阅读说明：本技术 法米替尼在制备用于治疗c-KIT或PDGFRA突变的肿瘤的药物中的用途 (Use of famitinib in preparation of drugs for treating c-KIT or PDGFRA mutated tumors ) 是由 王泉人 任文明 杨清 杨昌永 于 2021-05-26 设计创作，主要内容包括：本公开涉及法米替尼或其可药用盐在制备治疗c-KIT或PDGFRA突变的肿瘤的药物中的用途。具体而言,本公开涉及法米替尼或其可药用盐在制备治疗c-KIT或PDGFRA突变的胃肠道间质瘤、睾丸精原细胞瘤、肥大细胞疾病、黑色素瘤或急性髓细胞性白血病的药物中的用途。(The present disclosure relates to the use of famitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of c-KIT or PDGFRA mutated tumors. In particular, the disclosure relates to the use of famitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of c-KIT or PDGFRA mutated gastrointestinal stromal tumor, testicular seminoma, mast cell disease, melanoma or acute myeloid leukemia.)

1. Use of famitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of c-KIT or PDGFRA mutated tumors.

2. Use according to claim 1, wherein the c-KIT or PDGFRA mutated tumor is selected from c-KIT or PDGFRA mutated gastrointestinal stromal tumor, testicular seminoma, mast cell disease, melanoma or acute myeloid leukemia.

3. The use according to claim 1, wherein the c-KIT or PDGFRA mutated tumor is a c-KIT or PDGFRA mutated gastrointestinal stromal tumor.

4. The use according to claim 1, wherein the c-KIT or PDGFRA mutated tumor is a metastatic relapsed/unresectable gastrointestinal stromal tumor of c-KIT or PDGFRA mutation.

5. The use according to claim 1, wherein the c-KIT or PDGFRA mutated tumor is a c-KIT or PDGFRA mutated gastrointestinal stromal tumor that has failed treatment with imatinib or is not toxicity tolerant.

6. The use according to claim 1, wherein the c-KIT mutation is selected from one or more of Exon9, Exon11, Exon13, Exon17, Exon13/14, Exon 17/18.

7. Use according to claim 1, wherein the c-KIT mutation is selected from the group consisting of V559D, Del (559-560), Y503-F504 ins AY, D579-H580 ins IDPTQLPYD, V560G, V654A, T670I, D816A, D816G, D816H, D820H, N822H, Y823H, a 829H, V559H + V654H, V559H + T670H, V559H + D816H, V559H + D36820, V5572 + N H, V559H + Y H, V559H + a 5536829.

8. The use according to claim 1, wherein the PDGFRA mutation is selected from the group consisting of Exon12, Exon 14, Exon 18.

9. The use according to claim 1, wherein the PDGFRA mutation is selected from the group consisting of V561D, D842V.

10. Use of famitinib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of advanced gastrointestinal stromal tumors.

11. Use of famitinib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of metastatic relapsed/unresectable gastrointestinal stromal tumors (GIST).

12. Use of famitinib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of gastrointestinal stromal tumors that have failed therapy with imatinib or are intolerant to toxicity.

13. The use according to claim 1, 10, 11 or 12, wherein the c-KIT or PDGFRA mutated tumor, advanced gastrointestinal stromal tumor, metastatic relapsed/unresectable gastrointestinal stromal tumor, or gastrointestinal stromal tumor that has failed imatinib treatment or is not toxicity-resistant, is intolerant to sunitinib.

14. The use according to claim 12, wherein the patient has a median PFS ≧ 7 months, preferably a median PFS ≧ 10 months, more preferably a median PFS ≧ 12 months.

15. The use according to claim 12, wherein the median PFS is increased by 30% to 145%, preferably the median PFS is increased by 100% to 145% compared to the administration of a therapeutically effective amount of sunitinib to a patient.

16. The use according to claim 1, 10, 11 or 12, wherein the pharmaceutically acceptable salt of famitinib is selected from the group consisting of mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate and phosphate, preferably malate.

17. The use according to claim 1, 10, 11 or 12, wherein the famitinib or a pharmaceutically acceptable salt thereof is administered in a dose selected from 0.1-1000mg once a day, twice a day, three times a day, preferably once a day.

18. The use according to claim 1, 10, 11 or 12, wherein the famitinib, or a pharmaceutically acceptable salt thereof, is prepared as a pharmaceutical composition comprising a unit dose of famitinib, or a pharmaceutically acceptable salt thereof, selected from 0.1-100 mg.

