or solvate thereof.

In another aspect, the invention provides a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of picatinib, or a salt or solvate thereof, wherein the subject has not received treatment with a therapeutically effective amount of a substrate of MATE protein or a substrate of OCT for a period of time in which the therapeutically effective amount of picatinib, or a salt or solvate thereof, is administered. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for MATE protein within the past 7 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years prior to administration of the therapeutically effective amount of tucaninib, or a salt or solvate thereof. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for MATE protein within the last 7 days. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for MATE protein within the last 3 months. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for MATE protein within the past 12 months. In some embodiments, the subject has not previously received treatment with the substrate of the MATE protein. In some embodiments, the MATE protein is MATE 1. In some embodiments, the MATE protein is MATE 2K. In some embodiments, the substrate of the MATE protein is selected from the group consisting of metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin, and pyrimethamine. In some embodiments, the substrate of the MATE protein is metformin. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for OCT within the past 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years prior to administration of the therapeutically effective amount of the tocainib, or a salt or solvate thereof. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate of OCT within the last 7 days. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate of OCT within the last 3 months. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for an OCT protein within the past 12 months. In some embodiments, the subject has not previously been treated with the substrate of the OCT. In some embodiments, the OCT protein is OCT 1. In some embodiments, the OCT protein is OCT 2. In some embodiments, the substrate of the OCT protein is selected from the group consisting of metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin, and pyrimethamine. In some embodiments, the substrate of the OCT protein is metformin.

In another aspect, the present invention provides a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaserod, or a salt or solvate thereof, wherein the subject has no impaired renal function. In another aspect, the present invention provides a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tucaninib, or a salt or solvate thereof, wherein the subject has not experienced impaired renal function for a period of time during which the therapeutically effective amount of tucaninib, or a salt or solvate thereof, is administered. In some embodiments, the subject has not experienced impaired renal function within the past 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years prior to administration of the therapeutically effective amount of the tucaninib, or salt or solvate thereof. In some embodiments, the subject has not experienced impaired renal function within the past 12 months. In some embodiments, impaired renal function is determined based on serum creatinine levels in the subject. In some embodiments, the subject who is not impaired of renal function is male and has a serum creatinine level of less than 1.5mg/dL, less than 1.4mg/dL, less than 1.3mg/dL, less than 1.2mg/dL, less than 1.1mg/dL, or less than 1.0 mg/dL. In some embodiments, the subject without impaired renal function is male and has a serum creatinine level less than 1.5 mg/dL. In some embodiments, the subject who is not impaired of renal function is a female and has a serum creatinine level of less than 1.4mg/dL, less than 1.3mg/dL, less than 1.2mg/dL, less than 1.1mg/dL, or less than 1.0 mg/dL. In some embodiments, the subject without impaired renal function is a female and has a serum creatinine level less than 1.4 mg/dL. In some embodiments, impaired renal function is determined based on the subject having an abnormal creatinine clearance rate. In some embodiments, impaired renal function is determined based on the glomerular filtration rate of the subject.

In another aspect, the present invention provides a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaserod, or a salt or solvate thereof, wherein the subject is not being concurrently treated with a therapeutically effective amount of a compound that modulates the activity of a cytochrome p450 protein. When a subject is concurrently receiving treatment with a compound that modulates the activity of a cytochrome p450 protein, this means that the subject has been treated with the compound that modulates the activity of the cytochrome p450 protein within less than 7 days (e.g., within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, or within 6 days) of administering the therapeutically effective amount of the cartinib or a salt or solvate thereof. In some embodiments, the compound that modulates the activity of the cytochrome p450 protein is an inhibitor of the activity of the cytochrome p450 protein. In some embodiments, the cytochrome p450 protein is CYP3a 4. In some embodiments, the compound that inhibits the activity of CYP3a4 is selected from the group consisting of macrolide antibiotics (such as clarithromycin and oleandomycin), azole antibiotics (such as itraconazole, ketoconazole, voriconazole, and posaconazole), nefazodone, and diltiazem. In some embodiments, the compound that inhibits the activity of CYP3a4 is a macrolide antibiotic (e.g., clarithromycin and oleandomycin acetate). In some embodiments, the compound that inhibits the activity of CYP3a4 is clarithromycin. In some embodiments, the compound that inhibits the activity of CYP3a4 is oleandomycin acetate. In some embodiments, the compound that inhibits the activity of CYP3a4 is an azole antibiotic (such as itraconazole, ketoconazole, voriconazole, and posaconazole). In some embodiments, the compound that inhibits the activity of CYP3a4 is itraconazole. In some embodiments, the compound that inhibits the activity of CYP3a4 is ketoconazole. In some embodiments, the compound that inhibits the activity of CYP3a4 is voriconazole. In some embodiments, the compound that inhibits the activity of CYP3a4 is posaconazole. In some embodiments, the compound that inhibits the activity of CYP3a4 is nefazodone. In some embodiments, the compound that inhibits the activity of CYP3a4 is diltiazem. In some embodiments, the cytochrome p450 protein is CYP2C 8. In some embodiments, the compound that inhibits the activity of CYP2C8 is selected from the group consisting of gemfibrozil, montelukast, trimethoprim, and clopidogrel. In some embodiments, the compound that inhibits the activity of CYP2C8 is gemfibrozil. In some embodiments, the compound that inhibits the activity of CYP2C8 in some embodiments, the compound that inhibits the activity of CYP2C8 is montelukast. In some embodiments, the compound that inhibits the activity of CYP2C8 is trimethoprim. In some embodiments, the compound that inhibits the activity of CYP2C8 is clopidogrel. In some embodiments, the compound that modulates the activity of the cytochrome p450 protein is an inducer of the activity of the cytochrome p450 protein. In some embodiments, the cytochrome p450 protein is CYP3a 4. In some embodiments, the compound that induces the activity of CYP3a4 is selected from the group consisting of barbiturates, carbamazepine, phenytoin, rifampicin, and saint john's Wort. In some embodiments, the compound that induces the activity of CYP3a4 is a barbiturate. In some embodiments, the compound that induces the activity of CYP3a4 is carbamazepine. In some embodiments, the compound that induces the activity of CYP3a4 is phenytoin. In some embodiments, the compound that induces the activity of CYP3a4 is rifampin. In some embodiments, the compound that induces the activity of CYP3a4 is st. In some embodiments, the cytochrome p450 protein is CYP2C 8. In some embodiments, the compound that induces the activity of CYP2C8 is rifampin.

In another aspect, the invention provides a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tucaninib, or a salt or solvate thereof, wherein the subject has not received treatment with a therapeutically effective amount of a compound that modulates the activity of cytochrome p450 within the past 7 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years prior to administration of the therapeutically effective amount of tucaninib, or a salt or solvate thereof. In some embodiments, the subject has not received treatment with a therapeutically effective amount of the compound that modulates the activity of the cytochrome p450 protein within the last 7 days. In some embodiments, the subject has not received treatment with a therapeutically effective amount of the compound that modulates the activity of the cytochrome p450 protein within the last 3 months. In some embodiments, the subject has not received treatment with a therapeutically effective amount of the compound that modulates the activity of the cytochrome p450 protein within the past 12 months. In some embodiments, the subject has not previously been treated with the compound that modulates the activity of the cytochrome p450 protein. In some embodiments, the compound that modulates the activity of the cytochrome p450 protein is an inhibitor of the activity of the cytochrome p450 protein. In some embodiments, the compound that modulates the activity of the cytochrome p450 protein is a strong inhibitor of the activity of the cytochrome p450 protein. In some embodiments, the cytochrome p450 protein is CYP3a 4. In some embodiments, the compound that inhibits the activity of CYP3a4 is selected from the group consisting of macrolide antibiotics (such as clarithromycin and oleandomycin), azole antibiotics (such as itraconazole, ketoconazole, voriconazole, and posaconazole), nefazodone, and diltiazem. In some embodiments, the compound that inhibits the activity of CYP3a4 is a macrolide antibiotic (e.g., clarithromycin and oleandomycin acetate). In some embodiments, the compound that inhibits the activity of CYP3a4 is clarithromycin. In some embodiments, the compound that inhibits the activity of CYP3a4 is oleandomycin acetate. In some embodiments, the compound that inhibits the activity of CYP3a4 is an azole antibiotic (such as itraconazole, ketoconazole, voriconazole, and posaconazole). In some embodiments, the compound that inhibits the activity of CYP3a4 is itraconazole. In some embodiments, the compound that inhibits the activity of CYP3a4 is ketoconazole. In some embodiments, the compound that inhibits the activity of CYP3a4 is voriconazole. In some embodiments, the compound that inhibits the activity of CYP3a4 is posaconazole. In some embodiments, the compound that inhibits the activity of CYP3a4 is nefazodone. In some embodiments, the compound that inhibits the activity of CYP3a4 is diltiazem. In some embodiments, the cytochrome p450 protein is CYP2C 8. In some embodiments, the compound that inhibits the activity of CYP2C8 is selected from the group consisting of gemfibrozil, montelukast, trimethoprim, and clopidogrel. In some embodiments, the compound that inhibits the activity of CYP2C8 is gemfibrozil. In some embodiments, the compound that inhibits the activity of CYP2C8 in some embodiments, the compound that inhibits the activity of CYP2C8 is montelukast. In some embodiments, the compound that inhibits the activity of CYP2C8 is trimethoprim. In some embodiments, the compound that inhibits the activity of CYP2C8 is clopidogrel. In some embodiments, the compound that modulates the activity of the cytochrome p450 protein is an inducer of the activity of the cytochrome p450 protein. In some embodiments, the compound that modulates the activity of the cytochrome p450 protein is a strong inducer of the activity of the cytochrome p450 protein. In some embodiments, the cytochrome p450 protein is CYP3a 4. In some embodiments, the compound that induces the activity of CYP3a4 is selected from the group consisting of barbiturates, carbamazepine, phenytoin, rifampicin, and saint john's wort. In some embodiments, the compound that induces the activity of CYP3a4 is a barbiturate. In some embodiments, the compound that induces the activity of CYP3a4 is carbamazepine. In some embodiments, the compound that induces the activity of CYP3a4 is phenytoin. In some embodiments, the compound that induces the activity of CYP3a4 is rifampin. In some embodiments, the compound that induces the activity of CYP3a4 is st. In some embodiments, the cytochrome p450 protein is CYP2C 8. In some embodiments, the compound that induces the activity of CYP2C8 is rifampin. In some embodiments, administration of a therapeutically effective amount of tocaininib, or a salt or solvate thereof, to a subject concomitantly with a strong CYP3A/CYP2C8 inducer reduces tocaininib AUC, which may reduce tocaininib efficacy. In some embodiments, administration of a therapeutically effective amount of tocaininib, or a salt or solvate thereof, to a subject concomitantly with a strong CYP2C8 inhibitor increases tocaininib AUC, which may increase toxicity risk.

In another aspect, the present invention provides a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tucaninib, or a salt or solvate thereof, wherein the subject has not received treatment with a therapeutically effective amount of a substrate for a cytochrome p450 protein for a period of time in which the therapeutically effective amount of tucaninib, or a salt or solvate thereof, is administered. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for a cytochrome p450 protein within the past 7 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years prior to administration of the therapeutically effective amount of the tucaninib, or the salt or solvate thereof. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for a cytochrome p450 protein within the last 7 days. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for a cytochrome p450 protein within the last 3 months. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for a cytochrome p450 protein within the past 12 months. In some embodiments, the subject has not previously received treatment with the substrate of the cytochrome p450 protein. In some embodiments, the cytochrome p450 protein is CYP3a 4. In some embodiments, the cytochrome p450 protein is CYP2C 8. In some embodiments, the substrate of the cytochrome p450 protein is a sensitive CYP3A substrate. In some embodiments, a sensitive CYP3A substrate refers to a drug that has been shown to increase plasma AUC values 5-fold or more when co-administered with a known CYP3A inhibitor. In some embodiments, the substrate of the cytochrome p450 protein is selected from the group consisting of budesonide, buspirone, eplerenone, eletriptan, felodipine, fluticasone, lovastatin, midazolam, saquinavir, sildenafil, simvastatin, triazolam, and vardenafil. In some embodiments, the substrate of the cytochrome p450 protein is budesonide. In some embodiments, the substrate of the cytochrome p450 protein is buspirone. In some embodiments, the substrate of the cytochrome p450 protein is eplerenone. In some embodiments, the substrate of the cytochrome p450 protein is eletriptan. In some embodiments, the substrate of the cytochrome p450 protein is felodipine. In some embodiments, the substrate of the cytochrome p450 protein is fluticasone. In some embodiments, the substrate of the cytochrome p450 protein is lovastatin. In some embodiments, the substrate of the cytochrome p450 protein is midazolam. In some embodiments, the substrate of the cytochrome p450 protein is saquinavir. In some embodiments, the substrate of the cytochrome p450 protein is sildenafil. In some embodiments, the substrate of the cytochrome p450 protein is simvastatin. In some embodiments, the substrate of the cytochrome p450 protein is triazolam. In some embodiments, the substrate of the cytochrome p450 protein is vardenafil. In some embodiments, administration of a therapeutically effective amount of the tonatinib, or a salt or solvate thereof, to a subject concomitantly with a CYP3A substrate may increase the plasma concentration of the CYP3A substrate, which may result in increased toxicity of the CYP3A substrate.

In another aspect, the invention provides a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of picatinib, or a salt or solvate thereof, wherein the subject has not received treatment with a therapeutically effective amount of a substrate for P-glycoprotein (P-gp) for a period of time in which the therapeutically effective amount of picatinib, or a salt or solvate thereof, is administered. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for P-gp within the past 7 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years prior to administration of the therapeutically effective amount of the tocainib, or a salt or solvate thereof. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for P-gp within the last 7 days. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for P-gp within the last 3 months. In some embodiments, the subject has not received treatment with a therapeutically effective amount of a substrate for P-gp within the past 12 months. In some embodiments, the subject has not previously received treatment with the substrate of P-gp. In some embodiments, the substrate of P-gp is a substrate with a narrow therapeutic index. In some embodiments, the substrate of P-gp is selected from amitriptyline, carbamazepine, clonidine, cyclosporine, digoxigenin, digoxin, imipramine, phenobarbital, phenytoin, quinidine, rifampin, sirolimus, tacrolimus, temsirolimus, trimipramine, vincristine, paclitaxel, and dabigatran etexilate. In some embodiments, the substrate of P-gp is amitriptyline. In some embodiments, the substrate of P-gp is carbamazepine. In some embodiments, the substrate of P-gp is clonidine. In some embodiments, the substrate of P-gp is cyclosporine. In some embodiments, said substrate of P-gp is digoxigenin. In some embodiments, the substrate of P-gp is digoxin. In some embodiments, the substrate for P-gp is imipramine. In some embodiments, the substrate for P-gp is phenobarbital. In some embodiments, the substrate of P-gp is phenytoin. In some embodiments, the substrate of P-gp is quinidine. In some embodiments, the substrate of P-gp is rifampicin. In some embodiments, the substrate of P-gp is sirolimus. In some embodiments, the substrate of P-gp is tacrolimus. In some embodiments, the substrate of P-gp is temsirolimus. In some embodiments, the substrate of P-gp is trimipramine. In some embodiments, the substrate of P-gp is vincristine. In some embodiments, the substrate of P-gp is paclitaxel. In some embodiments, the substrate of P-gp is dabigatran etexilate. In some embodiments, concomitant administration of a therapeutically effective amount of tegaininib or a salt or solvate thereof to a subject with a P-gp substrate (e.g., digoxin) may increase the plasma concentration of said P-gp substrate, which may lead to an increased risk of adverse reactions.

B. Pocatinib dosage and administration

In some embodiments, the dose of tegaserod is between about 0.1mg and 10mg/kg of body weight of the subject (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10mg/kg of body weight of the subject). In other embodiments, the dose of cartinib is between about 10mg and 100mg/kg of body weight of said subject (e.g., about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100mg/kg of body weight of said subject). In some embodiments, the dose of cartinib is at least about 100mg to 500mg/kg of body weight of the subject (e.g., at least about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500mg/kg of body weight of the subject). In particular embodiments, the dose of cartinib is between about 1mg and 50mg/kg of body weight of said subject (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50mg/kg of body weight of said subject). In some cases, the dose of ceratinib is about 50mg/kg of the subject's body weight.

In some embodiments, the dose of cartinib comprises between about 1mg and 100mg (e.g., about 1,2, 3,4, 5,6, 7,8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100mg) of cartinib. In other embodiments, the dose of cartinib comprises between about 100mg and 1,000mg (e.g., about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1,000mg) of cartinib. In a particular embodiment, the dose of ceratinib is about 300mg (e.g., when administered twice daily).

In some embodiments, a dose of ticarcillin comprises at least about 1,000mg to 10,000mg (e.g., at least about 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600, 3,700, 3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600, 4,700, 4,800, 4,900, 5,000, 5,100, 5,200, 5,300, 5,400, 5,500, 5,600, 6,500, 6,600, 7,800, 7,500, 8,800, 7,500, 8,8,800, 8,500, 8,800, 8,500, 8,800, 7,500, 8,8,8,500, 8,8,800, 8,9,800, 8,500, 8,900, 8,8,8,8,8,8,8,8,500, 8,500, 8,8,8,8,500, 8,900, 8,8,500, 2,500, 2,500,500, 2,500, or more of ticannitinidazzl.

In some embodiments, the dose of either tucaninib or a salt or solvate thereof comprises a therapeutically effective amount of either tucaninib or a salt or solvate thereof. In other embodiments, the dose of tucaninib, or a salt or solvate thereof, contains less than a therapeutically effective amount of tucaninib, or a salt or solvate thereof (e.g., when multiple doses are administered in order to achieve a desired clinical or therapeutic effect).

The administration of the drug substance can be by any suitable route. Suitable routes of administration of the antibodies and/or antibody-drug conjugates of the invention are well known in the art and can be selected by one of ordinary skill in the art. In one embodiment, the picatinib is administered parenterally. Parenteral administration refers to modes of administration other than enteral and topical administration, typically by injection, and includes epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural, and intrasternal injection and infusion. In some embodiments, the route of administration of the cartinib is intravenous injection or infusion. In some embodiments, the route of administration of the cartinib is intravenous infusion. In some embodiments, the route of administration of the cartinib is intravenous injection or infusion. In some embodiments, the cartinib is an intravenous infusion. In some embodiments, the route of administration of the cartinib is oral.

In one embodiment of the method or use or product for use provided herein, the subject is administered the cartinib daily, twice daily, three times daily or four times daily. In some embodiments, the method further comprises administering to the subject one or more additional doses of the anti-inflammatory agent. In some embodiments, the method further comprises administering to the subject one or more additional doses of the anti-inflammatory agent. In some embodiments, the method further comprises administering to the subject one or more additional doses of the anti-inflammatory agent. In some embodiments, the subject is administered the icaritinib at a dose of about 300mg twice daily. In some embodiments, the subject is administered the cartinib at a dose of 300mg twice daily. In some embodiments, the procatinib is administered to the subject once daily at a dose of about 600 mg. In some embodiments, the procatinib is administered to the subject once daily at a dose of 600 mg. In some embodiments, the procatinib is administered to the subject twice daily on each day of a 21-day treatment cycle. In some embodiments, the method further comprises administering to the subject an oral dose of icaritinib.

C. Breast cancer

The 2014World Cancer Report (2014World Cancer Report) by WHO (World health organization) reports that breast Cancer is the second most common Cancer worldwide, accounting for slightly more than 100 million new cases per year. It was reported that in 2000, about 400,000 women died of breast cancer, accounting for 1.6% of all women's deaths. The proportion of breast cancer deaths in affluent countries (2% of all female deaths) is much higher than in economically poor regions (0.5%). Therefore, breast cancer is closely related to western lifestyle. With the success of developing countries to achieve a lifestyle similar to that of europe, north america, australia, new zealand and japan, they will also encounter a much higher incidence of cancer, particularly breast cancer. Recent data supports this prediction and shows a 20% increase in breast cancer from 2008 to 2012. (Carter D. "New spherical surfaces an increasing growing cancer garden". Am J Nurs.2014 3 months; 114(3): 17).

In some aspects, the present invention provides a method for treating breast cancer in a subject, the method comprising administering a therapeutically effective amount of the cartinib, or a salt or solvate thereof, as described herein. In some embodiments, the breast cancer is HER2 positive breast cancer. In some embodiments, the cancer is HER2 positive as determined using in situ hybridization, fluorescence in situ hybridization, or immunohistochemistry.