19. The use according to claim 1, 10, 11 or 12, wherein the famitinib or a pharmaceutically acceptable salt thereof is prepared as a composition further comprising a pharmaceutically acceptable carrier.

Technical Field

The disclosure belongs to the field of medicine, and relates to an application of famitinib or a pharmaceutically acceptable salt thereof in preparing a medicine for treating c-KIT or PDGFRA mutant tumors.

Background

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tissue-derived tumors of the gastrointestinal tract, and the incidence rate of GIST in the population is about 1/10-2/10 thousands of people, accounting for 1% -4% of gastrointestinal tumors. Most commonly in the stomach (60% to 70%), followed by the small intestine (20% to 30%), colorectal only 5%, less than 5% in the esophagus, and occasionally retroperitoneum, mesentery, omentum, etc. The median age of GIST is 50-60 years, the median age is less than 40 years, the smaller the age of onset, the greater the possibility of malignancy; there is no significant difference in sex, but the small intestinal stromal tumor is common in women, and there is a family aggregation phenomenon.

Imatinib is a first line treatment for metastatic relapsed/unresectable GIST with an initial recommended dose of 400 mg/d. Median survival in patients with metastatic relapsed/unresectable GIST is about 20 months, with a dramatic improvement in prognosis after imatinib treatment with remission rates of 41-71% and overall clinical benefit rates of 73-90%, and long-term results with phase II and phase III clinical trials indicate that treatment with imatinib in unresectable or metastatic GIST increases Overall Survival (OS) in patients. If imatinib treatment is effective, the administration should be continued until disease progression or intolerable toxicity occurs. Common adverse events in imatinib treatment are edema, gastrointestinal reactions, leukopenia, anemia, rash, muscle spasm and diarrhea; most adverse events were mild to moderate, mostly transient and self-limiting within the first 8 weeks of drug administration, and improvement was achieved in symptomatic support therapy.

Despite the precise efficacy of imatinib treatment for GIST, treatment failure occurred in more than 50% of patients treated with imatinib for 2 years, and disease progression occurred in about 14% of patients after 6 months of treatment. Certain therapeutic effects (7% ORR, 24.1 weeks median PFS) were obtained with sunitinib in patients with GIST who failed or were intolerant to these imatinib treatments. GIST patients, who have progressed on both imatinib and sunitinib therapy, are either advised to participate in new drug clinical studies or are considered maintenance therapy with previous therapeutically effective and well tolerated drugs.

Mast/stem cell growth factor receptor (SCFR), also known as proto-oncogene c-KIT or tyrosine protein kinase KIT or CD117, is a receptor tyrosine kinase encoded by the human KIT gene.

Gastrointestinal stromal tumors are highly correlated with c-KIT over-activation, over 95% of gastrointestinal stromal tumors are organized to be cKIT (CD 117) positive, and CD117 becomes an important marker for diagnosing gastrointestinal stromal tumors. Meanwhile, most gastrointestinal stromal tumors are associated with c-KIT activating mutations, about 80% of gastrointestinal stromal tumors are accompanied by c-KIT activating mutations, and in addition, PDGFRA activating mutations account for a certain proportion of gastrointestinal stromal tumors, and about 7.2% of gastrointestinal stromal tumors are accompanied by PDGFRA mutations.

CN101007815A discloses famitinib (compound of formula (I)), and discloses that the compound has VEGF, EGFR inhibitory activity. CN107137407A discloses that famitinib can be used for the treatment of pancreatic cancer. CN106535896A discloses that fametinib can be used for the treatment of fibrotic diseases, such as pulmonary fibrosis, liver cirrhosis, scleroderma or renal fibrosis.

Disclosure of Invention

The present disclosure provides an application of famitinib or a pharmaceutically acceptable salt thereof in preparing a medicament for treating c-KIT or PDGFRA mutated tumors. The c-KIT mutated tumor is preferably a c-KIT activating mutated tumor. In some embodiments, the c-KIT or PDGFRA mutated tumor is selected from a c-KIT or PDGFRA mutated gastrointestinal stromal tumor, testicular seminoma, mast cell disease, melanoma, or acute myeloid leukemia. In some embodiments, the c-KIT or PDGFRA mutant tumor is a c-KIT or PDGFRA mutant gastrointestinal stromal tumor. In some embodiments, the c-KIT or PDGFRA mutant tumor is a metastatic relapsed/unresectable gastrointestinal stromal tumor of c-KIT or PDGFRA mutation. In some embodiments, the c-KIT or PDGFRA mutant tumor is a c-KIT or PDGFRA mutant gastrointestinal stromal tumor that has failed treatment with imatinib or is not toxicity-tolerant. In some embodiments, the c-KIT or PDGFRA mutated tumor is a c-KIT or PDGFRA mutated, advanced gastrointestinal stromal tumor.