In some embodiments, the breast cancer is metastatic. In some embodiments, the breast cancer has metastasized to the brain. In some embodiments, the breast cancer is locally advanced. In some embodiments, the breast cancer is unresectable. In some embodiments, the subject has been previously treated with one or more additional therapeutic agents for the breast cancer. In some embodiments, the subject has been previously treated with one or more additional therapeutic agents for the breast cancer and is non-responsive to the treatment. In some embodiments, the subject has been previously treated with one or more additional therapeutic agents for the breast cancer and relapsed after the treatment. In some embodiments, the subject has been previously treated with one or more additional therapeutic agents for the breast cancer and has experienced disease progression during the treatment. In some embodiments, the one or more additional therapeutic agents is an anti-HER 2 antibody or an anti-HER 2 antibody-drug conjugate. In some embodiments, the one or more additional therapeutic agents is an anti-HER 2 antibody. In some embodiments, the one or more additional therapeutic agents is an anti-HER 2 antibody-drug conjugate. In some embodiments, the subject has been previously treated with trastuzumab, pertuzumab, and/or T-DM 1. In some embodiments, the subject has been previously treated with trastuzumab. In some embodiments, the subject has been previously treated with pertuzumab. In some embodiments, the subject has been previously treated with T-DM 1. In some embodiments, the subject has been previously treated with trastuzumab and pertuzumab. In some embodiments, the subject has been previously treated with trastuzumab and T-DM 1. In some embodiments, the subject has been previously treated with pertuzumab and T-DM 1. In some embodiments, the subject has been previously treated with trastuzumab, pertuzumab, and T-DM 1. In some embodiments, the subject has not been previously treated with another therapeutic agent for the breast cancer within the past 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years prior to administration of the therapeutically effective amount of the tucaninib, or salt or solvate thereof. In some embodiments, the subject has not been previously treated with another therapeutic agent for the breast cancer within the past 12 months prior to administration of the therapeutically effective amount of the cartinib, or the salt or solvate thereof. In some embodiments, the subject has not been previously treated with another therapeutic agent for the breast cancer. In some embodiments, the subject has not been previously treated with lapatinib, neratinib, afatinib, or capecitabine. In some embodiments, the subject has not been previously treated with lapatinib. In some embodiments, the subject has not been previously treated with neratinib. In some embodiments, the subject has not been previously treated with afatinib. In some embodiments, the subject has not been previously treated with capecitabine.

In some embodiments, the HER2 status of the sample cell is determined. The determination may be made before treatment (i.e., administration of the cartinib) begins, during treatment, or after treatment has been completed. In some cases, determination of HER2 status leads to a decision to alter therapy (e.g., add anti-HER 2 antibody to a treatment regimen, discontinue use of cartinib, completely discontinue therapy, or switch from another treatment method to the methods of the invention).

In some embodiments, the sample cells are determined to overexpress or not overexpress HER 2. In particular embodiments, the cell is determined to be HER 23 +, HER 22 +, HER 21 +, or HER 20 (i.e., HER is not overexpressed).

In some embodiments, the sample cell is a cancer cell. In some cases, the sample cells are obtained from a subject having cancer. The sample cells may be obtained as a biopsy specimen, by surgical resection, or as a Fine Needle Aspiration (FNA). In some embodiments, the sample cells are Circulating Tumor Cells (CTCs).

HER2 expression can be compared to a reference cell. In some embodiments, the reference cell is a non-cancerous cell obtained from the same subject as the sample cell. In other embodiments, the reference cell is a non-cancerous cell obtained from a different subject or population of subjects. In some embodiments, measuring the expression of HER2 includes, for example, determining HER2 gene copy number or amplification, nucleic acid sequencing (e.g., sequencing of genomic DNA or cDNA), measuring mRNA expression, measuring protein abundance, or a combination thereof. HER2 test methods include Immunohistochemistry (IHC), in situ hybridization, Fluorescence In Situ Hybridization (FISH), Chromogenic In Situ Hybridization (CISH), ELISA, and RNA quantification (e.g., of HER2 expression) using techniques such as RT-PCR and microarray analysis.

In some embodiments, the sample cell is determined to be HER2 positive when HER2 is expressed at a higher level in the sample cell as compared to a reference cell. In some embodiments, a cell is determined to be HER2 positive when HER2 is overexpressed at least about 1.5 fold (e.g., about 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 5.5 fold, 6 fold, 6.5 fold, 7 fold, 7.5 fold, 8 fold, 8.5 fold, 9 fold, 9.5 fold, 10 fold, 11 fold, 12 fold, 13 fold, 14 fold, 15 fold, 16 fold, 17 fold, 18 fold, 19 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, 55 fold, 60 fold, 65 fold, 70 fold, 75 fold, 80 fold, 85 fold, 90 fold, 95 fold, 100 fold or more) as compared to a reference cell. In particular embodiments, the cell is determined to be HER2 positive when HER2 is overexpressed by at least about 1.5-fold as compared to the reference cell.

In some embodiments, the sample cell is determined to be HER2 positive when the FISH or CISH signaling ratio is greater than 2. In other embodiments, the sample cell is determined to be HER2 positive when the HER2 gene copy number is greater than 6.

D. Combination therapy

In some aspects, the treatment methods as described herein further comprise administering to the subject one or more additional therapeutic agents to treat the breast cancer. In some embodiments, the one or more additional therapeutic agents are selected from capecitabine and an anti-HER 2 antibody. In some embodiments, the one or more additional therapeutic agents is capecitabine. In some embodiments, the one or more additional therapeutic agents is an anti-HER 2 antibody. In some embodiments, the one or more additional therapeutic agents are capecitabine and an anti-HER 2 antibody. In some embodiments, the anti-HER 2 antibody is selected from trastuzumab, pertuzumab, adotrastuzumab-maytansine, magituximab, and combinations thereof. In some cases, the anti-HER 2 antibody is a combination of trastuzumab and pertuzumab. In some embodiments, the anti-HER 2 antibody is trastuzumab. In some embodiments, the one or more additional therapeutic agents are capecitabine and trastuzumab.

In some embodiments, the methods of treatment described herein further comprise administering capecitabine to the subject at a dose based on the body surface area of the subject. In some embodiments, capecitabine is administered at about 500mg/m²To about 1500mg/m²Is administered to the subject. In some embodiments, capecitabine is administered at about 500mg/m²About 550mg/m²About 600mg/m²About 650mg/m²About 700mg/m²About 750mg/m²About 800mg/m²About 850mg/m²About 900mg/m²About 950mg/m²About 1000mg/m²About 1050mg/m²About 1100mg/m²About 1150mg/m²About 1200mg/m²About 1250mg/m²About 1300mg/m²About 1350mg/m²About 1400mg/m²About 1450mg/m²Or about 1500mg/m²Is administered to the subject. In some embodiments, capecitabine is added at 500mg/m²To 1500mg/m²Is administered to the subject. In some embodiments, capecitabine is added at 500mg/m²、550mg/m²、600mg/m²、650mg/m²、700mg/m²、750mg/m²、800mg/m²、850mg/m²、900mg/m²、950mg/m²、1000mg/m²、1050mg/m²、1100mg/m²、1150mg/m²、1200mg/m²、1250mg/m²、1300mg/m²、1350mg/m²、1400mg/m²、1450mg/m²Or 1500mg/m²Is administered to the subject. In some embodiments, capecitabine is administered to said subject daily, twice daily, three times daily, or four times daily. In some embodiments, capecitabine is administered to said subject every other day, about once per week, or about once every three weeks. In some embodiments, capecitabine is administered to said subject once daily. In some embodiments, capecitabine is administered to said subject twice daily. In some embodiments, capecitabine is administered to the subject twice daily on days 1-14 of a 21-day treatment cycle. In some embodiments, capecitabine is administered twice daily at about 1000mg/m ²Is administered to the subject. In some embodiments, capecitabine is administered twice daily at 1000mg/m²Is administered to the subject. In some embodiments, capecitabine is administered twice daily at about 1000mg/m on days 1-14 of a 21-day treatment cycle²Is administered to the subject. In some embodiments, capecitabine is administered twice daily at 1000mg/m on days 1-14 of a 21-day treatment cycle²Is administered to the subject. In some embodiments, capecitabine is administered orally to the subject.

In some embodiments, the methods of treatment described herein further comprise administering to the subject an anti-HER 2 antibody. In some embodiments, the dose of the anti-HER 2 antibody is between about 0.1mg and 10mg/kg of the body weight of the subject (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10mg/kg of the body weight of the subject). In some embodiments, the dose of the anti-HER 2 antibody is between about 4mg and 10mg/kg of the body weight of the subject. In some embodiments, the dose of the anti-HER 2 antibody is between 4mg and 10mg/kg of the body weight of the subject. In some embodiments, the dose of the anti-HER 2 antibody is about 6mg/kg of the body weight of the subject. In some embodiments, the dose of the anti-HER 2 antibody is about 8mg/kg of the body weight of the subject. In some embodiments, the dose of the anti-HER 2 antibody is as follows: a first dose of the anti-HER 2 antibody for administration to the subject is about 8mg/kg of the subject's body weight followed by a subsequent dose of about 6mg/kg of the subject's body weight. In some embodiments, the dose of the anti-HER 2 antibody is 6mg/kg of the body weight of the subject. In some embodiments, the dose of the anti-HER 2 antibody is 8mg/kg of the body weight of the subject. In some embodiments, the dose of the anti-HER 2 antibody is as follows: the first dose of the anti-HER 2 antibody for administration to the subject is 8mg/kg of the subject's body weight followed by a subsequent dose of 6mg/kg of the subject's body weight. In other embodiments, the dose of the anti-HER 2 antibody is between about 10mg and 100mg/kg of the body weight of the subject (e.g., about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100mg/kg of the body weight of the subject). In some embodiments, the dose of the anti-HER 2 antibody is at least about 100mg to 500mg per kg of the body weight of the subject (e.g., at least about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more mg per kg of the body weight of the subject). In some cases, the dose of the anti-HER 2 antibody is about 6mg/kg of the subject's body weight. In other instances, the dose of the anti-HER 2 antibody is about 8mg/kg of the subject's body weight. In some other cases, the dose of the anti-HER 2 antibody is about 20mg/kg of the body weight of the subject. In some embodiments, the dose of the anti-HER 2 antibody comprises between about 1mg and 100mg (e.g., about 1,2, 3,4, 5,6, 7,8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100mg) of the anti-HER 2 antibody. In other embodiments, the dose of the anti-HER 2 antibody comprises between about 100mg and 1,000mg (e.g., about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1,000mg) of the anti-HER 2 antibody. In particular embodiments, the dose of the anti-HER 2 antibody comprises between about 100mg and 400mg (e.g., about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, or 400mg) of the anti-HER 2 antibody. In some embodiments, the dose of the anti-HER 2 antibody is between about 400mg and 800 mg. In some embodiments, the dose of the anti-HER 2 antibody is between 400mg and 800 mg. In some embodiments, the dose of the anti-HER 2 antibody is about 600 mg. In some embodiments, the dose of the anti-HER 2 antibody is 600 mg. By way of non-limiting example, when a dose of 6mg/kg is used, the dose for a 50kg subject will be about 300 mg. As another non-limiting example, when a dose of 8mg/kg is used, the dose for a 50kg subject will be about 400 mg. In some embodiments, the dose of the anti-HER 2 antibody comprises at least about 1,000mg to 10,000mg (e.g., at least about 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600, 3,700, 3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600, 4,700, 4,800, 4,900, 5,000, 5,100, 5,200, 5,300, 5,400, 5,500, 5,600, 5,500, 6,600, 7,800, 6,500, 6,600, 7,600, 7,800, 6,500, 6,600, 7,8, 7,800, 7,500, 6,800, 7,800, 6,500, 7,500, 6,500, 6,600, 7,8, 6,600, 7,9, 6,500, 7,500, 6,500, 7,500, 7,800, 6,500, 6,900, 6,500, 6,8, 6,900, 6,8, 7,500, 6,500, 6,900, 6,500, 6,900, 6,500, 6,900, 6,500, 6,900, 6,500, 6,900, 6,500, 6,900, 6,500, 6,900, 6,2,2,900, 6,500, 6,900, 6,500, 6,. In some embodiments, the dose of the anti-HER 2 antibody contains a therapeutically effective amount of the anti-HER 2 antibody. In other embodiments, the dose of the anti-HER 2 antibody contains less than a therapeutically effective amount of the anti-HER 2 antibody (e.g., when multiple doses are administered in order to achieve a desired clinical or therapeutic effect). In some embodiments, the anti-HER 2 antibody is administered to the subject about once every 1 to 4 weeks. In certain embodiments, the anti-HER 2 antibody is administered about once every 1 week, about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks. In one embodiment, the anti-HER 2 antibody is administered about once every 3 weeks. In some embodiments, the anti-HER 2 antibody is administered to the subject every 1 to 4 weeks. In certain embodiments, the anti-HER 2 antibody is administered once every 1 week, about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks. In one embodiment, the anti-HER 2 antibody is administered once every 3 weeks. In some embodiments, the anti-HER 2 antibody is administered subcutaneously to the subject. In some embodiments, the anti-HER 2 antibody is administered to the subject intravenously. In some embodiments, the anti-HER 2 antibody is selected from trastuzumab, pertuzumab, adotrastuzumab-maytansine, magituximab, and combinations thereof. In some cases, the anti-HER 2 antibody is a combination of trastuzumab and pertuzumab. In some embodiments, the anti-HER 2 antibody is trastuzumab. In some embodiments, the anti-HER 2 antibody is administered at a dose of about 600mg about once every 3 weeks and the anti-HER 2 antibody is administered subcutaneously. In some embodiments, the anti-HER 2 antibody is administered at a dose of 600mg once every 3 weeks and the anti-HER 2 antibody is administered subcutaneously. In some embodiments, the anti-HER 2 antibody is trastuzumab and is administered at a dose of about 600mg about once every 3 weeks and trastuzumab is administered subcutaneously. In some embodiments, the anti-HER 2 antibody is trastuzumab and is administered at a dose of 600mg once every 3 weeks and trastuzumab is administered subcutaneously. In some embodiments, the anti-HER 2 antibody is administered at a dose of about 6mg/kg about once every 3 weeks and the anti-HER 2 antibody is administered intravenously. In some embodiments, the anti-HER 2 antibody is administered at a dose of about 8mg/kg about once every 3 weeks and the anti-HER 2 antibody is administered intravenously. In some embodiments, the anti-HER 2 antibody is administered about once every 3 weeks as follows: (ii) at a dose of about 8mg/kg for a first dose of the anti-HER 2 antibody administered to the subject, followed by a subsequent dose of about 6mg/kg, wherein the anti-HER 2 antibody is administered intravenously. In some embodiments, the anti-HER 2 antibody is administered at a dose of 6mg/kg once every 3 weeks and the anti-HER 2 antibody is administered intravenously. In some embodiments, the anti-HER 2 antibody is administered at a dose of 8mg/kg once every 3 weeks and the anti-HER 2 antibody is administered intravenously. In some embodiments, the anti-HER 2 antibody is administered every 3 weeks as follows: (ii) at a dose of 8mg/kg for a first dose of the anti-HER 2 antibody administered to the subject, followed by a subsequent dose of 6mg/kg, wherein the anti-HER 2 antibody is administered intravenously. In some embodiments, the anti-HER 2 antibody is trastuzumab and is administered at a dose of about 6mg/kg about once every 3 weeks and trastuzumab is administered intravenously. In some embodiments, the anti-HER 2 antibody is trastuzumab and is administered at a dose of about 8mg/kg about once every 3 weeks and trastuzumab is administered intravenously. In some embodiments, the anti-HER 2 antibody is trastuzumab and is administered about once every 3 weeks as follows: (ii) at a dose of about 8mg/kg for a first dose of trastuzumab administered to the subject, followed by a subsequent dose of about 6mg/kg, wherein trastuzumab is administered intravenously. In some embodiments, the anti-HER 2 antibody is trastuzumab and is administered at a dose of 6mg/kg once every 3 weeks and trastuzumab is administered intravenously. In some embodiments, the anti-HER 2 antibody is trastuzumab and is administered at a dose of 8mg/kg once every 3 weeks and trastuzumab is administered intravenously. In some embodiments, the anti-HER 2 antibody is trastuzumab and is administered every 3 weeks as follows: (ii) at a dose of 8mg/kg for a first dose of trastuzumab administered to the subject, followed by a subsequent dose of 6mg/kg, wherein trastuzumab is administered intravenously. In some embodiments, the anti-HER 2 antibody is trastuzumab, and is administered to the subject in a 21-day treatment cycle and once per treatment cycle.

In some embodiments, the methods of treatment described herein comprise administering to the subject vectinib, capecitabine, and trastuzumab. In some embodiments, the capecitabine, and trastuzumab are administered to the subject at a 21 day treatment cycle. In some embodiments, the subject is administered the icaritinib at a dose of about 300mg twice daily. In some embodiments, the subject is administered the cartinib at a dose of 300mg twice daily. In some embodiments, the procatinib is administered to the subject once daily at a dose of about 600 mg. In some embodiments, the procatinib is administered to the subject once daily at a dose of 600 mg. In some embodiments, the procatinib is administered to the subject twice daily on each day of a 21-day treatment cycle. In some embodiments, the method further comprises administering to the subject an oral dose of icaritinib. In some embodiments, capecitabine is administered to said subject twice daily. In some embodiments, capecitabine is administered to the subject twice daily on days 1-14 of a 21-day treatment cycle. In some embodiments, capecitabine is administered twice daily at about 1000mg/m ²Is administered to the subject. In some embodiments, capecitabine is administered twice daily at 1000mg/m²Is administered to the subject. In some embodiments, capecitabine is administered twice daily at about 1000mg/m on days 1-14 of a 21-day treatment cycle²Of (2)The amount is administered to the subject. In some embodiments, capecitabine is administered twice daily at 1000mg/m on days 1-14 of a 21-day treatment cycle²Is administered to the subject. In some embodiments, capecitabine is administered orally to the subject. In some embodiments, the anti-HER 2 antibody is administered at a dose of about 6mg/kg about once every 3 weeks and the anti-HER 2 antibody is administered intravenously. In some embodiments, the anti-HER 2 antibody is administered at a dose of about 8mg/kg about once every 3 weeks and the anti-HER 2 antibody is administered intravenously. In some embodiments, the anti-HER 2 antibody is administered about once every 3 weeks as follows: (ii) at a dose of about 8mg/kg for a first dose of the anti-HER 2 antibody administered to the subject, followed by a subsequent dose of about 6mg/kg, wherein the anti-HER 2 antibody is administered intravenously. In some embodiments, the anti-HER 2 antibody is administered at a dose of 6mg/kg once every 3 weeks and the anti-HER 2 antibody is administered intravenously. In some embodiments, the anti-HER 2 antibody is administered at a dose of 8mg/kg once every 3 weeks and the anti-HER 2 antibody is administered intravenously. In some embodiments, the anti-HER 2 antibody is administered every 3 weeks as follows: (ii) at a dose of 8mg/kg for a first dose of the anti-HER 2 antibody administered to the subject, followed by a subsequent dose of 6mg/kg, wherein the anti-HER 2 antibody is administered intravenously. In some embodiments, the anti-HER 2 antibody is trastuzumab and is administered at a dose of about 6mg/kg about once every 3 weeks and trastuzumab is administered intravenously. In some embodiments, the anti-HER 2 antibody is trastuzumab and is administered at a dose of about 8mg/kg about once every 3 weeks and trastuzumab is administered intravenously. In some embodiments, the anti-HER 2 antibody is trastuzumab and is administered about once every 3 weeks as follows: (ii) at a dose of about 8mg/kg for a first dose of trastuzumab administered to the subject, followed by a subsequent dose of about 6mg/kg, wherein trastuzumab is administered intravenously. In some embodiments, the anti-HER 2 antibody is trastuzumab and is administered at a dose of 6mg/kg once every 3 weeks and trastuzumab is administered intravenously. In some embodiments The anti-HER 2 antibody is trastuzumab and is administered at a dose of 8mg/kg once every 3 weeks and trastuzumab is administered intravenously. In some embodiments, the anti-HER 2 antibody is trastuzumab and is administered every 3 weeks as follows: (ii) at a dose of 8mg/kg for a first dose of trastuzumab administered to the subject, followed by a subsequent dose of 6mg/kg, wherein trastuzumab is administered intravenously. In some embodiments, the anti-HER 2 antibody is trastuzumab, and is administered to the subject in a 21-day treatment cycle and once per treatment cycle.

E. Treatment outcome

In some embodiments, treating the subject comprises inhibiting growth of breast cancer cells, inhibiting proliferation of breast cancer cells, inhibiting migration of breast cancer cells, inhibiting invasion of breast cancer cells, reducing or eliminating one or more signs or symptoms of breast cancer, reducing the size (e.g., volume) of a breast cancer tumor, reducing the number of breast cancer tumors, reducing the number of breast cancer cells, inducing necrosis, pyrodeath, oncosis, apoptosis, autophagy, or other cell death of breast cancer cells, increasing the survival time of the subject, or enhancing the therapeutic effect of another drug or therapy.

In some embodiments, treating the subject as described herein results in a Tumor Growth Inhibition (TGI) index of between about 10% and 70% (e.g., about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%). Preferably, treating the subject results in a TGI index of at least about 70% (e.g., about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%). More preferably, treating the subject results in a TGI index of at least about 85% (e.g., about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%). Even more preferably, treating the subject results in a TGI index of at least about 95% (e.g., about 95%, 96%, 97%, 98%, 99%, or 100%). Most preferably, treating the subject results in a TGI index of about 100% or greater (e.g., about 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 125%, 130%, 135%, 140%, 145%, 150% or greater).

In certain embodiments, treatment of the subject with vectinib, capecitabine, and trastuzumab results in a TGI index that is greater than the TGI index observed when vectinib, capecitabine, or trastuzumab is used alone. In some cases, treating the subject results in a TGI index that is greater than the TGI index observed when using cartinib alone. In other cases, treating the subject results in a TGI index that is greater than the TGI index observed when capecitabine is used alone. In other cases, treating the subject results in a TGI index that is greater than the TGI index observed when trastuzumab alone is used. In some embodiments, treating the subject results in a TGI index that is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% greater than the TGI index observed when using either vecatinib, capecitabine, or trastuzumab alone.

In some embodiments, the combination of tucaninib, capecitabine, and trastuzumab is synergistic. In particular embodiments, with respect to synergistic combinations, treating the subject results in a TGI index that is greater than the TGI index expected when the combination of vectinib, capecitabine, and trastuzumab produces an additive effect. In some cases, the TGI index observed upon administration of the combination of tucaninib, capecitabine, and trastuzumab is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% greater than the TGI index expected when the combination of tucaninib, capecitabine, and trastuzumab produces an additive effect.

In one aspect, the method of treating cancer with picatinib as described herein results in an improvement in one or more therapeutic effects in the subject relative to baseline following administration of picatinib. In some embodiments, the one or more therapeutic effects is the size, objective response rate, duration of response, time to response, progression free survival, overall survival, or any combination thereof, of a tumor derived from the breast cancer. In one embodiment, the one or more therapeutic effects is the size of a tumor derived from the breast cancer. In one embodiment, the one or more therapeutic effects is a reduction in tumor size. In one embodiment, the one or more therapeutic effects is disease stabilization. In one embodiment, the one or more therapeutic effects is a partial response. In one embodiment, the one or more therapeutic effects is a complete response. In one embodiment, the one or more therapeutic effects is an objective response rate. In one embodiment, the one or more therapeutic effects is duration of response. In one embodiment, the one or more therapeutic effects is achieving a response time. In one embodiment, the one or more therapeutic effects is progression-free survival. In one embodiment, the one or more therapeutic effects is overall survival. In one embodiment, the one or more therapeutic effects is cancer regression.

In one embodiment of the methods or uses provided herein or products for said uses, the response to treatment with electrocatinib as described herein may comprise the following criteria (RECIST criteria 1.1):

in one embodiment of the method or use provided herein or the product for said use, the effectiveness of the treatment with electrocatinib described herein is assessed by measuring the objective response rate. In some embodiments, the objective response rate is the proportion of patients with a predefined amount of tumor size reduction and lasting for a minimum period of time. In some embodiments, the objective response rate is based on RECIST v 1.1. In one embodiment, the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%. In one embodiment, the objective response rate is at least about 20% to 80%. In one embodiment, the objective response rate is at least about 30% -80%. In one embodiment, the objective response rate is at least about 40% -80%. In one embodiment, the objective response rate is at least about 50% -80%. In one embodiment, the objective response rate is at least about 60% to 80%. In one embodiment, the objective response rate is at least about 70% to 80%. In one embodiment, the objective response rate is at least about 80%. In one embodiment, the objective response rate is at least about 85%. In one embodiment, the objective response rate is at least about 90%. In one embodiment, the objective response rate is at least about 95%. In one embodiment, the objective response rate is at least about 98%. In one embodiment, the objective response rate is at least about 99%. In one embodiment, the objective response rate is at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80%. In one embodiment, the objective response rate is at least 20% to 80%. In one embodiment, the objective response rate is at least 30% to 80%. In one embodiment, the objective response rate is at least 40% to 80%. In one embodiment, the objective response rate is at least 50% to 80%. In one embodiment, the objective response rate is at least 60% to 80%. In one embodiment, the objective response rate is at least 70% to 80%. In one embodiment, the objective response rate is at least 80%. In one embodiment, the objective response rate is at least 85%. In one embodiment, the objective response rate is at least 90%. In one embodiment, the objective response rate is at least 95%. In one embodiment, the objective response rate is at least 98%. In one embodiment, the objective response rate is at least 99%. In one embodiment, the objective response rate is 100%.

In one embodiment of the methods or uses provided herein or products for said uses, the response to a treatment with cartinib described herein is assessed by measuring the size of a tumor derived from said cancer (e.g., breast cancer). In one embodiment, the size of a tumor derived from said cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from said cancer prior to administration of cartilaginous. In one embodiment, the size of the tumor derived from the cancer is reduced by at least about 10% -80%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least about 20% -80%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least about 30% -80%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least about 40% -80%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least about 50% -80%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least about 60% -80%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least about 70% -80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 85%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 90%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 95%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 98%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 99%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70% or at least 80% relative to the size of the tumor derived from the cancer prior to administration of cartilaginous. In one embodiment, the size of the tumor derived from the cancer is reduced by at least 10% -80%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least 20% -80%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least 30% -80%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least 40% -80%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least 50% -80%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least 60% -80%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least 70% -80%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 85%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least 90%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 95%. In one embodiment, the size of the tumor derived from the cancer is reduced by at least 98%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 99%. In one embodiment, the size of the tumor derived from the cancer is reduced by 100%. In some embodiments, the size of a tumor derived from breast cancer is measured by mammography, ultrasonography, or Magnetic Resonance Imaging (MRI). See Gruber et al, 2013, BMC cancer.13: 328.

In one embodiment of the method or use provided herein or the product for use, the response to treatment with electrocatinib described herein promotes regression of a tumor derived from the cancer (e.g., breast cancer). In one embodiment, the tumor derived from the cancer regresses by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from the cancer prior to administration of the herein described cartilaginous. In one embodiment, the tumor regression from the cancer is at least about 10% to about 80%. In one embodiment, tumor regression from the cancer is at least about 20% to about 80%. In one embodiment, tumor regression from the cancer is at least about 30% to about 80%. In one embodiment, tumor regression from the cancer is at least about 40% to about 80%. In one embodiment, tumor regression from the cancer is at least about 50% to about 80%. In one embodiment, the tumor regression from the cancer is at least about 60% to about 80%. In one embodiment, tumor regression from the cancer is at least about 70% to about 80%. In one embodiment, the tumor derived from the cancer regresses by at least about 80%. In one embodiment, tumor regression from the cancer is at least about 85%. In one embodiment, the tumor derived from the cancer regresses by at least about 90%. In one embodiment, the tumor derived from the cancer regresses by at least about 95%. In one embodiment, the tumor resulting from the cancer regresses by at least about 98%. In one embodiment, the tumor derived from the cancer regresses by at least about 99%. In one embodiment, the tumor derived from the cancer regresses by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80% relative to the size of the tumor derived from the cancer prior to administration of picatinib as described herein. In one embodiment, the tumor arising from the cancer regresses by at least 10% to 80%. In one embodiment, the tumor arising from the cancer regresses by at least 20% to 80%. In one embodiment, the tumor arising from the cancer regresses by at least 30% to 80%. In one embodiment, the tumor regression from the cancer is at least 40% to 80%. In one embodiment, the tumor arising from the cancer regresses by at least 50% to 80%. In one embodiment, the tumor arising from the cancer regresses by at least 60% to 80%. In one embodiment, the tumor arising from the cancer regresses by at least 70% to 80%. In one embodiment, the tumor derived from the cancer regresses by at least 80%. In one embodiment, the tumor derived from the cancer regresses by at least 85%. In one embodiment, the tumor derived from the cancer regresses by at least 90%. In one embodiment, the tumor derived from the cancer regresses by at least 95%. In one embodiment, the tumor derived from the cancer regresses by at least 98%. In one embodiment, the tumor derived from the cancer regresses by at least 99%. In one embodiment, tumors derived from the cancer regress by 100%. In some embodiments, regression of the tumor is determined by mammography, ultrasound examination, or Magnetic Resonance Imaging (MRI). See Gruber et al, 2013, BMC cancer.13: 328.

In one embodiment of the method or use or product for use described herein, the response to treatment with picatinib described herein is assessed by measuring the time to progression free survival following administration of picatinib. In some embodiments, the subject exhibits progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of cartinib. In some embodiments, the subject exhibits progression-free survival of at least about 6 months after administration of cartinib. In some embodiments, the subject exhibits progression-free survival of at least about one year following administration of cartinib. In some embodiments, the subject exhibits progression-free survival of at least about two years following administration of cartinib. In some embodiments, the subject exhibits progression-free survival of at least about three years following administration of cartinib. In some embodiments, the subject exhibits progression-free survival of at least about four years following administration of cartinib. In some embodiments, the subject exhibits progression-free survival of at least about five years following administration of cartinib. In some embodiments, the subject exhibits progression free survival of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least eighteen months, at least two years, at least three years, at least four years, or at least five years after administration of cartinib. In some embodiments, the subject exhibits progression-free survival of at least 6 months following administration of cartinib. In some embodiments, the subject exhibits progression-free survival of at least one year following administration of cartinib. In some embodiments, the subject exhibits progression-free survival of at least two years following administration of cartinib. In some embodiments, the subject exhibits progression-free survival of at least three years following administration of cartinib. In some embodiments, the subject exhibits progression-free survival of at least four years following administration of cartinib. In some embodiments, the subject exhibits progression-free survival of at least five years following administration of cartinib.

In one embodiment of the method or use or product for use described herein, the response to treatment with picatinib described herein is assessed by measuring the time to overall survival following administration of picatinib. In some embodiments, the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of cartinib. In some embodiments, the subject exhibits overall survival of at least about 6 months after administration of cartinib. In some embodiments, the subject exhibits overall survival of at least about one year following administration of cartinib. In some embodiments, the subject exhibits overall survival of at least about two years following administration of cartinib. In some embodiments, the subject exhibits overall survival of at least about three years following administration of cartinib. In some embodiments, the subject exhibits overall survival of at least about four years following administration of cartinib. In some embodiments, the subject exhibits overall survival of at least about five years following administration of cartinib. In some embodiments, the subject exhibits an overall survival of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least about 12 months, at least eighteen months, at least two years, at least three years, at least four years, or at least five years after administration of cartinib. In some embodiments, the subject exhibits overall survival of at least 6 months following administration of cartinib. In some embodiments, the subject exhibits overall survival of at least one year following administration of cartinib. In some embodiments, the subject exhibits overall survival of at least two years following administration of cartinib. In some embodiments, the subject exhibits overall survival of at least three years following administration of cartinib. In some embodiments, the subject exhibits overall survival of at least four years following administration of cartinib. In some embodiments, the subject exhibits overall survival of at least five years following administration of cartinib.

In one embodiment of the method or use or product for use described herein, the response to treatment with picatinib described herein is assessed by measuring the duration of the response to picatinib after administration of picatinib. In some embodiments, the duration of the response to tucatinib is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of tucatinib. In some embodiments, the duration of the response to picatinib is at least about 6 months after administration of the picatinib. In some embodiments, the duration of the response to picatinib is at least about one year after administration of the picatinib. In some embodiments, the duration of the response to picatinib is at least about two years after administration of the picatinib. In some embodiments, the duration of the response to picatinib is at least about three years after administration of the picatinib. In some embodiments, the duration of the response to picatinib is at least about four years after administration of the picatinib. In some embodiments, the duration of the response to tocaininib is at least about five years after administration of tocaininib. In some embodiments, the duration of the response to tucatinib is at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least eighteen months, at least two years, at least three years, at least four years, or at least five years after administration of tucatinib. In some embodiments, the duration of the response to picatinib is at least 6 months after administration of the picatinib. In some embodiments, the duration of the response to picatinib is at least one year after administration of the picatinib. In some embodiments, the duration of the response to picatinib is at least two years after administration of the picatinib. In some embodiments, the duration of the response to picatinib is at least three years after administration of the picatinib. In some embodiments, the duration of the response to picatinib is at least four years after administration of the picatinib. In some embodiments, the duration of the response to picatinib is at least five years after administration of the picatinib.

F. Composition comprising a metal oxide and a metal oxide

In another aspect, the present invention provides a pharmaceutical composition comprising picatinib and a pharmaceutically acceptable carrier. In another aspect, the present invention provides a pharmaceutical composition comprising capecitabine and a pharmaceutically acceptable carrier. In another aspect, the invention provides a pharmaceutical composition comprising an anti-HER 2 antibody and a pharmaceutically acceptable carrier. In another aspect, the present invention provides a pharmaceutical composition comprising vecatinib, capecitabine, and a pharmaceutically acceptable carrier. In another aspect, the invention provides a pharmaceutical composition comprising cartinib, an anti-HER 2 antibody and a pharmaceutically acceptable carrier. In another aspect, the invention provides a pharmaceutical composition comprising capecitabine, an anti-HER 2 antibody, and a pharmaceutically acceptable carrier. In another aspect, the invention provides a pharmaceutical composition comprising vecatinib, capecitabine, an anti-HER 2 antibody, and a pharmaceutically acceptable carrier. In some embodiments, the anti-HER 2 antibody is a member selected from the group consisting of: trastuzumab, pertuzumab, adotrastuzumab-maytansine, magituximab, and combinations thereof. In some cases, the anti-HER 2 antibody is a combination of trastuzumab and pertuzumab. In some embodiments, the anti-HER 2 antibody is trastuzumab.

In some embodiments, the vecatinib is present at a concentration of between about 0.1nM and 10nM (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 nM). In other embodiments, the cartinib is present at a concentration of between about 10nM and 100nM (e.g., about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 nM). In some other embodiments, cartinib is present at a concentration of between about 100nM and 1,000nM (e.g., about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1,000 nM). In still other embodiments, the vectinib is present at a concentration of at least about 1,000nM to 10,000nM (e.g., at least about 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600, 3,700, 3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600, 4,700, 4,800, 4,900, 5,000, 5,100, 5,200, 5,300, 5,400, 5,500, 5,600, 7,500, 6,8,600, 6,800, 7,500, 7,8,800, 7,500, 8,800, 8,500, 7,800, 8,500, 8,800, 8,500, 8,9,500, 8,500, 8,9,2,500, 8,500, 8,2,2,500, 2,500, 2,2,500, 2,500, 2,2,500, 2,500, 2,2,2,2,2,2,2,2,500, 2,2,2,2,500,2,2,2,2,2,2,2,2,2,500, 2,500,2,2,2,2,2,2,2,2,2,2,500,500,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2.

In some embodiments, the anti-HER 2 antibody is present at a concentration of between about 0.1nM and 10nM (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 nM). In other embodiments, the anti-HER 2 antibody is present at a concentration of between about 10nM and 100nM (e.g., about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 nM). In some other embodiments, the anti-HER 2 antibody is present at a concentration of between about 100nM and 1,000nM (e.g., about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1,000 nM). In still other embodiments, the anti-HER 2 antibody is present at a concentration of at least about 1,000nM to 10,000nM (e.g., at least about 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600, 3,700, 3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600, 4,700, 4,800, 4,900, 5,000, 5,100, 5,200, 5,300, 5,400, 5,500, 5,600, 6,600, 6,500, 7,800, 6,800, 7,500, 6,8,600, 7,800, 7,500, 6,8, 7,800, 7,500, 6,800, 7,800, 7,500, 6,500, 6,8,8, 8,200, 8,800, 8,500, 7,500, 8,2,500, 6,500, 6,2,2,200, 2,500, 2,2,2,500, 2,200, 2,2,200, 2,500, 2,2,2,200, 2,200, 2,500, 2,200, 2,900, 2,500, 2,200, 2,500, 2,2,500, 2,500, 2,2,2,2,2,2,2,500,2,2,2,2,2,2,2,2,500, 2,500,2,500,2,2,2,2,2,2,2,2,2,2,500,500,2,2,2,2,2,2,2,2,2,2,2,2,2,2,500,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,.

In some embodiments, capecitabine is present at a concentration of between about 0.1nM and 10nM (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 nM). In other embodiments, capecitabine is present at a concentration of between about 10nM and 100nM (e.g., about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 nM). In some other embodiments, capecitabine is present at a concentration of between about 100nM and 1,000nM (e.g., about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1,000 nM). In still other embodiments, capecitabine is present at a concentration of at least about 1,000nM to 10,000nM (e.g., at least about 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600, 3,700, 3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600, 4,700, 4,800, 4,900, 5,000, 5,100, 5,200, 5,300, 5,400, 5,500, 5,600, 6,500, 7,600, 6,800, 7,500, 8,600, 8,800, 7,500, 8,800, 8,500, 8,800, 8,500, 8,800, 8,500, 8,2,500, 8,500, 8,800, 8,2,800, 8,500, 8,2,500, 8,2,2,500, 2,500, 8,500, 2,2,2,500, 2,500, 2,2,500, 2,500, 2,2,2,2,2,2,500, 2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,500, 2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2,2.

The pharmaceutical compositions of the present invention may be prepared by any method well known in the art of pharmacy. Pharmaceutically acceptable carriers suitable for use in the present invention include any of the standard pharmaceutical carriers, buffers and excipients, including phosphate buffered saline solutions, water and emulsions (e.g., oil/water or water/oil emulsions), as well as various types of wetting agents or adjuvants. Suitable Pharmaceutical carriers and formulations thereof are described in Remington's Pharmaceutical Sciences (Mack Publishing co., eiston, 19 th edition 1995). The preferred pharmaceutical carrier depends on the intended mode of administration of the active agent.

The pharmaceutical composition of the present invention may comprise a combination of drugs (e.g., vecatinib, capecitabine, and anti-HER 2 antibody) or any pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier or excipient or diluent. The pharmaceutical composition may optionally contain other therapeutic ingredients.

The compositions (e.g., comprising vectanib, capecitabine, anti-HER 2 antibody, or a combination thereof) as the active ingredient may be combined in intimate admixture with a suitable pharmaceutical carrier or excipient according to conventional pharmaceutical compounding techniques. Any carrier or excipient suitable for administration in the desired formulation is contemplated for use with the compounds disclosed herein.

Pharmaceutical compositions include those suitable for oral, topical, parenteral, pulmonary, nasal or rectal administration. In any given case, the most suitable route of administration will depend in part on the nature and severity of the cancer condition, and also optionally on the HER2 status or stage of the cancer.

Other pharmaceutical compositions include those suitable for systemic (e.g., enteral or parenteral) administration. Systemic administration includes oral, rectal, sublingual or sublabial administration. Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other delivery means include, but are not limited to, the use of liposome formulations, intravenous infusion, transdermal patches, and the like. In particular embodiments, the pharmaceutical compositions of the present invention may be administered intratumorally.

Compositions for pulmonary administration include, but are not limited to, dry powder compositions consisting of powders of the compounds described herein (e.g., vecatinib, capecitabine, anti-HER 2 antibody, or a combination thereof) or salts thereof and powders of a suitable carrier or lubricant. The composition for pulmonary administration may be inhaled from any suitable dry powder inhaler device known to those skilled in the art.

Compositions for systemic administration include, but are not limited to, dry powder compositions consisting of powders of the compositions as set forth herein (e.g., vecatinib, capecitabine, anti-HER 2 antibody, or a combination thereof) and a suitable carrier or excipient. Compositions for systemic administration may be presented as, but are not limited to, tablets, capsules, pills, syrups, solutions and suspensions.

In some embodiments, the composition (e.g., vecatinib, capecitabine, anti-HER 2 antibody, or a combination thereof) further comprises a pharmaceutical surfactant. In other embodiments, the composition further comprises a cryoprotectant. In some embodiments, the cryoprotectant is selected from the group consisting of glucose, sucrose (sucrose), trehalose, lactose, sodium glutamate, PVP, HP β CD, glycerol, maltose, mannitol, and sucrose (saccharose).

The pharmaceutical compositions or medicaments for use in the present invention may be formulated by standard techniques using one or more physiologically acceptable carriers or excipients. Suitable pharmaceutical carriers are described herein and Remington, The Science and Practice of Pharmacy, 21 st edition, University of The Sciences in Philadelphia, Lippencott Williams & Wilkins (2005).

Controlled release parenteral formulations of the compositions (e.g., vecatinib, capecitabine, anti-HER 2 antibody, or a combination thereof) can be prepared as implants, oily injections, or particulate systems. For an extensive overview of the DELIVERY system, see Banga, A.J., THERAPEUTIC PEPTIDES AND PROTECTINS: FORMULATION, PROCESSING, AND DELIVERY SYSTEMS, technical Publishing Company, Inc., Lankaster, Pa. (1995), which is incorporated herein by reference. Particle systems include microspheres, microparticles, microcapsules, nanocapsules, nanospheres, and nanoparticles.

Polymers may be used for ion controlled release of the compositions of the present invention. Various degradable and non-degradable polymeric matrices for controlled drug delivery are known in the art (Langer R., Accounts chem. Res.,26: 537-. For example, block copolymer poloxamer 407 exists as a viscous but flowable liquid at low temperature, but forms a semi-solid gel at body temperature. It has been shown to be an effective vehicle for the formulation and sustained delivery of recombinant interleukin 2 and urease (Johnston et al, pharm. Res.,9:425-434 (1992); and Pec et al, J.Parent. Sci. Tech.,44(2):5865 (1990)). Alternatively, hydroxyapatite has been used as a microcarrier for the controlled release of proteins (Ijntema et al, int. J. pharm.,112: 215-. In yet another aspect, LIPOSOMEs are used for controlled release and DRUG targeting of lipid encapsulated DRUGs (Betageri et al, Liposome DRUG DELIVERY SYSTEMS, Technomic Publishing Co., Inc., Lankast, Pa.). Many additional systems for controlled delivery of therapeutic proteins are known. See, for example, U.S. patent nos. 5,055,303, 5,188,837, 4,235,871, 4,501,728, 4,837,028, 4,957,735, and 5,019,369, 5,055,303, 5,514,670, 5,413,797, 5,268,164, 5,004,697, 4,902,505, 5,506,206, 5,271,961, 5,254,342, and 5,534,496, each of which is incorporated by reference herein.