In some embodiments, the c-KIT mutation can be selected from one or more of Exon9, Exon11, Exon13, Exon17, Exon13/14, Exon 17/18. In some embodiments, the c-KIT mutation may be selected from V559D, Del (559-560), Y503-F504 ins AY, D579-H580 ins IDPTQLPYD, V560G, V654A, T670I, D816A, D816G, D816H, D820H, N822H, Y823H, A829H, V559H + V654H, V559H + T670H, V559 553672 + D816H, V559H + D820H, V9 553672 + N822H, V559 + Y823H, V553672 + A H.

In some embodiments, the PDGFRA mutation may be selected from Exon12, Exon 14, Exon 18. In some embodiments, the PDGFRA mutation may be selected from V561D, D842V.

The present disclosure also provides a use of famitinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of metastatic relapsed/unresectable gastrointestinal stromal tumors (GIST). In some embodiments, the metastatic relapsed/unresectable gastrointestinal stromal tumor fails treatment with imatinib mesylate or is intolerant to toxicity.

The present disclosure also provides a use of famitinib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating advanced gastrointestinal stromal tumor (GIST). In some embodiments, the advanced gastrointestinal stromal tumor fails treatment with imatinib mesylate or is intolerant to toxicity.

The present disclosure also provides a use of famitinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of gastrointestinal stromal tumors that have failed therapy with imatinib or are intolerant to toxicity. In some embodiments, the gastrointestinal stromal tumor that has failed imatinib treatment or is intolerant to toxicity is an advanced gastrointestinal stromal tumor. In some embodiments, the gastrointestinal stromal tumor that has failed imatinib treatment or is not toxicity-tolerable is a metastatic relapsed/unresectable gastrointestinal stromal tumor.

The present disclosure also provides famitinib or a pharmaceutically acceptable salt thereof for use in the treatment of gastrointestinal stromal tumors that have failed therapy with imatinib or are not toxicity-tolerable. The present disclosure also provides famitinib, or a pharmaceutically acceptable salt thereof, for use in treating a c-KIT or PDGFRA mutated tumor. The present disclosure also provides famitinib or a pharmaceutically acceptable salt thereof for use in treating metastatic relapsed/unresectable gastrointestinal stromal tumors (GIST). The present disclosure also provides famitinib or a pharmaceutically acceptable salt thereof for use in treating advanced gastrointestinal stromal tumor (GIST).

The present disclosure also provides a method of treating gastrointestinal stromal tumors that have failed therapy with imatinib or are not toxicity-tolerable comprising administering to a patient an effective amount of famitinib or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising famitinib or a pharmaceutically acceptable salt thereof.

The present disclosure also provides a method of treating a c-KIT or PDGFRA mutated tumor comprising administering to a patient an effective amount of famitinib or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising famitinib or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method of treating gastrointestinal stromal tumors comprising performing a c-kit mutation assay on a patient diagnosed with gastrointestinal stromal tumors and administering an effective amount of famitinib, or a pharmaceutically acceptable salt thereof, to the patient if the c-kit mutation assay is positive. The present disclosure also provides a method of treating gastrointestinal stromal tumors comprising administering to a patient diagnosed with gastrointestinal stromal tumors an effective amount of famitinib, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising famitinib, or a pharmaceutically acceptable salt thereof, if the PDGFRA mutation analysis result is positive.

The present disclosure also provides a method of treating a patient with a gastrointestinal stromal tumor who has been diagnosed with metastatic relapse/unresectable GIST as determined by histopathological examination, has failed therapy with imatinib or is intolerant to toxicity, and is refractory to sunitinib, comprising administering to the patient famitinib or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising famitinib or a pharmaceutically acceptable salt thereof.

"treatment failure" refers to the determination of efficacy in imatinib mesylate treatment as disease progression as defined by RECIST criteria; "intolerance of toxicity" refers to the inability to receive further treatment with imatinib due to the development of intolerant adverse events during imatinib treatment.

The present disclosure also provides a method of treating metastatic relapsed/unresectable gastrointestinal stromal tumors (GIST), comprising administering to a patient an effective amount of famitinib, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising famitinib, or a pharmaceutically acceptable salt thereof.

The present disclosure also provides a method of treating advanced gastrointestinal stromal tumors (GIST), comprising administering to a patient an effective amount of famitinib, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising famitinib, or a pharmaceutically acceptable salt thereof.

In some embodiments, the gastrointestinal stromal tumor is a drug-resistant gastrointestinal stromal tumor. In some embodiments, the gastrointestinal stromal tumor is an imatinib-resistant gastrointestinal stromal tumor. In some embodiments, the gastrointestinal stromal tumor is sunitinib-resistant gastrointestinal stromal tumor. In some embodiments, the gastrointestinal stromal tumor is an imatinib and sunitinib resistant gastrointestinal stromal tumor.

In some embodiments, the c-KIT or PDGFRA mutated tumor, advanced gastrointestinal stromal tumor, metastatic relapsed/unresectable gastrointestinal stromal tumor, or gastrointestinal stromal tumor that has failed imatinib treatment or is not toxicity-resistant is intolerant to sunitinib.

In some embodiments, the method of treating c-KIT or PDGFRA mutated tumors, advanced gastrointestinal stromal tumors, metastatic relapsed/unresectable gastrointestinal stromal tumors, gastrointestinal stromal tumors that have failed therapy with imatinib or are not toxicity-tolerable, comprises administering to a patient an effective amount of famitinib or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising famitinib or a pharmaceutically acceptable salt thereof, wherein the patient has a median PFS of greater than 7 months, preferably a median PFS of greater than 10 months, more preferably a median PFS of greater than 12 months.

In some embodiments, the method of treating a c-KIT or PDGFRA mutated tumor, advanced gastrointestinal stromal tumor, metastatic relapsed/unresectable gastrointestinal stromal tumor, gastrointestinal stromal tumor that failed therapy with imatinib, or is not toxicity-tolerant, comprising administering to a patient an effective amount of famitinib or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising famitinib or a pharmaceutically acceptable salt thereof, wherein the patient has an increase in PFS by 30% to 145%, preferably an increase in PFS by 50% to 145%, compared to administration of a therapeutically effective amount of sunitinib to the patient; more preferably, the median PFS is increased by 100% to 145%.

In an alternative embodiment, the famitinib or a pharmaceutically acceptable salt thereof is administered in a dosage selected from 0.1-1000mg once a day, twice a day, three times a day, preferably once a day.

In an alternative embodiment, the famitinib or a pharmaceutically acceptable salt thereof is prepared in a unit dosage form containing 0.1-1000mg famitinib or a pharmaceutically acceptable salt thereof for once a day, twice a day or three times a day administration.

In alternative embodiments, the famitinib or a pharmaceutically acceptable salt thereof is prepared as a pharmaceutical composition comprising a unit dose of famitinib or a pharmaceutically acceptable salt thereof, the unit dose being selected from 0.1-100mg, specifically, 0.1mg, 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1.0mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 47mg, 52mg, 54mg, 52mg, 49mg, 52mg, 25mg, 11mg, 25mg, or a, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg or 100 mg.

In alternative embodiments, the famitinib or a pharmaceutically acceptable salt thereof is administered in an amount selected from the group consisting of 0.1-100mg, specifically, 0.1mg, 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1.0mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 50mg, 51mg, 52mg, 53mg, 58mg, 62mg, 55mg, 58mg, 52mg, 55mg, 58mg, 60mg, 52mg, 60mg, 23mg, or a, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, and the administration frequency may be once a day, twice a day, three times a day, preferably once a day.

In an alternative embodiment of the disclosure, the famitinib or a pharmaceutically acceptable salt thereof is administered by body weight, and the dose is selected from 0.1-10.0 mg/kg. In a regimen for administration by body weight, the dose of famitinib or a pharmaceutically acceptable salt thereof may be 0.1mg/kg, 0.2mg/kg, 0.3mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.5 mg/kg, 5mg/kg, 4.5 mg/kg, 5mg/kg, 5.5 mg/kg, 2.6mg/kg, 2mg/kg, 5.6mg/kg, 5.8mg/kg, 6.0mg/kg, 6.2mg/kg, 6.4mg/kg, 6.6mg/kg, 6.8mg/kg, 7.0mg/kg, 7.2mg/kg, 7.4mg/kg, 7.6mg/kg, 7.8mg/kg, 8.0mg/kg, 8.2mg/kg, 8.4mg/kg, 8.6mg/kg, 8.8mg/kg, 9.0mg/kg, 9.2mg/kg, 9.4mg/kg, 9.6mg/kg, 9.8mg/kg, 10.0mg/kg, the frequency of administration may be once a day, twice a day, three times a day, preferably once a day.