For oral administration of a combination of tegasertib, capecitabine and/or anti-HER 2 antibody, the pharmaceutical composition or medicament may take the form of a tablet or capsule, for example, prepared by conventional means together with pharmaceutically acceptable excipients. The present invention provides tablets and gelatin capsules comprising tegaininib, capecitabine, anti-HER 2 antibody, or a combination thereof, or a dry solid powder of these drugs, and (a) diluents or fillers such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose (e.g., ethyl cellulose, microcrystalline cellulose), glycine, pectin, polyacrylates or dibasic calcium phosphate, calcium sulfate; (b) lubricants, for example silica, talc, stearic acid, magnesium or calcium salts, metal stearates, colloidal silica, hydrogenated vegetable oils, corn starch, sodium benzoate, sodium acetate or polyethylene glycol; for tablets, it also contains (c) a binder, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, or hydroxypropylmethylcellulose; if desired, (d) disintegrating agents, such as starches (e.g., potato starch or sodium starch), glycolate salts, agar, alginic acid or a sodium salt thereof or effervescent mixtures; (e) wetting agents, such as sodium lauryl sulfate; or (f) absorbents, coloring agents, flavoring agents, and sweeteners.

The tablets may be film coated or enteric coated according to methods known in the art. Liquid formulations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means together with pharmaceutically acceptable additives such as suspending agents, for example sorbitol syrup, cellulose derivatives or hydrogenated edible fats; emulsifying agents, for example lecithin or acacia; non-aqueous vehicles such as almond oil, oily esters, ethanol or fractionated vegetable oils; and preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid. The formulations may also suitably contain buffer salts, flavouring agents, colouring agents or sweetening agents. Formulations for oral administration may be suitably formulated to achieve controlled release of the active compound or compounds, if desired.

Typical formulations for topical administration of picatinib, capecitabine, anti-HER 2 antibody, or a combination thereof include creams, ointments, sprays, lotions, and patches. However, the pharmaceutical composition may be formulated for any type of administration, such as intradermal, subdermal, intravenous, intramuscular, subcutaneous, intranasal, intracerebral, intratracheal, intraarterial, intraperitoneal, intravesical, intrapleural, intracoronary or intratumoral injection with a syringe or other device. Formulations for administration by inhalation (e.g., aerosols) or for oral or rectal administration are also contemplated.

Suitable formulations for transdermal application include an effective amount of one or more of the compounds described herein and optionally a carrier. Preferred carriers include absorbable pharmacologically acceptable solvents to aid penetration through the skin of the host. For example, the transdermal device is in the form of a bandage comprising a backing member, a reservoir containing the compound and optionally a carrier, an optional rate control barrier (for delivering the compound to the skin of the host at a controlled and predetermined rate over an extended period of time), and means to secure the device to the skin. Matrix transdermal formulations may also be used.

The compositions and formulations set forth herein (e.g., tegaininib, capecitabine, anti-HER 2 antibody, or a combination thereof) may be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. Injectable compositions are preferably isotonic aqueous solutions or suspensions, and suppositories are preferably prepared from fatty emulsions or suspensions. The compositions may be sterilized or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure or buffers. Alternatively, the active ingredient(s) may be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use. In addition, they may contain other therapeutically valuable substances. The compositions are prepared separately according to conventional mixing, granulating or coating methods.

For administration by inhalation, the compositions (e.g., comprising tegasertib, capecitabine, an anti-HER 2 antibody, or a combination thereof) can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer with the aid of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound or compounds and a suitable powder base such as lactose or starch.

The compositions (e.g., comprising tegasertib, capecitabine, anti-HER 2 antibodies, or combinations thereof) may also be formulated as rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases (e.g., cocoa butter or other glycerides).

In addition, the one or more active ingredients may be formulated as a depot formulation. Such long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, one or more of the compounds described herein can be formulated with a suitable polymeric or hydrophobic material (e.g., as an emulsion in an acceptable oil) or ion exchange resin, or as a sparingly soluble derivative (e.g., as a sparingly soluble salt).

G. Article and kit

In another aspect, the invention provides an article of manufacture or a kit for treating or ameliorating the effects of breast cancer in a subject, the article of manufacture or kit comprising a pharmaceutical composition of the invention (e.g., a pharmaceutical composition comprising tegasertib, capecitabine, an anti-HER 2 antibody, or a combination thereof). In some embodiments, the anti-HER 2 antibody is trastuzumab, pertuzumab, adotrastuzumab-maytansine, magituximab, or a combination thereof. In some cases, the anti-HER 2 antibody is a combination of trastuzumab and pertuzumab. In some embodiments, the anti-HER 2 antibody is trastuzumab.

The article of manufacture or kit is suitable for treating or ameliorating the effects of breast cancer, particularly HER2 positive and/or metastatic breast cancer. In some embodiments, the cancer is an advanced cancer. In some other embodiments, the cancer is a drug-resistant cancer. In some cases, the cancer is a multi-drug resistant cancer.

Materials and reagents for practicing the various methods of the invention may be provided in articles of manufacture or kits to facilitate performance of the methods. As used herein, the term "kit" includes a combination of items that facilitate processing, assaying, analysis, or manipulation. In particular, the kits of the invention may be used for a wide range of applications including, for example, diagnosis, prognosis, treatment, and the like.

The article of manufacture or kit may contain chemical reagents as well as other components. Furthermore, the article of manufacture or kit of the invention may include, but is not limited to, instructions to the user, equipment and reagents for administering the combination of tegaininib, capecitabine and anti-HER 2 antibody or pharmaceutical compositions thereof, sample tubes, holders, trays, racks, dishes, plates, solutions, buffers or other chemical reagents. In some embodiments, the article of manufacture or kit contains instructions, devices, or reagents for determining the genotype of a gene (e.g., KRAS, NRAS, BRAF) or determining the expression of HER2 in a sample. The articles or kits of the invention may also be packaged for storage and safe transport, for example in boxes with lids.

Exemplary embodiments

Embodiments provided herein include:

1. a method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaininib or a salt or solvate thereof, wherein the subject is not being concurrently treated with a therapeutically effective amount of a substrate of a multidrug and toxin efflux (MATE) protein.

2. The method of embodiment 1, wherein the subject has not received treatment with the substrate of the MATE protein within the past 7 days.

3. The method of embodiment 1, wherein the subject has not received treatment with the substrate of the MATE protein within the last 3 months.

4. The method of embodiment 1, wherein the subject has not received treatment with the substrate of the MATE protein within the past 12 months.

5. The method of embodiment 1, wherein the subject has not previously been treated with the substrate of the MATE protein.

6. The method according to any one of embodiments 1-5, wherein said MATE protein is MATE 1.

7. The method according to any one of embodiments 1-5, wherein the MATE protein is MATE 2K.

8. The method according to any one of embodiments 1-7, wherein the substrate of the MATE protein is selected from the group consisting of metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin and pyrimethamine.

9. The method of embodiment 8, wherein the substrate is metformin.

10. A method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaserod or a salt or solvate thereof, wherein the subject is not being treated simultaneously with a therapeutically effective amount of a substrate for Organic Cation Transporter (OCT).

11. The method of embodiment 10, wherein the subject has not received treatment with the substrate of the OCT within the past 7 days.

12. The method of embodiment 10, wherein the subject has not received treatment with the substrate of the OCT within the past 3 months.

13. The method of embodiment 10, wherein the subject has not received treatment with the substrate of the OCT protein within the past 12 months.

14. The method of embodiment 10, wherein the subject has not previously been treated with the substrate of the OCT.

15. The method of any of embodiments 10-14, wherein the OCT is OCT 1.

16. The method of any of embodiments 10-14, wherein the OCT is OCT 2.

17. The method according to any one of embodiments 10-16, wherein the substrate of the OCT is selected from the group consisting of metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin, and pyrimethamine.

18. The method of embodiment 17, wherein the substrate is metformin.

19. The method according to any one of embodiments 10-18, wherein the subject is not being concurrently treated with a therapeutically effective amount of a substrate for MATE protein.

20. The method of embodiment 19, wherein the subject has not received treatment with the substrate of the MATE protein within the past 7 days.

21. The method of embodiment 19, wherein the subject has not received treatment with the substrate of the MATE protein within the last 3 months.

22. The method of embodiment 19, wherein the subject has not received treatment with the substrate of the MATE protein within the past 12 months.

23. The method of embodiment 19, wherein the subject has not previously been treated with the substrate of the MATE protein.

24. The method of any one of embodiments 19-23, wherein the MATE protein is MATE 1.

25. The method according to any one of embodiments 19-23, wherein said MATE protein is MATE 2K.

26. A method for treating breast cancer in a subject, comprising administering to the subject a therapeutically effective amount of tegaininib or a salt or solvate thereof, wherein the subject has no impaired renal function.

27. The method of embodiment 26, wherein the subject has not suffered an impairment of renal function within the past 12 months.

28. The method according to any one of embodiments 1-25, wherein the subject has not had impaired renal function.

29. The method of embodiment 28, wherein the subject has not suffered an impairment of renal function within the past 12 months.

30. The method of any one of embodiments 26-29, wherein impaired renal function is determined based on serum creatinine levels in the subject.

31. The method of embodiment 30, wherein a) the subject is male and the subject has a serum creatinine level less than 1.5mg/dL or b) the subject is female and has a serum creatinine level less than to 1.4 mg/dL.

32. The method of any one of embodiments 26-29, wherein impaired renal function is determined based on the subject having an abnormal creatinine clearance rate.

33. The method of any one of embodiments 26-29, wherein impaired renal function is determined based on the glomerular filtration rate of the subject.

34. The method according to any one of embodiments 1-33, wherein the subject is not being concurrently treated with a therapeutically effective amount of a compound that modulates the activity of a cytochrome p450 protein.

35. The method of embodiment 34, wherein the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the last 7 days.

36. The method of embodiment 34, wherein the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the past 3 months.

37. The method of embodiment 34, wherein the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the past 12 months.

38. The method of embodiment 34, wherein the subject has not previously been treated with a compound that modulates the activity of the cytochrome p450 protein.

39. The method according to any one of embodiments 34-38, wherein said compound that modulates the activity of said cytochrome p450 protein is an inhibitor of the activity of said cytochrome p450 protein.

40. The method of embodiment 39, wherein said cytochrome p450 protein is CYP3A 4.

41. The method of embodiment 40, wherein the compound that inhibits the activity of CYP3A4 is itraconazole.

42. The method of embodiment 39, wherein said cytochrome p450 protein is CYP2C 8.

43. The method of embodiment 42, wherein the compound that inhibits the activity of CYP2C8 is gemfibrozil.

44. The method according to any one of embodiments 34-38, wherein said compound that modulates the activity of said cytochrome p450 protein is an inducer of the activity of said cytochrome p450 protein.

45. The method of embodiment 44, wherein the cytochrome p450 protein is CYP3A 4.

46. The method of embodiment 44, wherein the cytochrome p450 protein is CYP2C 8.

47. The method according to any one of embodiments 44-46, wherein said compound that induces the activity of said cytochrome p450 protein is rifampicin.

48. A method for treating breast cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of tegaserod, or a salt or solvate thereof, wherein the subject is not being treated simultaneously with a therapeutically effective amount of a compound that modulates the activity of a cytochrome p450 protein.

49. The method of embodiment 48, wherein said subject has not received treatment with said compound that modulates the activity of said cytochrome p450 protein within the last 7 days.

50. The method of embodiment 48, wherein said subject has not received treatment with said compound that modulates the activity of said cytochrome p450 protein within the last 3 months.

51. The method of embodiment 48, wherein said subject has not received treatment with said compound that modulates the activity of said cytochrome p450 protein within the past 12 months.

52. The method of embodiment 48, wherein said subject has not previously been treated with a compound that modulates the activity of said cytochrome p450 protein.

53. The method according to any one of embodiments 48-52, wherein said compound that modulates the activity of said cytochrome p450 protein is an inhibitor of the activity of said cytochrome p450 protein.

54. The method of embodiment 53, wherein said cytochrome p450 protein is CYP3A 4.

55. The method of embodiment 54, wherein the compound that inhibits the activity of CYP3a4 is itraconazole.

56. The method of embodiment 53, wherein said cytochrome p450 protein is CYP2C 8.

57. The method of embodiment 56, wherein the compound that inhibits the activity of CYP2C8 is gemfibrozil.

58. The method according to any one of embodiments 48-52, wherein said compound that modulates the activity of said cytochrome p450 protein is an inducer of the activity of said cytochrome p450 protein.

59. The method of embodiment 58, wherein said cytochrome p450 protein is CYP3A 4.

60. The method of embodiment 58, wherein said cytochrome p450 protein is CYP2C 8.

61. The method of any one of embodiments 58-60, wherein said compound that induces the activity of said cytochrome p450 protein is rifampicin.

62. The method according to any one of embodiments 1-61, wherein the subject is administered cartinib at a dose of about 150mg to about 650 mg.

63. The method of embodiment 62, wherein the procatinib is administered to the subject at a dose of about 300 mg.

64. The method of embodiment 62 or embodiment 63, wherein the cartinib is administered once or twice daily.

65. The method of embodiment 64, wherein the subject is administered cartinib at a dose of about 300mg twice daily.

66. The method according to any one of embodiments 1-65, wherein icaritinib is orally administered to the subject.

67. The method according to any one of embodiments 1-66, wherein said breast cancer is HER2 positive breast cancer.

68. The method of embodiment 67, wherein said cancer is HER2 positive as determined using in situ hybridization, fluorescence in situ hybridization, or immunohistochemistry.

69. The method according to any one of embodiments 1-68, wherein said breast cancer is metastatic.

70. The method of embodiment 69, wherein said breast cancer has metastasized to the brain.

71. The method according to any one of embodiments 1-70, wherein said breast cancer is locally advanced.

72. The method according to any one of embodiments 1-71, wherein said breast cancer is unresectable.

73. The method according to any one of embodiments 1-72, further comprising administering to the subject one or more additional therapeutic agents to treat the breast cancer.

74. The method of embodiment 73, wherein the one or more additional therapeutic agents is selected from capecitabine and an anti-HER 2 antibody.

75. The method of embodiment 73, wherein said one or more additional therapeutic agents is capecitabine.

76. The method of embodiment 73, wherein the one or more additional therapeutic agents is trastuzumab.

77. The method of embodiment 73, wherein the one or more additional therapeutic agents is capecitabine and trastuzumab.

78. The method of embodiment 75 or embodiment 77, wherein capecitabine is administered at about 500mg/m²To about 1500mg/m²Is administered to the subject.

79. The method of embodiment 78, wherein capecitabine is administered at about 1000mg/m²Is administered to the subject.

80. The method of embodiment 78 or embodiment 79, wherein capecitabine is administered orally to the subject.

81. The method according to any one of embodiments 77-80, wherein capecitabine is administered to the subject twice daily.

82. The method of embodiment 76 or embodiment 77, wherein trastuzumab is administered to the subject at a dose of about 400mg to about 800 mg.

83. The method of embodiment 82, wherein trastuzumab is administered to the subject at a dose of about 600 mg.

84. The method of embodiment 82 or embodiment 83, wherein trastuzumab is administered subcutaneously to the subject.

85. The method of embodiment 76 or embodiment 77, wherein trastuzumab is administered to the subject at a dose of about 4mg/kg to about 10 mg/kg.

86. The method of embodiment 85, wherein trastuzumab is administered to the subject at a dose of about 6 mg/kg.

87. The method of embodiment 85, wherein trastuzumab is administered to the subject at a dose of about 8 mg/kg.

88. The method of embodiment 85, wherein trastuzumab is administered to the subject at an initial dose of about 8mg/kg followed by a subsequent dose of about 6 mg/kg.

89. The method according to any one of embodiments 85-88, wherein trastuzumab is administered intravenously.

90. The method of any one of embodiments 82-89, wherein trastuzumab is administered about once every 1 week, about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks.

91. The method of embodiment 90, wherein trastuzumab is administered about once every 3 weeks.

92. The method of embodiment 77, wherein the capecitabine, and trastuzumab are administered to the subject in a 21 day treatment cycle.

93. The method of embodiment 92, wherein the procatinib is administered to the subject twice daily on each day of the 21-day treatment cycle.

94. The method of embodiment 92 or 93, wherein capecitabine is administered to the subject twice daily on each of days 1-14 of the 21-day treatment cycle.

95. The method according to any one of embodiments 92-94, wherein trastuzumab is administered to the subject once every 21 days of the treatment cycle.

96. The method of embodiment 95, wherein the dose of trastuzumab during the first 21-day treatment cycle is 8mg/kg and the dose of trastuzumab during the subsequent 21-day treatment cycle is 6 mg/kg.

97. The method according to any one of embodiments 1-96, wherein the subject has been previously treated with one or more additional therapeutic agents for the breast cancer.

98. The method of embodiment 97, wherein the one or more additional therapeutic agents is an anti-HER 2 antibody or an anti-HER 2 antibody-drug conjugate.

99. The method of embodiment 98, wherein the one or more additional therapeutic agents is trastuzumab, pertuzumab, and/or T-DM 1.

100. The method according to any one of embodiments 1-99, wherein the subject has not been treated with another therapeutic agent for the breast cancer within the past 12 months.

101. The method of any one of embodiments 1-96, wherein the subject has not previously been treated with another therapeutic agent for the breast cancer.

102. The method according to any one of embodiments 1-101, wherein the subject has not been previously treated with lapatinib, lenatinib, afatinib, or capecitabine.

103. The method of any one of embodiments 1-102, wherein treating the subject results in a Tumor Growth Inhibition (TGI) index of at least about 85%.

104. The method according to any one of embodiments 1-102, wherein treating the subject results in a TGI index of about 100%.

105. The method of any one of embodiments 1-104, wherein one or more therapeutic effects in the subject are improved relative to baseline following administration of cartinib to the subject.

106. The method of embodiment 105, wherein the one or more therapeutic effects is selected from the group consisting of: size, objective response rate, duration of response, time to response, progression-free survival and overall survival of tumors derived from the breast cancer.

107. The method according to any one of embodiments 1-106, wherein the size of the tumor derived from the breast cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from the breast cancer prior to administration of cartilaginib to the subject.

108. The method according to any one of embodiments 1-107, wherein the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%.

109. The method according to any one of embodiments 1-108, wherein upon administration of cartinib to the subject, the subject exhibits progression free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years.

110. The method according to any one of embodiments 1-109, wherein upon administration of cartinib to the subject, the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years.

111. The method according to any one of embodiments 1-110, wherein the duration of the response to tucatinib is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of tucatinib to the subject.

112. The method according to any one of embodiments 1-111, wherein the subject is a human.

113. A therapeutically effective amount of tegaininib, or a salt or solvate thereof, for use in treating breast cancer in a subject, wherein said subject is not being concurrently treated with a therapeutically effective amount of a substrate of a multidrug and toxin efflux (MATE) protein.

114. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for said use according to embodiment 113, wherein said subject has not received treatment with said substrate of said MATE protein within the last 7 days.

115. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use according to embodiment 113, wherein said subject has not received treatment with said substrate of said MATE protein within the last 3 months.

116. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for said use according to embodiment 113, wherein said subject has not received treatment with said substrate of said MATE protein within the past 12 months.

117. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for said use according to embodiment 113, wherein said subject has not previously been treated with said substrate of said MATE protein.

118. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for the use according to any one of embodiments 113-117, wherein said MATE protein is MATE 1.

119. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for the use according to any one of embodiments 113-117, wherein said MATE protein is MATE 2K.

120. A therapeutically effective amount of tegaininib, or a salt or solvate thereof, for said use according to any one of embodiments 113-119, wherein said substrate of said MATE protein is selected from the group consisting of metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin and pyrimethamine.

121. The therapeutically effective amount of tegaserod, or a salt or solvate thereof, for the use according to embodiment 120, wherein the substrate is metformin.

122. A therapeutically effective amount of picatinib, or a salt or solvate thereof, for use in treating breast cancer in a subject, wherein the subject is not being concurrently treated with a therapeutically effective amount of a substrate of Organic Cation Transporter (OCT).

123. The therapeutically effective amount of picatinib, or a salt or solvate thereof, for the use of embodiment 122, wherein the subject has not received treatment with the substrate of the OCT within the past 7 days.

124. The therapeutically effective amount of picatinib, or a salt or solvate thereof, for the use of embodiment 122, wherein the subject has not received treatment with the substrate of the OCT within the past 3 months.

125. The therapeutically effective amount of picatinib, or a salt or solvate thereof, for the use of embodiment 122, wherein the subject has not received treatment with the substrate of the OCT protein within the past 12 months.

126. The therapeutically effective amount of picatinib, or a salt or solvate thereof, for the use of embodiment 122, wherein the subject has not previously been treated with the substrate of the OCT.

127. A therapeutically effective amount of tocaintinib, or a salt or solvate thereof, for said use according to any one of embodiments 122-126, wherein said OCT is OCT 1.

128. A therapeutically effective amount of tocaintinib, or a salt or solvate thereof, for said use according to any one of embodiments 122-126, wherein said OCT is OCT 2.

129. A therapeutically effective amount of tegaininib or a salt or solvate thereof for the use according to any one of embodiments 122-128, wherein said substrate of said OCT is selected from metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin and pyrimethamine.

130. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use according to embodiment 129, wherein said substrate is metformin.

131. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for the use according to any one of embodiments 122-130, wherein the subject is not being concurrently treated with a therapeutically effective amount of a substrate for MATE protein.

132. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for said use of embodiment 131, wherein said subject has not received treatment with said substrate of said MATE protein within the last 7 days.

133. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for said use of embodiment 131, wherein said subject has not received treatment with said substrate of said MATE protein within the last 3 months.

134. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for said use of embodiment 131, wherein said subject has not received treatment with said substrate of said MATE protein within the past 12 months.

135. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for said use of embodiment 131, wherein said subject has not previously been treated with said substrate of said MATE protein.

136. The therapeutically effective amount of cartilaginib, or a salt or solvate thereof, for use according to any one of embodiments 131-135, wherein the MATE protein is MATE 1.

137. The therapeutically effective amount of cartilaginib, or a salt or solvate thereof, for use according to any one of embodiments 131-135, wherein the MATE protein is MATE 2K.

138. A therapeutically effective amount of picatinib, or a salt or solvate thereof, for use in treating breast cancer in a subject, wherein the subject has no impaired renal function.

139. The therapeutically effective amount of tegaininib or a salt or solvate thereof for said use according to embodiment 138, wherein said subject has not suffered an impaired renal function within the past 12 months.

140. The therapeutically effective amount of cartilaginib, or a salt or solvate thereof, for use according to any one of embodiments 113-137, wherein the subject has no impaired renal function.

141. The therapeutically effective amount of tegaininib or a salt or solvate thereof for said use according to embodiment 140, wherein said subject has not suffered an impaired renal function within the past 12 months.

142. The therapeutically effective amount of Tucanitinib, or a salt or solvate thereof, for said use according to any one of embodiments 138-141, wherein impaired renal function is determined based on the serum creatinine level in said subject.

143. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for the use according to embodiment 142, wherein a) the subject is male and the subject has a serum creatinine level less than 1.5mg/dL or b) the subject is female and has a serum creatinine level less than to 1.4 mg/dL.

144. The therapeutically effective amount of cartinib or a salt or solvate thereof for the use according to any one of embodiments 138-141, wherein impaired renal function is determined based on the subject having abnormal creatinine clearance.

145. The therapeutically effective amount of Tucaninib, or a salt or solvate thereof, for use according to any one of embodiments 138-141, wherein impaired renal function is determined based on the glomerular filtration rate of the subject.

146. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for the use according to any one of embodiments 113-145, wherein the subject is not being concurrently treated with a therapeutically effective amount of a compound that modulates the activity of a cytochrome p450 protein.

147. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use according to embodiment 146, wherein said subject has not received treatment with said compound that modulates activity of said cytochrome p450 protein within the last 7 days.

148. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use according to embodiment 146, wherein said subject has not received treatment with said compound that modulates activity of said cytochrome p450 protein within the last 3 months.

149. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use according to embodiment 146, wherein said subject has not received treatment with said compound that modulates activity of said cytochrome p450 protein within the past 12 months.

150. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use according to embodiment 146, wherein said subject has not previously been treated with a compound that modulates activity of said cytochrome p450 protein.

151. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for the use according to any one of embodiments 145-150, wherein said compound that modulates the activity of said cytochrome p450 protein is an inhibitor of the activity of said cytochrome p450 protein.

152. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for the use of embodiment 151, wherein said cytochrome p450 protein is CYP3A 4.

153. The therapeutically effective amount of tegaininib or a salt or solvate thereof for the use according to embodiment 152, wherein said compound that inhibits the activity of CYP3a4 is itraconazole.

154. The therapeutically effective amount of Tucaninib, or a salt or solvate thereof, for said use according to embodiment 151, wherein said cytochrome p450 protein is CYP2C 8.

155. The therapeutically effective amount of tegaserod, or a salt or solvate thereof, for the use according to embodiment 154, wherein the compound that inhibits CYP2C8 is gemfibrozil.

156. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for the use according to any one of embodiments 145-150, wherein said compound modulating the activity of said cytochrome p450 protein is an inducer of the activity of said cytochrome p450 protein.

157. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use according to embodiment 156, wherein said cytochrome p450 protein is CYP3A 4.

158. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use according to embodiment 156, wherein said cytochrome p450 protein is CYP2C 8.

159. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for the use according to any one of embodiments 156-158, wherein said compound inducing the activity of said cytochrome p450 protein is rifampicin.

160. A therapeutically effective amount of tegaserod, or a salt or solvate thereof, for use in treating breast cancer in a subject, wherein the subject is not being concurrently treated with a therapeutically effective amount of a compound that modulates the activity of a cytochrome p450 protein.

161. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use according to embodiment 160, wherein said subject has not received treatment with said compound that modulates activity of said cytochrome p450 protein within the last 7 days.

162. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use according to embodiment 160, wherein said subject has not received treatment with said compound that modulates activity of said cytochrome p450 protein within the last 3 months.

163. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use according to embodiment 160, wherein said subject has not received treatment with said compound that modulates activity of said cytochrome p450 protein within the past 12 months.

164. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use according to embodiment 160, wherein said subject has not previously been treated with a compound that modulates activity of said cytochrome p450 protein.

165. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for the use according to any one of embodiments 160-164, wherein said compound that modulates the activity of said cytochrome p450 protein is an inhibitor of the activity of said cytochrome p450 protein.

166. The therapeutically effective amount of Tucaninib, or a salt or solvate thereof, for said use according to embodiment 165, wherein said cytochrome p450 protein is CYP3A 4.

167. The therapeutically effective amount of tegaininib or a salt or solvate thereof for the use according to embodiment 166, wherein said compound that inhibits the activity of CYP3a4 is itraconazole.

168. The therapeutically effective amount of Tucaninib, or a salt or solvate thereof, for said use according to embodiment 165, wherein said cytochrome p450 protein is CYP2C 8.

169. The therapeutically effective amount of tegaserod, or a salt or solvate thereof, for the use according to embodiment 168, wherein the compound that inhibits the activity of CYP2C8 is gemfibrozil.

170. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for the use according to any one of embodiments 160-164, wherein said compound that modulates the activity of said cytochrome p450 protein is an inducer of the activity of said cytochrome p450 protein.

171. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use of embodiment 170, wherein said cytochrome p450 protein is CYP3A 4.

172. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use of embodiment 170, wherein said cytochrome p450 protein is CYP2C 8.

173. The therapeutically effective amount of Tucaninib, or a salt or solvate thereof, for use according to any one of embodiments 170-172, wherein said compound that induces the activity of said cytochrome p450 protein is rifampicin.

174. The therapeutically effective amount of tocaininib, or a salt or solvate thereof, for the use according to any one of embodiments 113-173, wherein tocaininib is administered to the subject at a dose of about 150mg to about 650 mg.

175. The therapeutically effective amount of iconinib or a salt or solvate thereof for the use of embodiment 174, wherein the subject is administered with approximately 300mg of iconinib at a dose.

176. The therapeutically effective amount of iconinib or a salt or solvate thereof for the use of embodiment 174 or embodiment 63, wherein iconazole is administered once or twice daily.

177. The therapeutically effective amount of tucaninib, or a salt or solvate thereof, for said use according to embodiment 176, wherein tucaninib is administered to said subject at a dose of about 300mg twice daily.

178. The therapeutically effective amount of tocaininib, or a salt or solvate thereof, for the use according to any one of embodiments 113-177, wherein tocaininib is orally administered to the subject.

179. The therapeutically effective amount of Tucaninib, or a salt or solvate thereof, for use according to any one of embodiments 113-178, wherein the breast cancer is HER2 positive breast cancer.

180. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use of embodiment 179, wherein said cancer is HER2 positive as determined using in situ hybridization, fluorescence in situ hybridization, or immunohistochemistry.

181. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for the use according to any one of embodiments 113-180, wherein said breast cancer is metastatic.

182. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use of embodiment 181, wherein said breast cancer has metastasized to the brain.

183. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for the use according to any one of embodiments 113-182, wherein the breast cancer is locally advanced.

184. The therapeutically effective amount of tocaintinib, or a salt or solvate thereof, for said use according to any one of embodiments 113-183, wherein said breast cancer is unresectable.

185. A therapeutically effective amount of tocaintinib, or a salt or solvate thereof, for said use according to any one of embodiments 113-184, wherein tocaintinib is for administration, or is administered in combination with one or more additional therapeutic agents for the treatment of said breast cancer.

186. The therapeutically effective amount of tegasertib or a salt or solvate thereof for the use according to embodiment 185, wherein the one or more additional therapeutic agents is selected from capecitabine and an anti-HER 2 antibody.

187. The therapeutically effective amount of tegasertib or a salt or solvate thereof for the use according to embodiment 185, wherein the one or more additional therapeutic agents is capecitabine.

188. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for said use according to embodiment 185, wherein said one or more additional therapeutic agents is trastuzumab.

189. The therapeutically effective amount of tegasertib or a salt or solvate thereof for the use according to embodiment 185, wherein the one or more additional therapeutic agents is capecitabine and trastuzumab.

190. A therapeutically effective amount of tegaininib or a salt or solvate thereof for the use according to embodiment 187 or embodiment 189, wherein capecitabine is present at about 500mg/m²To about 1500mg/m²Is administered to the subject.

191. The therapeutically effective amount of tegaininib or a salt or solvate thereof for the use according to embodiment 190, wherein capecitabine is added at about 1000mg/m²Is administered to the subject.

192. The therapeutically effective amount of tegasertib or a salt or solvate thereof for the use according to embodiment 190 or embodiment 191, wherein capecitabine is administered orally to the subject.

193. The therapeutically effective amount of tegasertib or a salt or solvate thereof for use according to any one of embodiments 189-192, wherein capecitabine is administered to the subject twice daily.

194. The therapeutically effective amount of tuchatinib, or a salt or solvate thereof, for the use according to embodiment 188 or embodiment 189, wherein trastuzumab is administered to the subject at a dose of about 400mg to about 800 mg.

195. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for the use of embodiment 194, wherein trastuzumab is administered to the subject at a dose of about 600 mg.

196. The therapeutically effective amount of Tucurinib, or a salt or solvate thereof, for the use of embodiment 194 or embodiment 195, wherein trastuzumab is administered subcutaneously to the subject.

197. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for the use of embodiment 188 or embodiment 189, wherein trastuzumab is administered to the subject at a dose of about 4mg/kg to about 10 mg/kg.

198. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for the use according to embodiment 197, wherein trastuzumab is administered to the subject at a dose of about 6 mg/kg.

199. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for the use according to embodiment 197, wherein trastuzumab is administered to the subject at a dose of about 8 mg/kg.

200. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for the use according to embodiment 197, wherein trastuzumab is administered to the subject at an initial dose of about 8mg/kg followed by a subsequent dose of about 6 mg/kg.

201. A therapeutically effective amount of cartilaginib, or a salt or solvate thereof, for use according to any one of embodiments 197-200, wherein trastuzumab is administered intravenously.

202. A therapeutically effective amount of tegasertib or a salt or solvate thereof for use according to any of embodiments 194-201, wherein trastuzumab is administered about once every 1 week, about once every 2 weeks, about once every 3 weeks or about once every 4 weeks.

203. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for the use according to embodiment 202, wherein trastuzumab is administered about once every 3 weeks.

204. The therapeutically effective amount of tucaninib, or a salt or solvate thereof, for the use according to embodiment 189, wherein tucaninib, capecitabine, and trastuzumab are administered to the subject on a 21 day treatment cycle.

205. The therapeutically effective amount of iconinib or a salt or solvate thereof for the use according to embodiment 204, wherein on each day of the 21-day treatment cycle, iconinib is administered to the subject twice daily.

206. The therapeutically effective amount of tegasertib or a salt or solvate thereof for the use according to embodiment 204 or 205, wherein capecitabine is administered to the subject twice daily on each of days 1-14 of the 21-day treatment cycle.

207. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for the use according to any one of embodiments 204-206, wherein trastuzumab is administered to the subject once every 21 days of the treatment cycle.

208. The therapeutically effective amount of tuchatinib, or a salt or solvate thereof, for the use according to embodiment 207, wherein the dose of trastuzumab during the first 21-day treatment cycle is 8mg/kg and the dose of trastuzumab during the subsequent 21-day treatment cycle is 6 mg/kg.

209. The therapeutically effective amount of cartilaginib, or a salt or solvate thereof, for use according to any one of embodiments 113-208, wherein the subject has been previously treated with one or more additional therapeutic agents for the breast cancer.

210. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for the use of embodiment 209, wherein said one or more additional therapeutic agents is an anti-HER 2 antibody or an anti-HER 2 antibody-drug conjugate.

211. The therapeutically effective amount of Tucotinib or a salt or solvate thereof for the use according to embodiment 210, wherein said one or more additional therapeutic agents is trastuzumab, pertuzumab, and/or T-DM 1.

212. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for said use according to any one of embodiments 113-211, wherein said subject has not been treated with another therapeutic agent for said breast cancer within the past 12 months.

213. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for said use according to any one of embodiments 113-208, wherein said subject has not previously been treated with another therapeutic agent for said breast cancer.

214. The therapeutically effective amount of Tucanitinib, or a salt or solvate thereof, for said use according to any one of embodiments 113-213, wherein said subject has not previously been treated with lapatinib, lenatinib, afatinib or capecitabine.

215. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for the use according to any one of embodiments 113-214, wherein treating the subject results in a Tumor Growth Inhibition (TGI) index of at least about 85%.

216. The therapeutically effective amount of Tucotinib, or a salt or solvate thereof, for the use according to any one of embodiments 113-214, wherein treating the subject results in a TGI index of about 100%.

217. The therapeutically effective amount of cartinib, or a salt or solvate thereof, for said use according to any one of embodiments 113-216, wherein one or more therapeutic effects in said subject is improved relative to baseline following administration of cartinib to said subject.

218. A therapeutically effective amount of tegaininib or a salt or solvate thereof for the use according to embodiment 217, wherein said one or more therapeutic effects is selected from the group consisting of: size, objective response rate, duration of response, time to response, progression-free survival and overall survival of tumors derived from the breast cancer.

219. The therapeutically effective amount of cartilaginib, or a salt or solvate thereof, for use according to any one of embodiments 113-218, wherein the size of the tumor derived from the breast cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70% or at least about 80% relative to the size of the tumor derived from the breast cancer prior to administration of cartilaginib to the subject.

220. The therapeutically effective amount of tembotinib, or a salt or solvate thereof, for said use according to any one of embodiments 113-219, wherein the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70% or at least about 80%.

221. The therapeutically effective amount of cartinib, or a salt or solvate thereof, for said use according to any one of embodiments 113-220, wherein said subject exhibits a progression free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of cartinib to said subject.

222. The therapeutically effective amount of cartinib, or a salt or solvate thereof, for said use according to any one of embodiments 113-221, wherein said subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of cartinib to said subject.

223. The therapeutically effective amount of tucaninib, or a salt or solvate thereof, for said use according to any one of embodiments 113-222, wherein the duration of the response to tucaninib is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of tucaninib to said subject.

224. A therapeutically effective amount of cartilaginib, or a salt or solvate thereof, for use according to any one of embodiments 113 and 223, wherein the subject is a human.

225. Use of a therapeutically effective amount of Tucotinib or a salt or solvate thereof, for the manufacture of a medicament for treating breast cancer in a subject, wherein said subject is not being concurrently treated with a therapeutically effective amount of a substrate for multidrug and toxin efflux (MATE) protein.

226. The use of embodiment 225, wherein the subject has not received treatment with the substrate of the MATE protein within the past 7 days.

227. The use of embodiment 225, wherein the subject has not received treatment with the substrate of the MATE protein within the past 3 months.

228. The use of embodiment 225, wherein the subject has not received treatment with the substrate of the MATE protein within the past 12 months.

229. The use of embodiment 225, wherein the subject has not previously been treated with the substrate of the MATE protein.

230. The use of any one of embodiments 225-229, wherein said MATE protein is MATE 1.

231. The use of any one of embodiments 225-229, wherein said MATE protein is MATE 2K.

232. The use according to any one of embodiments 225-231, wherein the substrate of the MATE protein is selected from the group consisting of metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin and pyrimethamine.

233. The use of embodiment 232, wherein the substrate is metformin.

234. Use of a therapeutically effective amount of Tucotinib or a salt or solvate thereof, for the manufacture of a medicament for treating breast cancer in a subject, wherein said subject is not being concurrently treated with a therapeutically effective amount of a substrate of Organic Cation Transporter (OCT).

235. The use of embodiment 234, wherein the subject has not received treatment with the substrate of the OCT within the past 7 days.

236. The use of embodiment 234, wherein the subject has not received treatment with the substrate of the OCT within the past 3 months.

237. The use of embodiment 234, wherein the subject has not received treatment with the substrate of the OCT protein within the past 12 months.

238. The use of embodiment 234, wherein the subject has not previously been treated with the substrate of the OCT.

239. The use according to any one of embodiments 234-238, wherein the OCT is OCT 1.

240. The use according to any one of embodiments 234-238, wherein the OCT is OCT 2.

241. The use according to any one of embodiments 234-240, wherein said substrate of said OCT is selected from the group consisting of metformin, oxazolidinone, fexofenadine, Tetraethylammonium (TEA), N-methylphenylpyridinium (MPP +), paraquat, agmatine, cimetidine, procainamide, pramipexole, atenolol, 5-hydroxytryptamine, quinidine, verapamil, cisplatin, oxaliplatin and pyrimethamine.

242. The use according to embodiment 241, wherein the substrate is metformin.

243. The use according to any one of embodiments 234-242, wherein the subject is not being concurrently treated with a therapeutically effective amount of a substrate for MATE protein.

244. The use of embodiment 243, wherein said subject has not received treatment with said substrate of said MATE protein within the last 7 days.

245. The use of embodiment 243, wherein said subject has not received treatment with said substrate of said MATE protein within the last 3 months.

246. The use of embodiment 243, wherein said subject has not received treatment with said substrate of said MATE protein within the past 12 months.

247. The use of embodiment 243, wherein said subject has not previously received treatment with said substrate of said MATE protein.

248. The use according to any one of embodiments 243-247, wherein the MATE protein is MATE 1.

249. The use according to any one of embodiments 243-247, wherein the MATE protein is MATE 2K.

250. Use of a therapeutically effective amount of Tucotinib or a salt or solvate thereof, for the manufacture of a medicament for treating breast cancer in a subject, wherein said subject has no impaired renal function.

251. The use of embodiment 250, wherein the subject has not suffered an impairment of renal function within the past 12 months.

252. The use of any one of embodiments 225-249, wherein the subject has no impaired renal function.

253. The use of embodiment 252, wherein the subject has not suffered an impairment of renal function within the past 12 months.

254. The use of any one of embodiments 250-253, wherein impaired renal function is determined based on serum creatinine levels in the subject.

255. The use of embodiment 254, wherein a) the subject is male and the subject has a serum creatinine level less than 1.5mg/dL or b) the subject is female and has a serum creatinine level less than to 1.4 mg/dL.

256. The use of any one of embodiments 250-253, wherein impaired renal function is determined based on the subject having an abnormal creatinine clearance rate.

257. The use of any one of embodiments 250-253, wherein impaired renal function is determined based on the glomerular filtration rate of the subject.

258. The use according to any one of embodiments 225-257, wherein the subject is not being concurrently treated with a therapeutically effective amount of a compound that modulates the activity of a cytochrome p450 protein.

259. The use of embodiment 258, wherein the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the past 7 days.

260. The use of embodiment 258, wherein the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the past 3 months.

261. The use of embodiment 258, wherein the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the past 12 months.

262. The use of embodiment 258, wherein the subject has not previously been treated with a compound that modulates the activity of the cytochrome p450 protein.

263. The use according to any one of embodiments 258-262, wherein said compound modulating the activity of said cytochrome p450 protein is an inhibitor of the activity of said cytochrome p450 protein.

264. The use of embodiment 263, wherein the cytochrome p450 protein is CYP3a 4.

265. The use of embodiment 264, wherein the compound that inhibits the activity of CYP3a4 is itraconazole.

266. The use of embodiment 263, wherein the cytochrome p450 protein is CYP2C 8.

267. The use of embodiment 266, wherein the compound that inhibits the activity of CYP2C8 is gemfibrozil.

268. The use according to any one of embodiments 258-262, wherein said compound modulating the activity of said cytochrome p450 protein is an inducer of the activity of said cytochrome p450 protein.

269. The use of embodiment 268, wherein the cytochrome p450 protein is CYP3a 4.

270. The use of embodiment 268, wherein the cytochrome p450 protein is CYP2C 8.

271. The use according to any one of embodiments 268-270, wherein said compound inducing the activity of said cytochrome p450 protein is rifampicin.

272. Use of a therapeutically effective amount of Tucotinib or a salt or solvate thereof, for the manufacture of a medicament for treating breast cancer in a subject, wherein said subject is not being concurrently treated with a therapeutically effective amount of a compound that modulates the activity of cytochrome p450 protein.

273. The use of embodiment 4272, wherein the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the last 7 days.

274. The use of embodiment 272, wherein the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the past 3 months.

275. The use of embodiment 272, wherein the subject has not received treatment with the compound that modulates the activity of the cytochrome p450 protein within the past 12 months.

276. The use of embodiment 272, wherein the subject has not previously been treated with a compound that modulates the activity of the cytochrome p450 protein.

277. The use according to any one of embodiments 272-276, wherein the compound modulating the activity of the cytochrome p450 protein is an inhibitor of the activity of the cytochrome p450 protein.