In an alternative embodiment, famitinib or a pharmaceutically acceptable salt thereof is prepared in a unit dosage form comprising 1-25mg of famitinib or a pharmaceutically acceptable salt thereof, specifically optionally 10mg, 15mg, 20mg, 25mg, administered once a day, twice a day or three times a day, preferably once a day.

In an alternative embodiment, famitinib or a pharmaceutically acceptable salt thereof is prepared in a unit dosage form containing 25mg of famitinib or a pharmaceutically acceptable salt thereof for once daily administration.

The pharmaceutically acceptable salts described in this disclosure are selected from, but not limited to, mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate, preferably malate. The farnesyl malate described in this disclosure is farnesyl malate.

Famitinib or a pharmaceutically acceptable salt thereof can also be formulated together with a pharmaceutically acceptable carrier into a composition form well known in the art, such as tablets, capsules, granules, injections, and the like. The disclosure also relates to methods of treating c-KIT or PDGFRA mutated tumors using pharmaceutical compositions containing famitinib or a pharmaceutically acceptable salt thereof. The present disclosure also relates to methods of treating metastatic relapsed/unresectable gastrointestinal stromal tumors (GIST) using pharmaceutical compositions containing famitinib or a pharmaceutically acceptable salt thereof. The present disclosure also relates to methods of treating advanced gastrointestinal stromal tumors using pharmaceutical compositions containing famitinib or a pharmaceutically acceptable salt thereof. The present disclosure also relates to the treatment of gastrointestinal stromal tumors that have failed therapy with imatinib or are not toxicity-tolerant using a pharmaceutical composition comprising famitinib or a pharmaceutically acceptable salt thereof. The disclosure also relates to a method of treating a gastrointestinal stromal tumor comprising detecting whether a patient has developed a c-KIT or PDGFRA mutation and, if so, administering famitinib or a pharmaceutically acceptable salt thereof to the patient.

In some embodiments, the mortality rate is reduced by at least 40% using a pharmaceutical composition comprising famitinib or a pharmaceutically acceptable salt thereof for treating metastatic relapsed/unresectable gastrointestinal stromal tumors (GIST) as compared to treating metastatic relapsed/unresectable gastrointestinal stromal tumors (GIST) using a pharmaceutical composition comprising sunitinib or a pharmaceutically acceptable salt thereof; in certain embodiments, mortality is reduced by at least 35%; in certain embodiments, mortality is reduced by at least 30%; in certain embodiments, mortality is reduced by at least 25%; in certain embodiments, mortality is reduced by at least 20%; in certain embodiments, mortality is reduced by at least 15%; in certain embodiments, mortality is reduced by at least 10%.

"treatment failure or toxicity intolerant gastrointestinal stromal tumors of imatinib" comprises treatment failure or toxicity intolerant gastrointestinal stromal tumors of imatinib or a pharmaceutically acceptable salt thereof, in particular gastrointestinal stromal tumors that have failed or are intolerant to imatinib mesylate.

An "effective amount" comprises an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: for example, the condition to be treated, the general health of the patient, the method and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

"metastatic relapse/unresectable" means metastatic relapse and/or unresectable.

The gastrointestinal stromal tumor described in the present disclosure can be selected from the group consisting of gastric stromal tumor, esophageal stromal tumor, small intestine stromal tumor, rectal stromal tumor, and the like.

Detailed Description

Example 1: cell proliferation inhibition assay

1. Inhibition of proliferation of 32D cells transfected with multiple c-KIT mutations by famitinib, sunitinib and imatinib

Materials and methods

A compound: famitinib malate, imatinib mesylate, and sunitinib malate were synthesized and provided by Jiangsu Henry medicine, Inc. (Jiangsu province, China).

Site-directed mutagenesis

Michael h.tomasson (washington university medical school, st louis, mo) generously provided a murine stem cell virus-based retroviral construct carrying either murine-human heterozygote WT KIT cDNA or activated mutant D816V (816Asp → Val) KIT cDNA. Heterozygous KIT alleles were generated by in-frame fusion of the extracellular and transmembrane regions of murine KIT with the intracellular region of human KIT. Studies have shown that replacement of the human extracellular and transmembrane domains of KIT with homologous murine sequences can increase expression efficiency and increase the transformation potential of certain KIT mutants in murine cells. Since the GFP domain is enhanced by the downstream internal ribosome entry site, the KIT allele will co-express with the enhanced GFP. KIT point mutations were generated according to mutagenesis protocol 3 in molecular cloning (3 rd edition). For deletion and insertion mutagenesis, the mutagenic primers are designed to avoid deleted sequences or sequences containing insertions, respectively. All of the above PCRs use high fidelity Primestar hot start DNA polymerase (Chinese Dalian, Takara). Other enzymes used in the above experiments were also purchased from Takara. The sequences of all mutants in this study were verified by direct sequencing.