278. The use of embodiment 277, wherein the cytochrome p450 protein is CYP3a 4.

279. The use of embodiment 278, wherein the compound that inhibits the activity of CYP3a4 is itraconazole.

280. The use of embodiment 277, wherein the cytochrome p450 protein is CYP2C 8.

281. The use of embodiment 280, wherein the compound that inhibits the activity of CYP2C8 is gemfibrozil.

282. The use according to any one of embodiments 272-276, wherein the compound modulating the activity of the cytochrome p450 protein is an inducer of the activity of the cytochrome p450 protein.

283. The use of embodiment 282, wherein said cytochrome p450 protein is CYP3a 4.

284. The use of embodiment 282, wherein said cytochrome p450 protein is CYP2C 8.

285. The use according to any one of embodiments 282-284, wherein said compound that induces the activity of said cytochrome p450 protein is rifampicin.

286. The use of any one of embodiments 225-285, wherein the cartinib is administered to the subject in a dose of about 150mg to about 650 mg.

287. The use of embodiment 286, wherein the procatinib is administered to the subject at a dose of about 300 mg.

288. The use of embodiment 286 or embodiment 287, wherein the cartinib is administered once or twice daily.

289. The use of embodiment 288, wherein the subject is administered the cartinib at a dose of about 300mg twice daily.

290. The use according to any one of embodiments 225-289, wherein the licarbatinib is administered orally to the subject.

291. The use according to any one of embodiments 225-290, wherein the breast cancer is HER2 positive breast cancer.

292. The use of embodiment 291, wherein the cancer is HER2 positive as determined using in situ hybridization, fluorescence in situ hybridization, or immunohistochemistry.

293. The use according to any one of embodiments 225-292, wherein the breast cancer is metastatic.

294. The use of embodiment 293, wherein the breast cancer has metastasized to the brain.

295. The use according to any one of embodiments 225-7294, wherein the breast cancer is locally advanced.

296. The use according to any one of embodiments 225-295, wherein the breast cancer is unresectable.

297. The use according to any one of embodiments 225-296, wherein the medicament is for use in combination with one or more additional therapeutic agents for the treatment of the breast cancer.

298. The use of embodiment 297, wherein the one or more additional therapeutic agents are selected from capecitabine and an anti-HER 2 antibody.

299. The use of embodiment 297, wherein the one or more additional therapeutic agents is capecitabine.

300. The use of embodiment 297, wherein the one or more additional therapeutic agents is trastuzumab.

301. The use of embodiment 297, wherein the one or more additional therapeutic agents are capecitabine and trastuzumab.

302. The use of embodiment 299 or embodiment 301, wherein capecitabine is administered at about 500mg/m²To about 1500mg/m²Is administered to the subject.

303. The use of embodiment 302, wherein capecitabine is administered at about 1000mg/m²Is administered to the subject.

304. The use of embodiment 302 or embodiment 303, wherein capecitabine is administered orally to said subject.

305. The use according to any one of embodiments 301-304, wherein capecitabine is administered to the subject twice daily.

306. The use of embodiment 300 or embodiment 7301, wherein trastuzumab is administered to the subject at a dose of about 400mg to about 800 mg.

307. The use of embodiment 306, wherein trastuzumab is administered to the subject at a dose of about 600 mg.

308. The use of embodiment 306 or embodiment 307, wherein trastuzumab is administered subcutaneously to the subject.

309. The use of embodiment 300 or embodiment 301, wherein trastuzumab is administered to the subject at a dose of about 4mg/kg to about 10 mg/kg.

310. The use of embodiment 309, wherein trastuzumab is administered to the subject at a dose of about 6 mg/kg.

311. The use of embodiment 309, wherein trastuzumab is administered to the subject at a dose of about 8 mg/kg.

312. The use of embodiment 309, wherein trastuzumab is administered to the subject at an initial dose of about 8mg/kg followed by a subsequent dose of about 6 mg/kg.

313. The use according to any one of embodiments 309-312, wherein trastuzumab is administered intravenously.

314. The use according to any one of embodiments 306-313, wherein trastuzumab is administered about once every 1 week, about once every 2 weeks, about once every 3 weeks, or about once every 4 weeks.

315. The use of embodiment 314, wherein trastuzumab is administered about once every 3 weeks.

316. The use of embodiment 301, wherein the capecitabine, and trastuzumab are administered to the subject in a 21 day treatment cycle.

317. The use of embodiment 316, wherein the procatinib is administered to the subject twice daily on each day of the 21-day treatment cycle.

318. The use of embodiment 316 or 317, wherein capecitabine is administered to the subject twice daily on each of days 1-14 of the 21-day treatment cycle.

319. The use according to any one of embodiments 316-318, wherein trastuzumab is administered to the subject once every 21 days of the treatment cycle.

320. The use of embodiment 319, wherein the dose of trastuzumab during the first 21-day treatment cycle is 8mg/kg and the dose of trastuzumab during the subsequent 21-day treatment cycle is 6 mg/kg.

321. The use according to any one of embodiments 225-320, wherein the subject has been previously treated with one or more additional therapeutic agents for the breast cancer.

322. The use of embodiment 321, wherein the one or more additional therapeutic agents is an anti-HER 2 antibody or an anti-HER 2 antibody-drug conjugate.

323. The use of embodiment 322, wherein the one or more additional therapeutic agents is trastuzumab, pertuzumab, and/or T-DM 1.

324. The use according to any one of embodiments 225-323, wherein the subject has not been treated with another therapeutic agent for the breast cancer within the past 12 months.

325. The use according to any one of embodiments 225-320, wherein the subject has not been previously treated with another therapeutic agent for the breast cancer.

326. The use according to any one of embodiments 225-325, wherein the subject has not been previously treated with lapatinib, lenatinib, afatinib, or capecitabine.

327. The use of any one of embodiments 225-326, wherein treating the subject results in a Tumor Growth Inhibition (TGI) index of at least about 85%.

328. The use according to any one of embodiments 225-326, wherein treating the subject results in a TGI index of about 100%.

329. The use of any one of embodiments 225-328, wherein the one or more therapeutic effects in the subject are improved relative to baseline following administration of cartinib to the subject.

330. The use of embodiment 329, wherein the one or more therapeutic effects are selected from: size, objective response rate, duration of response, time to response, progression-free survival and overall survival of tumors derived from the breast cancer.

331. The use according to any one of embodiments 225-330, wherein the size of the tumor derived from the breast cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70% or at least about 80% relative to the size of the tumor derived from the breast cancer prior to administration of cartilaginib to the subject.

332. The use according to any one of embodiments 225-331, wherein the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%.

333. The use according to any one of embodiments 225-332, wherein the subject exhibits progression free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years following administration of cartinib to the subject.

334. The use of any one of embodiments 225-333, wherein the subject exhibits an overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of cartinib to the subject.

335. The use of any one of embodiments 225-334, wherein the duration of the response to cartinib is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after administration of cartinib to the subject.

336. The use according to any one of embodiments 225-335, wherein the subject is a human.

The invention will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the invention. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.

Examples

Example 1: phase I drug-drug pair of Tucanitinib in healthy subjects receiving MATE1/2K substrate Study of physical interactions

Tucaninib is a potent, selective, Adenosine Triphosphate (ATP) competitive small molecule inhibitor of the receptor tyrosine kinase HER 2. In clinical trials for treating patients with advanced solid tumors, including HER2+ breast cancer, the use of icaritinib as a single agent or in combination with capecitabine and trastuzumab, was studied (see, e.g., HER2CLIMB clinical trial (clinical trials. gov Identifier # NCT 02614794)).

Drug-drug interactions may have a significant impact on the efficacy and toxicity of therapeutic agents administered to cancer patients. In the proximal tubule, the basal drug is transported from the renal cells to the tubule lumen by the synergistic effect of H +/organic cation antiporter, multidrug and toxin efflux proteins 1(MATE1) and 2K (MATE 2K). Inhibitors of MATE transporters have been shown to have clinically relevant effects on the Pharmacokinetics (PK) of concomitantly administered drugs such as metformin.

Metformin is a commonly used oral hypoglycemic agent for type 2 diabetes. In drug-drug interaction (DDI) studies conducted during development of inhibitors of OCT and/or MATE, the drugs are also commonly used as in vivo OCT2/MATE1/MATE2K probes.

In vitro evaluation of the activity of Tucotinib to inhibit Organic Cation Transporter (OCT)2, Breast cancer drug resistance protein (BCRP) and bile acid salt export Pump (BSEP), with 50% Inhibitory Concentration (IC)₅₀) The values were 14.7. mu.M, 8.98. mu.M and 8.48. mu.M, respectively. Tucotinib also inhibits MATE1 in vitroAnd MATE2K transporter, which inhibits IC₅₀The values were 0.34. mu.M and 0.14. mu.M, respectively.

Tucanitinib has the potential to affect the PK of drugs affected by OCT2/MATE1/MATE2K molecules. Given the importance of these pathways to drug metabolism, it is important to understand how charatinib acts on these molecules to more accurately understand their potential drug-drug interaction potential. This is important in view of the large number of treatments that may be prescribed to cancer patients.

Method

A phase 1, single-center, open label, fixed sequence, drug-drug interaction (DDI) study was performed to evaluate the effect of tegaininib on the pharmacokinetics of metformin in healthy male and female subjects.

The primary objective of this study was to evaluate the effect of multiple bid oral doses of vecatinib on a single dose PK of metformin, a substrate for multidrug and toxin efflux protein (MATE) 1/2K. Secondary objectives of the study included: in the study subjects, metformin was evaluated for safety and tolerability when co-administered with tucaninib; assessing the effect of picatinib on renal function using iohexol as a GFR marker; and assessing PK of the plurality of bid oral doses of cartilaginib (e.g., a valley PK profile).

18 healthy subjects were recruited to complete treatment and evaluation as shown in figure 1. Subjects were allowed to enter the clinical study center in the afternoon of day-1 (which is the day of first drug administration, i.e., the day prior to day 1). They were discharged on day 9 after completion of the hospitalization assessment. After discharge, subjects returned to the clinical study center for an out-patient follow-up on day 16. Of the 18 subjects, 17 completed the study for evaluation of PK and PD profiles.

On days 1 and 8, each subject received oral administration of 850mg metformin and a 3 hour oral glucose tolerance test in the morning after at least an overnight fast of ≧ 8 hours. Each subject was also given 1500mg of iohexol (contrast agent and GFR marker for plasma clearance testing) push injections 10 hours after metformin administration over 5 minutes on days 1 and 8. On days 2-8, each subject received oral administration of 300mg of cartinib in 2x150mg tablets, twice daily (bid) (approximately 12 hours apart). Morning doses of Tucanitinib were administered on days 2 and 8 after an overnight fast of 8 hours or more. On day 8, morning doses of tocaintinib were administered immediately after metformin administration. The tocainib and metformin are provided in an oral tablet, and iohexol is provided in a solution of suitable concentration.

Safety assessments and blood/urine samples for pharmacokinetic/pharmacodynamic (PK/PD) determinations were performed from day-1 to day 9 according to the schedule shown in figure 1. PK endpoints include: plasma picatinib (and metabolite ONT-993) trough concentrations, plasma and urine concentrations of metformin, plasma PK parameters of metformin estimated using non-compartmental analysis (NCA) (e.g., maximum plasma concentration (Cmax), time to maximum plasma concentration (tmax), half-life (t1/2), area under plasma concentration-time curve from time 0 to the last available measurement (AUC0-last), area under plasma concentration-time curve extrapolated from time 0 to infinity (AUC0-inf), Clearance (CL), apparent volume of distribution (Vz/F) and oral clearance (CL/F)), picatinib trough concentrations and iohexol plasma clearance. The PD endpoint was assessed by: a 3 hour oral glucose tolerance test (OGTT, at 75 g) was performed 2 hours after metformin administration with or without tucatinib and serum levels of creatinine and cystatin C and 24 hours urinary creatinine and microalbumin levels were measured. Safety endpoints include Adverse Event (AE) assessment, clinical laboratory tests, vital sign measurements, 12-lead Electrocardiogram (ECG), and physical examination.

Clinical laboratory tests measured the following parameters: (1) hematology, including Red Blood Cells (RBCs), differential White Blood Cells (WBCs) (neutrophils, eosinophils, lymphocytes, monocytes, and basophils), hemoglobin, hematocrit, and platelet count; (2) blood chemistry including sodium, potassium, chloride, bicarbonate, creatinine, Creatine Kinase (CK), amylase, lipase, glucose (fasting), urea, albumin, calcium, magnesium, inorganic phosphorus, alkaline phosphatase, ASAT (aspartate aminotransferase), ALAT (alanine aminotransferase), total bilirubin, indirect and direct bilirubin, total protein, total cholesterol, High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), triglycerides, and uric acid; and (3) urinalysis: a mid-section, clean-up captured urine sample was collected for dipstick analysis (to be captured in the database) of protein, blood, glucose, WBC and pH. Additionally, urine was collected for evaluation of the following drugs of abuse: alcohol, cannabinoids, amphetamines, opioids, methadone, cocaine, cotinine, benzodiazepines and barbiturates. The results were reviewed before dosing on day 1. Serology was collected for measurement of HIV-1 and HIV-2 antibodies, hepatitis B surface antigen and hepatitis C antibody. For women, serum pregnancy tests were collected and the results were reviewed prior to dosing on day 1.

Inclusion criteria for a qualified subject include the following: (1) male or female with no fertility potential; (2) 18 to 65 years old (inclusive) at screening; (3) body Mass Index (BMI) of 18.0-32.0kg/m²(inclusive); (4) the weight is more than or equal to 60 kg; (5) the state is healthy. State health is defined as the absence of any clinically significant, active or chronic evidence of disease after detailed medical and surgical history, complete physical examination (including vital signs), 12-lead ECG, hematology, blood chemistry, serology and urinalysis; (6) capable and willing to discard alcoholic, caffeine and xanthine-containing beverages or foods (e.g., coffee, tea, cola, chocolate, energy drinks) from 48 hours (2 days) before each admission to the clinic to leave the study (including office vacation); (7) all values for hematologic and clinical chemistry tests of blood and urine were within the upper 1.5x normal range or showed no clinically relevant deviation; (8) men sexually active with women having fertility potential and not surgically infertile for at least 90 days must agree to use a barrier method of birth control for the duration of the study plus 3 months after receiving the end-dose study medication, such as condoms or companions using an occlusive cap (septum or cervical cap/domed cap) containing spermicidal foam/gel/film/cream/suppository, and all men must not donate sperm during the study and within 3 months after receiving the end-dose study medication. In addition, their female partners should be considered for at least the same duration Using additional methods of birth control (which may include hormonal methods, intrauterine devices [ IUDs ]]Or intrauterine systems [ IUS ]]) (ii) a And (9) all non-conventional medications (including over-the-counter medications, health supplements, and herbal therapies such as st. john's herbal extract) must be discontinued at least 28 days before admission to the clinical research center. An exception is acetaminophen (paracetamol), which is allowed until admission to the clinical research center.

Exclusion criteria included the following: (1) a female with childbearing potential; (2) a female who is nursing; (3) the female partner was pregnant, nursing or a male scheduled to attempt pregnancy during the study or within 90 days after study drug administration; (4) any investigational drug or device used within 30 days after the first dose of investigational drug; (5) any disease or medical condition that poses an unacceptable risk to a subject; (6) any condition that may affect drug absorption (including gastric or intestinal surgery); (7) a significant history of metabolic, allergic, cutaneous, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorders; (8) hypersensitivity, intolerance or history of allergy to any pharmaceutical compound, food or other substance; (9) tobacco products were used within 28 days prior to admission; (10) daily or long-term use of more than 3 grams of acetaminophen per day; (11) heavy physical work, sunbathing and physical exposure programs were performed 48 hours (2 days) before (first) admission to the clinical site and for the duration of the study; (12) transfusion within 90 days of study drug administration; (13) inability to venipuncture and/or tolerate venous access (venous access); (14) within 8 weeks of initial study drug administration, blood was donated to blood banks or in clinical studies (except screening visits); (15) a history of donations of more than 450mL of blood within 60 days prior to administration in a clinical research center, or scheduled donations 30 days prior to the past day after administration of a study drug; (16) donated plasma or platelets within 7 days of initial study drug administration; (17) history of alcohol or drug abuse within 2 years; (18) a history of alcohol consumption by female subjects over 7 standard cups per week or by male subjects over 14 cups per week. Drinking was prohibited 48 hours prior to admission to the clinical site and throughout the study until discharge; (19) any prescribed medication was used or intended to be used within 28 days prior to the initial dose of study treatment; (20) positive screening test for hepatitis b surface antigen (HBsAg), anti-Hepatitis C Virus (HCV) antibody, or anti-Human Immunodeficiency Virus (HIV)1 and 2 antibody; (21) acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma; and (22) renal disease or dysfunction (e.g., as indicated by serum creatinine levels ≧ 1.5mg/dL [ male ], > 1.4mg/dL [ female ], or abnormal creatinine clearance).

Results

As shown in figure 2, metformin C at steady state after metformin and vectinib combined administration on day 8_maxPlasma concentrations were higher than metformin C after metformin alone on day 1_maxPlasma concentrations, with a similarly shaped curve after both treatments.

As shown in FIG. 3, the plasma concentrations of iohexol after administration were higher than the lower limit of quantitation (LLOQ: 5. mu.g/mL) in all subjects on days 1 and 8 within 4 hours after administration, and the mean iohexol plasma concentrations were similar.

As shown in fig. 4, a steady state plasma concentration of chart caritinib was reached by day 6.

Pharmacokinetic parameters

Iohexol

The mean iohexol PK parameters were similar after co-administration of both vecatinib and metformin compared to metformin alone. Use ofAndthe estimated aGFR of the Mortens equation remains constant (94.99 mL/min/1.73m for metformin alone)²In contrast, 94.56mL/min/1.73m for metformin plus Tunicanib²)。

Metformin

Arithmetic mean metformin C compared to metformin alone after co-administration of ceratinib with metformin_max、AUC_0-lastAnd AUC_0-infIncrease by 1.102 times, 1.376 times and 1.409 times respectively. The exposure variability (CV%) for both treatments was generally lower (ranging from 18.0% to 30.5%). Median T of metformin at steady state after combined administration with Tomentinib, compared to metformin alone (2.500 hours) _maxSlightly delayed (3.000 hours). Although metformin T_maxThe range was similar (1.50 to 4.00 hours for metformin alone; 1.00 to 4.07 hours for the combination), but most subjects showed T after combination therapy_maxThe delay of (2). Average terminal elimination half-life (t) after combination therapy compared to metformin alone (4.546 hours)_1/2) Appearing slightly longer (5.569 hours). In the presence of Pointinib, the average CL/F decreased from 105.4L/h to 77.4L/h, while the average apparent distribution volume (Vz/F) decreased slightly from 695.4L to 627.2L (Table 1).

Table 1: summary statistics of plasma metformin pharmacokinetic parameters

Summary statistics of plasma metformin pharmacokinetic parameters

^aFor T_maxThe median (range) is presented instead of the arithmetic mean (CV%).

Statistical analysis of pharmacokinetic parameters

Co-administration with Tucanitinib on plasma metformin C_maxThere was no significant effect because the geometric LS mean of metformin (tested) relative to metformin alone (reference) after co-administration with carteninib was close to 1 and 90% CI was contained within the standard dead zone (no-effect boundary) of (0.80, 1.25). Co-administration of metformin and Tucotinib resulted in plasma metformin AUC _0-lastAnd AUC_0-infApproximately 1.357 and 1.387 times higher, respectively (table 2), with 90% CI above the standard dead zone.

Table 2: effect of Pottinib on metformin pharmacokinetic parametersStatistical analysis

Statistical analysis of the effects of Tucotinib on metformin pharmacokinetic parameters

Based on comparison, co-administration of ceratinib resulted in metformin AUC_0-lastAnd AUC_0-infHas a statistically significant increase in exposure, but C_maxNone. CL/F and CL of metformin_{Kidney (Kidney)}The decrease in value is consistent with an increase in exposure. Considering that the administration of picatinib did not reduce aGFR (as measured by iohexol) or eGFR (as calculated using cystatin C), the CL for metformin_{Kidney (Kidney)}The reduction in (D) is consistent with specific inhibition of MATE1/MATE2-K renal efflux transporter. However, since AUC is less than 2-fold inhibited, charatinib is classified as a weak inhibitor of these transporters.

Conclusion

When metformin was co-administered with vectinib, a statistically significant increase in metformin exposure was observed, as well as CL/F and CL_{Kidney (Kidney)}Consistent with the inhibition of renal secretion of metformin by tocatinib. In addition, an increase in mean serum creatinine was observed after multiple doses of cartinib; however, measures of renal function including aGFR (as assessed by iohexol) and urinary albumin levels were not affected. These results are consistent with the role of Tucaninib as a weak inhibitor of the renal OCT2/MATE1/MATE2-K pathway and indicate that Tucaninib does not cause renal injury.