Cell culture and retroviral transfection

IL-3 dependent murine hematopoietic cell line 32D (ATCC, Manassas, VA, USA) was maintained in RPMI-1640 supplemented with 10% FBS and 15% WEHI-3B (ATCC) conditioned medium as the source of murine IL-3. Retrovirus preparation and transfection was performed according to protocols and guidelines provided by the university of Stanford (Stanford, Calif.) Nolan laboratory. Retroviral supernatants were obtained 48 hours after transfection of the plasmid encoding the KIT mutant into a Phoenix-Eco packaging cell line using Fugene 6(Roche Diagnostics, Indianapolis, IN, USA). The 32D cells were infected with viral supernatant and then screened 48 hours later and used for independent growth of IL-3. WT KIT transfected cells were screened using 200ng/mLrmSCF (R & D Systems, Minneapolis, Minn., USA).

Cell proliferation assay

Cells (5X 103) in 200. mu.L of medium with or without IL-3 were incubated in triplicate in 96-well plates with different concentrations of imatinib, famitinib. We added MTT (Sigma-Aldrich, st louis, missouri, usa) and incubated the cells for 4 hours. A solubilizing solution (a solution of detergent SDS in dilute hydrochloric acid) was added to dissolve the insoluble purple formazan product into the colored solution. The absorbance of the colored solution was quantified by measuring with a reference filter at 650nm at 570nm by a spectrophotometer (Molecular Devices, Sunnyvale, Calif., USA). Growth inhibition was plotted as the ratio of the average absorbance of drug-treated wells relative to non-drug controls. IC (integrated circuit)₅₀Values were calculated by curve fitting software GraphPad Prism version 5(GraphPad software, san diego, california, usa).

TABLE 1 Famirtinib, sunitinibAnd inhibition of proliferation of c-KIT mutant 32D cells by imatinib IC₅₀Value (nM)

Remarking: wherein Exon9, Exon11 and Exon17 are primary mutations, and Exon11 + Exon13, Exon11 + Exon 14, Exon11 + Exon17 and Exon11 + Exon 18 are secondary mutations.

The famitinib has better activity than imatinib/sunitinib aiming at wild c-KIT/various types of c-KIT mutation, and can effectively overcome imatinib drug resistance caused by c-KIT wild mutation, Exon9 mutation, Exon11 + Exon13 mutation and Exon11 + Exon 14 mutation.

2. Inhibition of kinase Activity (IC) of famitinib on multiple PDGFRA mutants₅₀)

Using ICs₅₀Profiler^TMMethod for determining kinase inhibition activity of famitinib malate on PDGFRA mutant and calculating IC₅₀The value is obtained.

TABLE 2 kinase Activity measurement reaction System

The experimental steps are as follows:

a proper amount of kinase and a proper amount of polypeptide substrate are respectively mixed with Famirtinib malate (1nM, 3nM, 10nM, 30nM, 100nM, 300nM, 1 muM, 3 muM, 10 muM) with different concentrations. Adding magnesium acetate and [ gamma-^33P]ATP initiates the kinase catalyzed reaction for 40 minutes at room temperature. After the reaction, 0.5% phosphoric acid solution was added to terminate the reaction. 10 μ L of the reaction mixture was filtered through a P30 filter, washed 3 times for 4min with 75mM phosphate buffer, and washed once with 0.425% phosphate solution to remove free [ gamma-^33P]-ATPAnd fixing the protein, drying the membrane, counting by a liquid scintillation counter, and determining whether the polypeptide substrate is³³The amount of P.

The experimental results are as follows: IC obtained after fitting according to concentration-inhibition curve₅₀The value is obtained.

TABLE 3 inhibition of kinase Activity (IC) by famitinib against various PDGFRA mutants₅₀)

As can be seen, famitinib has strong inhibitory effect on wild-type c-KIT and PDGFRA/B, as well as c-KIT exon11 (V560G), exon13 (V654A) and exon17 (D816H) mutations, and PDGFRAexon 12 (V561D) and exon 18 (D842V). Except the mutation occurring in exon11, the other mutations are imatinib-resistant mutations, wherein the PDGFRAexon 18(D842V) mutation is sunitinib-resistant mutation, and the effect of famitinib in treating imatinib-resistant advanced gastrointestinal stromal tumor is prompted.