Example 2: in healthy subjects receiving substrates for CYP3A4, CYP2C8, CYP2C9 and P-glycoprotein Study of phase 1 drug-drug interactions for Tucotinib

Drug-drug interactions of tocaininib with substrates for CYP3a4, CYP2C8, CYP2C9, and P-glycoprotein were evaluated. It is predicted that cartinib has good to moderate stability with respect to liver metabolism across species, and that it is metabolized in human liver primarily by cytochrome P450(CYP)2C8 to produce the metabolite ONT-993. Tucaninib inhibited CYP2C8, CYP2C9 and CYP3A4 in vitro with Ki values of 0.17. mu.M, 4.57. mu.M and 0.81. mu.M, respectively, but no time-dependent inhibition of CYP3A4 was observed. The mean clinical maximum observed concentration (Cmax) of cartinib is about 1 to 2 μ M; thus, at clinically relevant drug levels, it is possible that the risk of inhibition of CYP2C8, CYP2C9 and CYP3a4 by cartinib is. Tucotinib did not induce in vitro enzymatic activity or mRNA associated with CYP3A4 or CYP1A2 in human hepatocytes. In addition, it was found that vectinib is a weak inhibitor of P-glycoprotein (P-gp) substrate and P-gp mediated digoxin efflux (half maximal inhibitory concentration [ IC50] approximately 10 to 30 μ M).

Method

A phase 1, open label, fixed sequence, 5-part drug-drug interaction study of cartainib was conducted in healthy male and female subjects to evaluate the effect of CYP3a4 and CYP2C8 inhibition and induction on the pharmacokinetics of cartainib and to evaluate the effect of cartainib on the pharmacokinetics of substrates for CYP3a4, CYP2C8, CYP2C9 and P-glycoprotein.

A total of 116 patients were recruited into five different groups: part a, part B, part C, part D and part E. Section a the effect of itraconazole, a strong CYP3a4 inhibitor, on the PK of tucatinib was evaluated. Section B the effect of rifampicin, a potent inducer of CYP3a4 and CYP2C8, on the PK of tegaininib was evaluated. Section C the effect of the strong CYP2C8 inhibitor gemfibrozil on the PK of tegaininib was evaluated. Section D evaluates the effect of cartilaginib on PK of substrate probes for the metabolic enzymes CYP2C8 (repaglinide), CYP2C9 (tolbutamide) and CYP3a4 (midazolam). Section E evaluates the effect of Tucotinib on the PK of the substrate probe for transport protein P-gp (digoxin). Portions A, B, C, D and E of the present study are independent of each other and need not be performed in any particular order. For parts A, B and C, the vectinib was administered as a single oral dose, as evaluation of plasma exposure after a single dose of vectinib was expected to provide an appropriate assessment of the effect of probe drug on vectinib PK. In sections D and E, the cartinib was administered as a multiple dosing regimen in order to examine its effect on the probe drug at steady state where maximum inhibition of CYP2C8, CYP2C9, CYP3a4 and P-gp should be achieved.

Part A

The main objective of this study was to evaluate the effect of a strong CYP3a4 inhibitor (itraconazole) on a single dose PK of chart tinib. A secondary objective of this study was to evaluate the safety and tolerability of picatinib when administered alone as well as when co-administered with a strong CYP3a4 inhibitor. The exploratory objectives of this study included: (1) assessing the effect of a strong CYP3a4 inhibitor on the PK of the tocainib metabolite ONT-993 following a single dose of tocainib; and (2) assessing the potential effect of genetic CYP polymorphisms or other genetic polymorphisms on any observed variable response in the magnitude of drug interaction between cartinib and any probe drug or substrate.

28 healthy subjects were recruited to complete treatment and evaluation as shown in figure 5. Subjects were allowed to enter the clinical study center in the afternoon of day-1 (which is the day of first drug administration, i.e., the day prior to day 1). They were discharged on day 8 after completion of the hospitalization assessment. After discharge, subjects returned to the clinical study center for an out-patient follow-up on day 11, day 12, or day 13.

On day 1, each subject received a single oral dose of 300mg of Tucanitinib in the morning about 2 hours after breakfast was completed. On day 3, each subject received an oral dose of 200mg of itraconazole twice daily (BID). From day 4 to day 7, each subject received a single oral dose of 200mg of itraconazole, once daily (QD). Itraconazole is administered in the fed state (within 5 minutes after completion of the meal). On day 6, each subject received a single oral dose of 300mg of vecatinib about 2 hours after breakfast was completed and after itraconazole in the morning. The cartinib is provided in 150mg tablets (2 tablets for a 300mg dose) and the itraconazole is provided in 100mg capsules (2 capsules for a 200mg dose).

To assess the PK endpoint, blood samples were collected according to the schedule in fig. 5 for analysis of plasma concentrations of both cartinib and ONT-993. In at leastWhen enabled, the following PK parameters were calculated using a standard non-compartmental method: area under the concentration-time curve (AUC) from time 0 to infinity (AUC0- ∞), AUC from time 0 to time of the last quantifiable concentration (AUClast), extrapolated percentage of AUC (AUCextrap%), maximum observed concentration (Cmax), maximum observed concentration time (Tmax), apparent terminal elimination half-life (t1/2), apparent total clearance (CL/F; Tucotinib only), apparent volume of distribution (Vz/F; Tucotinib only), and metabolite-to-parent ratio based on AUC (MR)_AUC(ii) a ONT-993 only). Other non-compartmental PK parameters may be reported. In addition, blood samples were collected for determining the trough level of itraconazole prior to morning dosing on the date indicated in fig. 5. Single genotyping blood samples were collected to assess the possible effect of CYP polymorphisms or other genetic polymorphisms on the magnitude of drug interactions of cartinib with probe drugs and substrates.

Safety endpoints for this study were assessed by monitoring Adverse Events (AEs), clinical laboratory evaluations (clinical chemistry, hematology and urinalysis), vital sign measurements, 12-lead Electrocardiograms (ECGs) and physical examinations.

Part B

The main objective of this study was to evaluate the effect of inducers of CYP3a4 and CYP2C8 (rifampicin) on a single dose PK of tegaininib. A secondary objective of this study was to evaluate the safety and tolerability of ceratinib when administered alone and when co-administered with strong inducers of CYP3a4 and CYP2C 8. The exploratory objectives of this study included: (1) assessing the effect of an inducer of CYP3a4 and CYP2C8 on the PK of ONT-993 following a single dose of cartinib; and (2) assessing the potential effect of genetic CYP polymorphisms or other genetic polymorphisms on any observed variable response in the magnitude of drug interaction between cartinib and any probe drug or substrate.

28 healthy subjects were recruited to complete treatment and evaluation as shown in figure 6. Subjects were allowed to enter the clinical study center in the afternoon of day-1 (which is the day of first drug administration, i.e., the day prior to day 1). They were discharged on day 12 after completion of the hospitalization assessment. After discharge, subjects returned to the clinical study center for an out-patient follow-up on day 15, day 16, or day 17.

On day 1, each subject received a single oral dose of 300mg of Tucanitinib. Each subject received a single oral dose of 600mg of rifampicin once daily (QD) on days 3 to 11. On day 10, each subject received a single oral dose of 300mg of Tucanitinib. Tucotinib was provided in 150mg tablets (2 tablets for a 300mg dose) and rifampin was provided in 300mg capsules (2 capsules for a 600mg dose). After an overnight fast of at least 8 hours, both intatinib and rifampicin were administered before meals.

To assess the PK endpoint, blood samples were collected according to the schedule in fig. 6 for analysis of plasma concentrations of both cartinib and ONT-993. When possible, the following PK parameters were calculated using a standard non-compartmental method: area under the concentration-time curve (AUC) from time 0 to infinity (AUC0- ∞), AUC from time 0 to time of the last quantifiable concentration (AUClast), extrapolated percentage of AUC (AUCextrap%), maximum observed concentration (Cmax), maximum observed concentration time (Tmax), apparent terminal elimination half-life (t1/2), apparent total clearance (CL/F; Tucotinib only), apparent volume of distribution (Vz/F; Tucotinib only), and metabolite-to-parent ratio based on AUC (MR)_AUC(ii) a ONT-993 only). Other non-compartmental PK parameters may be reported. In addition, blood samples were collected for determining the trough levels of rifampicin prior to morning dosing on the date indicated in figure 6. Single genotyping blood samples were collected to assess the possible effect of CYP polymorphisms or other genetic polymorphisms on the magnitude of drug interactions of cartinib with probe drugs and substrates.

Safety endpoints for this study were assessed by monitoring Adverse Events (AEs), clinical laboratory evaluations (clinical chemistry, hematology and urinalysis), vital sign measurements, 12-lead Electrocardiograms (ECGs) and physical examinations.

Part C

The primary objective of this study was to evaluate the effect of a strong CYP2C8 inhibitor (gemfibrozil) on a single dose PK of tegaininib. A secondary objective of this study was to evaluate the safety and tolerability of picatinib when administered alone as well as when co-administered with a strong CYP2C8 inhibitor. The exploratory objectives of this study included: (1) assessing the effect of a strong CYP2C8 inhibitor on the PK of ONT-993 following a single dose of cartinib; and (2) assessing the potential effect of genetic CYP polymorphisms or other genetic polymorphisms on any observed variable response in the magnitude of drug interaction between cartinib and any probe drug or substrate.

28 healthy subjects were recruited to complete treatment and evaluation as shown in figure 7. Subjects were allowed to enter the clinical study center in the afternoon of day-1 (which is the day of first drug administration, i.e., the day prior to day 1). They were discharged on day 9 after completion of the hospitalization assessment. After discharge, subjects returned to the clinical study center for an out-patient follow-up on day 12, day 13, or day 14.

On day 1, each subject received a single oral dose of 300mg of Tucanitinib. Each subject received a single oral dose of 600mg of gemfibrozil (BID), twice daily (BID), from day 3 to day 8. On day 7, each subject received a single oral dose of 300mg of Tucanitinib. Tucotinib is provided in 150mg tablets (2 tablets for a 300mg dose) and gemfibrozil is provided in 600mg tablets. After an overnight fast of at least 8 hours, both picatinib and gemfibrozil were administered prior to the meal.

To assess the PK endpoint, blood samples were collected according to the schedule in fig. 7 for analysis of plasma concentrations of both cartinib and ONT-993. When possible, the following PK parameters were calculated using a standard non-compartmental method: area under the concentration-time curve (AUC) from time 0 to infinity (AUC0- ∞), AUC from time 0 to time of the last quantifiable concentration (AUClast), extrapolated percentage of AUC (AUCextrap%), maximum observed concentration (Cmax), maximum observed concentration time (Tmax), apparent terminal elimination half-life (t1/2), apparent total clearance (CL/F; Tucotinib only), apparent volume of distribution (Vz/F; Tucotinib only), and metabolite-to-parent ratio based on AUC (MR)_AUC(ii) a ONT-993 only). Other non-compartmental PK parameters may be reported. In addition, blood samples were collected for determining the trough levels of gemfibrozil prior to morning dosing on the date indicated in fig. 7. Collection of single genotyping blood samples to assess CYP polymorphisms or other genetic polymorphisms versus Tucotinib and Probe drugsThe potential effect of the magnitude of drug interaction of the substance and the substrate.

Safety endpoints for this study were assessed by monitoring Adverse Events (AEs), clinical laboratory evaluations (clinical chemistry, hematology and urinalysis), vital sign measurements, 12-lead Electrocardiograms (ECGs) and physical examinations.

Moiety D

The main objective of this study was to evaluate the effect of picatinib on a single dose PK of substrate probes for CYP2C8 (repaglinide), CYP2C9 (tolbutamide) and CYP3a4 (midazolam). Secondary objectives of the study included: in healthy subjects, (1) assessing the safety and tolerability of tegasertib when administered alone and when co-administered with substrate probes for CYP2C8, CYP2C9 and CYP3a 4; and (2) assessing single dose PK and multi-dose steady state PK of vecatinib, alone and in the presence of substrate probes for CYP2C8, CYP2C9 and CYP3a 4. The exploratory objectives of this study included: (1) assessing the effect of Tucotinib on the PK of related metabolites of tolbutamide (4-hydroxytolbutamide) and midazolam (1-hydroxymidazolam); and (2) assessing the potential effect of genetic CYP polymorphisms or other genetic polymorphisms on any observed variable response in the magnitude of drug interaction between cartinib and any probe drug or substrate.

17 healthy subjects were enrolled to complete treatment and evaluation as shown in figure 8. Subjects were allowed to enter the clinical study center in the afternoon of day-1 (which is the day of first drug administration, i.e., the day prior to day 1). They were discharged on day 14 after completion of the hospitalization assessment. After discharge, subjects returned to the clinical study center for an out-patient follow-up on day 20, day 21, or day 22.

On day 1, each subject received a single oral dose of 0.5mg of repaglinide. On day 2, each subject received 2mg of a single oral dose of midazolam and 500mg of a single oral dose of tolbutamide administered together. From day 4 to day 13, each subject received a 300mg oral dose of chart caritinib, twice daily (BID). On day 11, each subject received a single oral dose of repaglinide. On day 12, each subject received 2mg of a single oral dose of midazolam and 500mg of a single oral dose of tolbutamide administered together. Tucotinib is provided as 150mg tablets (2 tablets for a 300mg dose), repaglinide is provided as 0.5mg tablets, tolbutamide is provided as 500mg tablets, and midazolam is provided as a syrup (2 mg/mL; 1mL syrup for a 2mg dose). After an overnight fast of at least 8 hours, picatinib, repaglinide, tolbutamide and midazolam were administered prior to meals.

To assess PK endpoints, blood samples were collected for analysis of repaglinide according to the schedule in fig. 8; tolbutamide and its 4-hydroxytolbutamide metabolite; and plasma concentrations of midazolam and its 1-hydroxymidazolam metabolites. When possible, the following PK parameters were calculated using a standard non-compartmental method: AUC0- ∞, AUClast, AUCextrap%, Cmax, Tmax, t1/2, CL/F (repaglinide, tolbutamide, and midazolam only), Vz/F (repaglinide, tolbutamide, and midazolam only), and MR _AUC(only 4-hydroxytolbutamide and 1-hydroxymidazolam). Other non-compartmental PK parameters may be reported. In addition, blood samples for determining the plasma concentrations of both Charcotinib and ONT-993 were collected at the time points indicated in FIG. 8. When possible, the following PK parameters were calculated using a standard non-compartmental method: AUC0- ∞ (days 4 and 8), AUClast, AUCextrap%, AUC within dosing interval (AUCtau), Cmax, Tmax, t1/2, CL/F (days 4 and 8, Charcotinib only), apparent total clearance at steady state (CLss/F; days 10, 11, 12, 14, and 15, Charcotinib only), Vz/F (days 4 and 8, Charcotinib only), apparent volume of distribution at steady state (Vss/F; days 10, 11, 12, 14, and 15, Charcotinib only), accumulation ratio (Rac; days 10, 11, 12, 14, and 15 only), and MR_AUC(ONT-993 only). Single genotyping blood samples were collected to assess the possible effect of CYP polymorphisms or other genetic polymorphisms on the magnitude of drug interactions of cartinib with probe drugs and substrates.

Safety endpoints for this study were assessed by monitoring Adverse Events (AEs), clinical laboratory evaluations (clinical chemistry, hematology and urinalysis), vital sign measurements, 12-lead Electrocardiograms (ECGs) and physical examinations.

Part E

The main objective of this study was to evaluate the effect of Tucaninib on a single dose PK of the substrate probe for P-gp (digoxin). Secondary objectives of the study included: in healthy subjects, (1) assessing the safety and tolerability of vecatinib when administered alone and when co-administered with a substrate probe for P-gp; and (2) assessing single dose PK and multi-dose steady state PK of vecatinib, alone and in the presence of substrate probe for P-gp. The exploratory goal of this study was to evaluate the potential impact of genetic CYP polymorphisms or other genetic polymorphisms on any observed variable response in the magnitude of drug interaction between cartinib and any probe drug or substrate.

15 healthy subjects were recruited to complete treatment and evaluation as shown in figure 9. Subjects were allowed to enter the clinical study center in the afternoon of day-1 (which is the day of first drug administration, i.e., the day prior to day 1). They were discharged on day 22 after completion of the hospitalization assessment. After discharge, subjects returned to the clinical study center for an out-patient follow-up on day 28, day 29, or day 30.

On day 1, each subject received a single oral dose of 0.5mg of digoxin. From day 8 to day 21, each subject received a 300mg oral dose of chart caritinib, twice daily (BID). On day 15, each subject received a single oral dose of 0.5mg of digoxin. Tucotinib is provided in 150mg tablets (2 tablets for a 300mg dose) and digoxin is provided in 0.25mg tablets (2 tablets for a 0.5mg dose). After an overnight fast of at least 8 hours, both picatinib and digoxin were administered prior to meals.

To assess PK endpoints, blood samples were collected according to the schedule in fig. 9 for analysis of plasma concentrations of digoxin. When possible, the following PK parameters were calculated using a standard non-compartmental method: AUC0- ∞, AUClast, AUCextrap%, Cmax, Tmax, t1/2, CL/F and Vz/F. Other non-compartmental PK parameters may be reported. In addition, plasma concentrations for determining Charcotinib and ONT-993 were collected at the time points indicated in FIG. 9Blood samples of degrees. When possible, the following PK parameters were calculated using a standard non-compartmental method: AUC0- ∞ (days 4 and 8), AUClast, AUCextrap%, AUC within dosing interval (AUCtau), Cmax, Tmax, t1/2, CL/F (days 4 and 8, Charcotinib only), apparent total clearance at steady state (CLss/F; days 10, 11, 12, 14, and 15, Charcotinib only), Vz/F (days 4 and 8, Charcotinib only), apparent volume of distribution at steady state (Vss/F; days 10, 11, 12, 14, and 15, Charcotinib only), accumulation ratio (Rac; days 10, 11, 12, 14, and 15 only), and MR_AUC(ONT-993 only). Single genotyping blood samples were collected to assess the possible effect of CYP polymorphisms or other genetic polymorphisms on the magnitude of drug interactions of cartinib with probe drugs and substrates.

Safety endpoints for this study were assessed by monitoring Adverse Events (AEs), clinical laboratory evaluations (clinical chemistry, hematology and urinalysis), vital sign measurements, 12-lead Electrocardiograms (ECGs) and physical examinations.

Inclusion criteria for eligible subjects in sections a-E include the following: (1) men and women between the ages of 18 and 65 (inclusive) at screening; (2) at screening, body mass index was between 18.0 and 32.0kg/m2 (inclusive) and total body weight was between 50.0 and 100.0kg (inclusive); (3) the female subjects involved in this study did not have fertility potential and therefore did not require contraceptive measures. Male subjects are surgically infertile for at least 90 days, or agree to use contraception when sexually active with a female partner having fertility potential; and (4) being able to understand and be willing to sign ICFs and comply with research restrictions.

Exclusion criteria for parts a-E include the following: (1) any significant medical history or clinical manifestation of metabolic, allergic, cutaneous, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorders; (2) any condition that may affect drug absorption (e.g., gastrectomy, gastric banding, gastric bypass); (3) a significant hypersensitivity, intolerance or history of allergy to any pharmaceutical compound, food or other substance; (4) potentially altering the history of gastric or intestinal surgery or resection (allowing uncomplicated appendectomies, cholecystectomies and herniorrhaphy) of the absorption and/or excretion of orally administered drugs; (5) a history of hyperbilirubinemia (e.g., gilbert syndrome); (6) history of alcohol abuse or drug/chemical abuse within 2 years prior to enrollment; (7) daily alcohol consumption history for female subjects over 7 cups/week or for male subjects over 14 cups/week. 1 unit of alcohol equals 12oz (360mL) beer, 11/2oz (45mL) white spirit, or 5oz (150mL) wine; (8) positive urine drug screening (including cotinine) at screening or stay, or positive alcohol breath test at stay; (9) hepatitis virus detection (hepatitis panel) positive and/or human immunodeficiency virus test positive; (10) screening liver function tests (alanine transaminase, aspartate transaminase and total bilirubin), serum creatinine, hemoglobin or hematocrit values outside normal reference ranges; (11) (ii) for subjects involved in part E, the potassium or magnesium levels at screening or enrollment are outside the normal range; (12) at screening or check-in, a single 12-lead ECG shows QT interval (QTcF) >450ms (for males) and >470ms (for females) corrected for heart rate using Fridericia formula (which can be repeated twice at screening and/or check-in for inclusion/exclusion purposes and averaged over all 3 ECG QTcF values), or a history/evidence of long QT syndrome; (13) participation in clinical studies involving the administration of investigational drugs (new chemical entities) within the past 30 days or 5 half-lives (whichever is longer) prior to enrollment; (14) within 30 days prior to enrollment and during the study period, any drug/product known to alter the absorption, metabolism or elimination process of the drug is used or intended for use, including john's wort and known strong inhibitors or inducers of CYP3a4 or CYP2C8, except that drugs prescribed as study drugs in the regimen will be used during the study period; (15) any prescribed medication/product is used or intended to be used within 28 days prior to check-in; (16) any over-the-counter medication/product (excluding acetaminophen/acetaminophen) used or intended for use within 14 days prior to enrollment, including vitamins, minerals, and phytotherapeutics/herbs/botanical preparations; (17) using a tobacco or nicotine containing product within 3 months prior to enrollment; (18) eating a food or beverage containing poppy seeds, grapefruit or sevieria orange 7 days before the stay; (19) eating a caffeine-containing food or beverage within 48 hours prior to lodging; (20) drinking within 48 hours before the live; (21) receiving a blood product within 2 months prior to enrollment; (22) blood donation from 56 days prior to screening, plasma donation from 2 weeks prior to screening, or platelet donation from 6 weeks prior to screening; (23) poor peripheral venous access; and (24) the study, or any other study cartinib, has been previously completed or withdrawn from the study and has previously received the investigational product.