Example 2: multicenter, open, single-arm phase II clinical trial dosing regimen for treating gastrointestinal stromal tumor with famitinib malate

Fametinib 25mg was taken orally before breakfast every day. The dosage can be adjusted to 20mg/d according to toxic and side effects; the administration was carried out for 28 consecutive days for 1 treatment cycle, with the intention of taking the drugs approximately at the same time each day. During the period, if toxic and side effects occur, the administration can be suspended, and the administration suspension time is included in the treatment period. The initial dose of fametinib was 25mg, which was allowed to downregulate to 20mg/d when downregulated as required for toxic response.

Group entry criteria

Patients must meet all of the following inclusion criteria to be enrolled in the cohort trial:

1) male or female, age 18-75 years;

2) patients diagnosed with metastatic relapsed/unresectable GIST, failed treatment with imatinib mesylate or intolerant toxicity, and who failed to use sunitinib by histopathological examination;

"treatment failure" refers to the determination of efficacy in imatinib mesylate treatment as disease progression as defined by RECIST criteria; "intolerance of toxicity" refers to the inability to receive further treatment with imatinib due to the development of intolerant adverse events during imatinib treatment.

3) The time interval between the last administration of the imatinib mesylate and the group entry time of the study is more than or equal to 2 weeks;

4) according to RECIST 1.1 standard, at least one measurable focus exists, namely the longest diameter of the focus is more than or equal to 10mm when CT thin layer scanning (the layer thickness is less than or equal to 5 mm);

5) ECOG physical condition: 0-1 min;

6) the main organs have basically normal functions and meet the following conditions:

ANC≥1.5×109/L；

PLT≥80×109/L；

hb is more than or equal to 90g/L (and transfusions are not carried out within 14 days);

AST and ALT are less than or equal to 2.5 multiplied by ULN; ALT and AST ≤ 5 × ULN if liver function abnormality is due to tumor metastasis;

TBIL≤1.5×ULN；

cholesterol is less than or equal to 7.75mmol/L and triglyceride is less than or equal to 1 × ULN;

serum creatinine < 1 × ULN and endogenous creatinine clearance >50 ml/min (Cockcroft-Gault formula);

urinary regular protein results <2 +; if the urine protein is more than or equal to 2+, the urine protein is quantitatively determined within 24 hours, and the urine protein can be put into the group within less than 1g/24 hours;

serum calcium, potassium, magnesium, phosphorus are within normal value ranges, or famitinib is corrected to normal value ranges before first administration;

INR is less than or equal to 1.5 and APTT is less than or equal to 1.5 multiplied by ULN;

LVEF≥50％。

exclusion criteria

Patients with any of the following were not enrolled in the study:

1) previous treatment with VEGFR-targeted tyrosine kinase inhibitors;

2) the acute toxicity reaction of the prior imatinib mesylate treatment or other treatments is not recovered or reaches NCI CTC AE 3.0-I degree;

3) receiving exaggerated surgery or radiotherapy within 4 weeks before entering the group, or receiving temporary palliative radiotherapy aiming at relieving pain within 2 weeks before entering the group;

4) bleeding greater than or equal to II (NCI CTC AE 3.0) occurred within 4 weeks prior to group entry;

5) the inability to swallow, chronic diarrhea and intestinal obstruction, the existence of a variety of factors that affect drug administration and absorption;

6) in the last 5 years, a2 nd primary malignancy, with the exception of basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix, which has been adequately treated;

7) occurred within 12 months prior to group entry: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass surgery, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or an arteriovenous embolic event that has occurred within 6 months (e.g., lower limb deep vein embolism, pulmonary embolism);

8) drug-uncontrollable thyroid dysfunction;

9) atrial fibrillation, prolonged QTc interval (450 ms in males, 470ms in females) or arrhythmia greater than or equal to II degrees still exists when the Chinese medicinal composition is used in the group;

10) hypertensive patients with poor drug control (systolic >140mmHg and/or diastolic >90 mmHg);

11) known patients with acute or chronic active hepatitis;

12) a history of immunodeficiency, including positive HIV detection, or other acquired, congenital immunodeficiency diseases, or a history of organ transplantation;

13) other medicine clinical tests are participated in within 4 weeks before group entry;

14) positive in a baseline pregnancy test for a pregnant, lactating female patient or a fertile female;

15) female or male patients of child bearing age who are reluctant to take effective contraceptive measures during the entire trial;

16) at the discretion of the investigator, there are serious concomitant diseases (e.g., severe diabetes, etc.) that compromise patient safety or affect the patient's completion of the study;

17) the past has a definite history of neurological or psychiatric disorders, such as epilepsy or dementia, with poor compliance;

18) researchers considered the group inapplicable.