Pharmacokinetic results

Part a: tucaninib/itraconazole

Itraconazole, a strong CYP3a4 inhibitor, increases plasma exposure to cartinib; AUC of Tucaninib administered in combination with itraconazole_last、AUC_0-∞And C_maxThe geometric LS mean ratios (90% CI) compared to the individual administered cartinib were 1.33(1.25, 1.41), 1.34(1.26, 1.43) and 1.32(1.23, 1.42), respectively. This effect was statistically significant based on the 90% CI value.

Itraconazole increases plasma exposure of ONT-993; AUC of ONT-993 following combined administration of Tucaninib and itraconazole_last、AUC_0-∞And C_maxThe geometric LS mean ratios (90% CI) compared to that after administration of picatinib alone were 1.58(1.49, 1.68), 1.58(1.49, 1.67) and 2.03(1.89, 2.18), respectively. These effects were statistically significant based on 90% CI values.

Geometric mean MR of ONT-993 after combined administration of Turkinib and itraconazole compared to that after administration of Turkinib alone_AUC0-∞And MR_CmaxValues are similar or slightly higher.

CYP3A4 plays a secondary role in the metabolism of Tucotinib, with little or no effect in the formation of ONT-993.

Part B: graph card tinib/rifampin

The strong CYP inducer rifampicin reduces plasma exposure to vectinib; AUC for Tucaninib administered in combination with rifampicin _last、AUC_0-∞And C_maxGeometric LS mean compared to Pottinib administered aloneThe ratios (90% CI) were 0.517(0.449, 0.596), 0.520(0.452, 0.597) and 0.632(0.531, 0.753), respectively. This effect was statistically significant based on the 90% CI value.

Rifampicin reduces plasma exposure of ONT-993 (based on AUC)_lastAnd AUC_0-∞) And increasing C of ONT-993_max. AUC of ONT-993 following administration of Tucaninib in combination with Rifampicin_last、AUC_0-∞And C_maxThe geometric LS mean ratios (90% CI) compared to after administration of picatinib alone were 0.750(0.636, 0.884), 0.748(0.640, 0.873) and 2.08(1.70, 2.55), respectively. These effects were statistically significant based on 90% CI values.

Geometric mean MR of ONT-993 after administration of Tucaninib in combination with Rifampicin compared to that after administration of Tucaninib alone_AUC0-∞And MR_CmaxThe values were approximately 1.4 and 3.3 times higher, respectively.

Rifampicin may induce enzymes involved in the metabolism of chart tinib (e.g. CYP2C8 and CYP3a 4).

Part C: graph card tinib/gemfibrozil

Gemfibrozil, a strong CYP2C8 inhibitor, increased plasma exposure to picatinib; AUC for Tucanitinib administered in combination with gemfibrozil_last、AUC_0-∞And C_maxThe geometric LS mean ratios (90% CI) compared to the individual administered cartinib were 2.99(2.62, 3.41), 3.04(2.66, 3.46) and 1.62(1.47, 1.79), respectively. These effects were statistically significant based on 90% CI values.

Gemfibrozil reduces plasma exposure of ONT-993; AUC of ONT-993 following administration of Tucotinib in combination with gemfibrozil_lastAUC0- ∞ and C_maxThe geometric LS mean ratios (90% CI) compared to that after administration of cartilaginib alone were 0.767(0.686, 0.858), 0.887(0.801, 0.982), and 0.304(0.263, 0.352), respectively. These effects were statistically significant based on 90% CI values.

Geometric mean MR of ONT-993 after administration of Tucotinib in combination with gemfibrozil, compared to that after administration of Tucotinib alone_AUC0-∞And MR_CmaxRespectively greatly reduced in valueAbout 71% and 81%.

CYP2C8 plays a role in the metabolism of Tucotinib and the formation of ONT-993.

Part D: tucotinib/repaglinide/tolbutamide/midazolam

The relatively weak effect of picatinib on increasing the plasma exposure of the CYP2C8 substrate repaglinide indicates that picatinib is a weak inhibitor of CYP2C8 in vivo. AUC for repaglinide administered in combination with steady state cartinib_last、AUC_0-∞And C_maxThe geometric LS mean ratios (90% CI) compared to repaglinide administered alone were 1.72(1.55, 1.91), 1.69(1.51, 1.90) and 1.69(1.37, 2.10), respectively. These effects were statistically significant based on 90% CI values.

Tucotinib had no effect on plasma exposure of the PK of the CYP2C9 substrate tolbutamide or the 4-hydroxytolbutamide metabolite of tolbutamide. AUC of tolbutamide following combined administration of tolbutamide/midazolam with Steady State Tucotinib _lastAUC0- ∞ and C_maxThe geometric LS mean ratios (90% CI) compared to tolbutamide/midazolam administered alone were 1.03(1.01, 1.06), 1.05(1.01, 1.09) and 0.961(0.904, 1.02), respectively. AUC of 4-hydroxytolbutamide following combined administration of tolbutamide/midazolam with stable Tucotinib_last、AUC_0-∞And C_maxThe geometric LS mean ratios (90% CI) compared to tolbutamide/midazolam administered alone were 0.900(0.868, 0.934), 0.918(0.880, 0.958) and 0.881(0.831, 0.934), respectively.

The strong effect of tucaninib on increasing plasma exposure of the CYP3a4 substrate midazolam suggests that tucaninib is a strong inhibitor of CYP3a4 in vivo. AUC of midazolam after combined administration of stable state cartinib with tolbutamide/midazolam_last、AUC_0-∞And C_maxThe geometric LS mean ratios (90% CI) compared to tolbutamide/midazolam administered alone were 5.30(4.65, 6.04), 5.74(5.05, 6.53) and 3.01(2.63, 3.45), respectively. These effects were statistically significant based on 90% CI values.

Do not affect the plasma exposure of 1-hydroxymidazolam (based on AUC)_lastAnd AUC_0-∞) But has a weaker effect on reducing exposure (based on C) _max). AUC of 1-hydroxymidazolam following steady-state combined administration of Tucotinib and tolbutamide/midazolam_last、AUC_0-∞And C_maxThe geometric LS mean ratios (90% CI) compared to after tolbutamide/midazolam alone were 0.945(0.848, 1.05), 1.02(0.903, 1.16) and 0.593(0.507, 0.694), respectively. Based on 90% CI value, for C_maxThe effect of (a) is statistically significant.

The Touretinib has a strong effect on reducing the metabolism of midazolam; tucotinib has a geometric mean MR of 1-hydroxymidazolam after combined administration of steady-state Tucotinib and tolbutamide/midazolam compared to that after tolbutamide/midazolam alone_AUC0-∞And MR_CmaxA reduction of about 82.8% and 80.4%, respectively.

Tucotinib had similar T after single (day 4) and multiple (day 10) doses_maxAnd t_1/2Values, and the Rac for picatinib after multiple doses was 1.85. Similarly, ONT-993 has a similar T after a single administration and multiple administrations_maxAnd t_1/2And the Rac of ONT-993 after multiple doses was 2.09.

Part E: picatinib/digoxin

Tucanitinib had a weaker effect on increasing plasma exposure of the P-gp substrate digoxin (based on AUC)_lastAnd AUC _0-∞) And has moderate effects on increasing plasma exposure (based on C)_max). AUC of digoxin administered in combination with steady state Tucaninib_last、AUC_0-∞And C_maxThe geometric LS mean ratios (90% CI) compared to digoxin dosed alone were 1.53(1.35, 1.74), 1.46(1.29, 1.66) and 2.35(1.90, 2.90), respectively. These effects were statistically significant based on 90% CI values. Overall, vecatinib is a weak inhibitor of P-gp in vivo.

Tucotinib at single dose (day 8) and multiple dosesSimilar T after administration (day 14)_maxAnd t_1/2Values, and the Rac for picatinib was 1.50 after multiple doses. Similarly, ONT-993 has a similar T after a single administration and multiple administrations_maxAnd t_1/2And the Rac of ONT-993 was 2.01 after multiple doses.

Example 3: evaluation of Tucaninib and ONT-993 as inhibitors of human OAT2, OCT2, MATE1 and MATE2-K mediated transport

Substrate-dependent inhibition is common in transporters including MATE1 and MATE 2-K. In this study, creatinine was used as a probe substrate to assess the inhibitory potency of both Potentitinib and ONT-993. OAT2, OCT2, OCT3, MATE1, and MATE2-K are renal transporters identified as transport creatinine. The use of creatinine as a probe substrate to test the group of Doxocotinib and its metabolite ONT-993 as potential inhibitors of OAT2, OCT2, MATE1 and MATE2-K mediated transport.

For this study, MDCK-II was maintained in DMEM with low glucose and 10% FBS. Approximately 24 hours prior to transfection, cells were seeded at 60K ± 10K cells/well on 96-well transwell membrane plates. Transport assays were performed approximately 48 hours after transfection. Cells are transfected and treated to express the transporter of interest, or treated with a control vector. Transport of creatinine was determined by radiometric detection.

The net transporter-mediated substrate uptake for each transporter was calculated as follows: net transporter mediated substrate uptake (pmol/min/cm)²) (cell accumulation in the presence of transporter) - (average cell accumulation in the absence of transporter).

Percent inhibition was calculated as follows: percent inhibition 100- (100 ═ transporter mediated uptake)_{Has inhibition}/(Transporter mediated uptake)_{Without inhibition})

The IC50 values for the uptake assay were determined using the following equation:

wherein V₀Is the average transporter-mediated flux in the absence of test article, V is the transporter-mediated flux in the presence of test article over the entire test concentration range, [ I]Is inhibitor concentration, IC₅₀Represents the value at which transport is inhibited by 50%, and n is the hill coefficient.

Results

The maximum inhibition of OAT2 mediated transport of creatinine was 14.7% and 44.9% at 10 μ M concentrations of both vectinib and ONT-993, respectively, using up to 10 μ M concentration range for OAT 2. It was observed that the suppression was not sufficient to determine IC for Charcotinib and ONT-993 for OAT2₅₀The value is obtained.

Concentration-dependent inhibition of OCT 2-mediated transport of creatinine was observed using either cartinib or ONT-993 at concentrations ranging from 0.03 to 10 μ M. For OCT2, determine IC₅₀The values are 0.107. + -. 0.0379. mu.M for Charcotinib and 0.544. + -. 0.278. mu.M for ONT-993.

Concentration-dependent inhibition of MATE 1-mediated transport of creatinine was observed using either Potentianib at concentrations ranging from 0.003 to 1 μ M or ONT-993 at concentrations ranging from 0.01 to 3 μ M. For MATE1, IC is determined₅₀The values were 0.0855. + -. 0.0175. mu.M for Tokyanib and 0.0863. + -. 0.0126. mu.M for ONT-993.

Using both Chartinib and ONT-993 at concentrations ranging up to 10. mu.M, it was observed that the net creatinine uptake was not sufficient to accurately determine the IC of either Chartinib or ONT-993 for MATE2-K₅₀The value is obtained.

Example 4: cytochrome P4503A 4/5 inhibition in human liver microsomes

The in vitro study was designed to evaluate the ability of picatinib to inhibit the major CYP enzyme CYP3a4/5 in human liver microsomes (using two different substrates) with the aim of determining the potential of picatinib to inhibit metabolism with concomitant administration of drugs. The inhibitory potency of Tecatinib was determined in vitro by measuring the activity of CYP3A4/5 in human liver microsomes in the presence and absence of Tecatinib. These in vitro experiments were designed to measure inhibition of 50% inhibition of the activity of the labeled substrate resulting in direct, time and metabolism dependent inhibition of CYP3A4/5 Agent concentration (IC)₅₀Value). Further evaluation of the metabolism-dependent inhibition to determine the rate of CYP3A4/5 inactivation by Picatinib (k)_inactValue) and degree (K)_IValue).

Method

Human liver microsomes from non-transplantable donated livers were prepared and characterized. A pooled gender pool of 200 individual human liver microsome samples was used for this study (Sekisui XenoTech catalog number: H2620, lot number: 1210347).

For measuring CYP activity, incubation was carried out at about 37 ℃ in 200. mu.L of an incubation mixture (pH 7.4) containing water, potassium phosphate buffer (50mM), MgCl₂(3mM), EDTA (1mM), NADPH regenerating system (always the mixture: NADP [1mM ]]Glucose 6 phosphate [5mM ]]Glucose 6 phosphate dehydrogenase [1 Unit/mL ]]) And labeled substrate at the indicated final concentration.

Aliquots of stock and/or working solutions of ceratinib were manually added to the above buffered mixtures. The incubation mixtures were prepared in large quantities to avoid the need to directly pipette very small volumes (i.e., 1 μ L or less). Incubations without picatinib (0 μ M; solvent control) contained the solvent used to dissolve the picatinib (i.e., DMSO).

In addition to centrifugation, the Tecan liquid processing system performs all remaining steps to determine IC ₅₀And K_I/k_inact. For these assays, duplicate aliquots of the buffer mixture were automatically added to the appropriate locations in the 96-well plate. An aliquot of the substrate working solution was added to a 96-well plate and the reaction was then initiated. The labeled substrate reaction was started by adding an aliquot of the NADPH regeneration system and terminated automatically at approximately 5 minutes by adding the appropriate internal standard and stop reagent acetonitrile. The samples were centrifuged at 920 Xg for 10min at 10 ℃. The supernatant fractions were analyzed by LC-MS/MS. Standards were similarly prepared by adding authentic metabolite standards.

Due to the possibility that cartinib may bind to microsomal proteins or lipids, attempts were made to design these experiments such that microsomal proteins, incubation times and buffer concentrations were 0.1mg/mL, 5min and 50mM, respectively, in as many cases as possible.

To examine its ability to act as a direct inhibitor of the enzyme, icaritinib (at concentrations ranging from 0.01 to 10 μ M) was incubated with labeled substrate and human liver microsomes. The concentration of the labeled substrate is based on the previously determined K_mOr S₅₀And (4) data.

To examine its ability to act as a metabolic-dependent inhibitor of the CYP3a4/5 enzyme, icaritinib (at the same concentration used to evaluate direct inhibition) was preincubated in duplicate with human liver microsomes and NADPH regeneration system at 37 ℃ ± 2 ℃ for approximately 30 min. This pre-incubation allows the production of intermediates that can inhibit human CYP3A4/5 activity. The pre-incubation was initiated by adding an aliquot of the NADPH regeneration system. To examine its ability to act as a time-dependent inhibitor of the CYP3a4/5 enzyme, additional replicate samples at all concentrations of picatinib were pre-incubated for 30min in the presence of pooled human liver microsomes but in the absence of NADPH. This pre-incubation allows to assess whether any potential increase in inhibition is NADPH dependent (e.g., potentially CYP mediated). After a 30min pre-incubation period, labelled substrate was automatically added and incubation was continued to measure residual CYP enzyme activity. Incubations without picatinib (0 μ M; solvent control) and incubations with picatinib without pre-incubation served as negative controls.

The experiment was designed to further investigate the apparent metabolism dependent inhibition of the enzyme and to determine the K of CYP3A4/5 inactivation_inactAnd K_IThe value is obtained. All incubations were performed with a Tecan liquid handling system.

To determine K for CYP3A4/5 inactivation_inactAnd K_IValues, procatinib was preincubated with pooled human liver microsomes and NADPH regeneration system at approximately 0.1mg/mL in duplicate for 0, 3, 6, 9, 15 and 30 min. After pre-incubation, an aliquot of the pre-incubation mixture (20 μ L) was transferred to a second tube (final volume of 200 μ L) containing the labeled substrate (approximately 10 times its Km) and NADPH regeneration system, resulting in a 10-fold dilution of the inhibitor to minimize direct inhibition of cartinib and a 10-fold dilution of microsomes. Incubation was then continued for 5min to allow bottom labelingFormation of any metabolite of the substance. The residual CYP3A4/5 activity was measured.

Incubations containing picatinib but no probe substrate were included to assess the likelihood of analytical interference of picatinib and/or possibly one or more metabolites with the substrate product (1' -hydroxymidazolam) in the assay.

Samples were analyzed by a multiplex reaction monitoring LC-MS/MS method. Metabolites were quantified by reference to a standard calibration curve generated using the simplest appropriate weighting and regression algorithm. The regression fit is based on the peak area ratio of the analyte to the internal standard calculated from the calibration standard sample. Stock standard and working solutions were prepared according to a custom made Tecan script EVO Std-QC Spiking Solution preparation (Tecan script EVO Std-QC Spiking Solution Prep). Chromatographic peaks were integrated using analytical instrument control and data processing software (SCIEX, version 1.6.1).

Results

Direct inhibition of CYP3A4/5 mediated midazolam 1' -hydroxylation by Tucotinib, its IC₅₀The value was 3.3. mu.M. A maximum of 44% direct inhibition, and hence associated IC, was observed for CYP3A4/5 mediated testosterone 6 β -hydroxylation₅₀The value is reported as>The highest concentration of the test article evaluated was 10 μ M. Tucotinib also causes metabolism-dependent inhibition due to the IC associated with CYP3A4/5₅₀The values (as measured by midazolam 1' -hydroxylation and testosterone 6 β -hydroxylation) decreased 2.71-fold and 2.13-fold, respectively, after 30 minutes of pre-incubation with NADPH.

The metabolic-dependent inhibition of CYP3A4/5 activity (as measured by midazolam 1' -hydroxylation) was further examined to measure k associated with inactivation of this enzyme activity_inactAnd K_IThe value is obtained. Tucanitinib inactivated CYP3A4/5 mediated midazolam 1' -hydroxylation, mean. + -. SE k_inactThe value is 0.011 +/-0.001 min^-1And mean value. + -. SE K_IThe value was 0.54. + -. 0.25. mu.M. Deactivation efficiency (k)_inact/K_I) Is 21min^-1mM^-1。

_iExample 5: evaluation of Ks against CYP2C8, CYP2C9, CYP3A4 and UGT1A1 for TucaninibPrice of

The objective of this study was to evaluate the K of cartaininib for the following human hepatocytochrome P450(CYP) enzymes (CYP2C8, CYP2C9 and CYP3a4) and UGT1a1 in vitro_i。

Used in combination with six concentrations (0.1X, 0.25X, 0.5X, 1X, 3X and 5 XK) _m) The inhibition constants (K) were determined by direct inhibition of CYP2C8, CYP2C9, CYP3A4 and UGT1A1 by the corresponding labeled substrates amodiaquine, diclofenac, midazolam and beta-estradiol, Tukatinib (0.1 to 25. mu.M)_i). Ks against CYP2C8, CYP2C9, CYP3A4 and UGT1A1_iValues were estimated to be 0.170, 4.57, 0.805 and 1.81 μ M, respectively. The inhibition mechanism was determined to be competitive inhibition from all four in vitro assays.

Pooled Human Liver Microsomes (HLM) from 150 individuals (79 males and 71 females) were obtained from bioremodelionivt (baltimore, ma) and stored at approximately-70 ℃. The suppliers characterized microsomes for total protein and selected cytochrome P450 activity.

To determine K_iUp to eight concentrations of Picatinib (0.1, 0.22, 0.484, 1.07, 2.35, 5.16, 11.4 and 25. mu.M) and six concentrations of labeled substrate (0.1, 0.25, 0.5, 1, 3 and 5 XK) were used_m) Incubation was performed. Including HLM, Tucaninib, labeled substrate and assay buffer [ 0.1M potassium phosphate buffer containing 1mM EDTA, pH 7.4(CYP) or 0.05M Tris buffer containing 150mM potassium chloride and 10mM magnesium chloride, pH 7.4(UGT)]The incubation mixture of (a) was preincubated at 37 ℃ for 10 minutes, followed by addition of pre-warmed NADPH [ nicotinamide adenine dinucleotide phosphate, reduced form, 1mM (CYP) ]Or UDPGA [ uridine 5' -diphosphoglucouronic acid, 2mM (UGT)]And (5) starting. The final organic solvent contribution rate is less than or equal to 1 percent. The incubation was terminated by the addition of chilled acetonitrile containing a stable isotope labeled internal standard. Control incubations included a test article solvent control (no test article), a positive control inhibitor, and an additional solvent control specific for the positive control inhibitor. All incubations were performed in triplicate. Estimation of inhibition constant (K)_i)。

Details of the incubation conditions for each assay are presented in the table below.

Cytochrome P450 Activity assay

min for the next minute.

Note that: the stop solution was acetonitrile containing an internal standard.

The incubation time for a 5. mu.M substrate was 5 minutes (bias).

The samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The analyte concentration was quantified by LC-MS/MS and interpolated according to a standard curve for the real analyte. Standards and quality control samples were prepared in duplicate. Activity was calculated based on analyte concentration, incubation time and protein concentration.

The enzyme activity (pmol/min/mg protein) is expressed as analyte formation/final protein concentration/incubation time. Residual activity is expressed as the enzyme activity at each concentration point of the test article normalized by the mean activity of the solvent control.

Calculations (biases) were performed for competitive, non-competitive and mixed inhibition.

Results

Inhibition constants of Tecaninib for CYP2C8, CYP2C9, CYP3A4, and UGT1A1 (K)_i) Estimated to be 0.170, 4.57, 0.805 and 1.81 μ M, respectively. The inhibition mechanism was determined to be competitive inhibition from all four in vitro assays.