Test drug

The common name is: famicanib malate capsules.

The name of English: famitiniib Malate Capsule.

The manufacturer: henry pharmaceutical products of Jiangsu, Inc.

Specification: 20mg, 25 mg.

And (3) test results:

can evaluate the curative effect

CR

PR

SD

PD

ORR

DCR

mPFS(mos)

82 examples of

Example 1

21 examples of

54 examples of

6 examples of

25.3％

87.4％

14.7

Example 3: randomized, open, controlled, multicenter phase III clinical study of Famirinib malate vs sunitinib malate for treatment of gastrointestinal stromal tumors that failed Imatinib therapy

Dosing regimens

Test groups:

famitinib: the oral administration is 25 mg/time, 1 time per day, and administration before or after meal. A fixed time daily dosing within 0.5h after a meal is recommended, with one treatment cycle every 6 weeks. Allowing dose adjustments and delayed dosing.

Control group:

sunitinib: oral administration, 50 mg/time, 1 time daily, either before or after meals, with a fixed time daily recommended, 4 weeks off for 2 weeks, and every 6 weeks for a treatment period. Dosage adjustments and delayed dosing are permitted, with specific dosing and adjustment regimens referenced to the drug insert.

Group entry criteria

Patients must meet all of the following criteria to be enrolled in the study:

1. patients voluntarily enter the group and sign written informed consent, the compliance is good, and follow-up visits are matched;

2. the age is more than or equal to 18 years (calculated on the day with informed consent), and the male and the female can both use the food;

3. the metastatic or non-radical gastrointestinal stromal tumor diagnosed by histology has at least one measurable focus meeting RECIST v1.1 standard, and the focus after radiotherapy is confirmed by imaging to show the progress after radiotherapy;

4. failure of treatment (disease progression or intolerance of toxicity during treatment) prior to treatment with imatinib;

5. the subject can be tested for biomarker analysis in conjunction with providing a 10ml blood sample and fresh or archived tumor tissue, or in conjunction with receiving a biopsy at baseline; note: if the tumor tissue sample without the storage is evaluated by researchers, the tumor tissue sample with high biopsy risk is accepted, if the tumor tissue sample can provide a previous c-KIT/PDGFRA detection reporter, the tumor tissue sample can be screened into a group;

ECOG scoring: 0 to 1;

7. the estimated life cycle is more than or equal to 12 weeks;

8. the functions of the vital organs and organisms meet the following requirements (no blood products and cytokine drugs are allowed to be used within 14 days before the first administration):

the absolute count of the neutrophils is more than or equal to 1.5 multiplied by 109/L;

the thrombocyte is more than or equal to 100 multiplied by 109/L;

the hemoglobin is more than or equal to 90 g/L;

bilirubin is less than or equal to 1.5 × ULN;

ALT and AST ≤ 2.5 × ULN

Serum creatinine is less than or equal to 1.5 multiplied by ULN;

urinary regular protein results <2 +; if the urine protein is more than or equal to 2+, the urine protein is quantitatively determined within 24 hours and can be put into groups within less than or equal to 1g/24 hours;

the serum calcium, potassium, magnesium and phosphorus are in the normal value range or corrected to the normal value range before random;

the international standardized ratio INR is less than or equal to 1.5, and the activated partial thromboplastin time APTT is less than or equal to 1.5 multiplied by ULN;

QTc is less than or equal to 450ms (male) and 470ms (female); the left ventricular ejection fraction LVEF is more than or equal to 50 percent.

9. A female patient of non-surgical sterilization or child bearing age who requires a medically approved contraceptive procedure (e.g., an intrauterine device, a contraceptive, or a condom) during and 90 days after the end of the study treatment period; female patients of childbearing age who are not surgically sterilized must be negative for serum HCG examination within 72 hours prior to randomization; and must be non-lactating; for male patients whose partner is a woman of childbearing age, contraception should be effected during the study treatment period and within 90 days after the end of the study treatment period.

Exclusion criteria

Patients will not be admitted to the study if they meet any of the following criteria:

1. has received molecular targeted therapy for the treatment of gastrointestinal stromal tumors other than imatinib;

2. the toxic response of the prior imatinib treatment or other treatments has not been restored or achieved NCI CTC AE 5.0 ≤ grade 1;

3. ascites or pleural effusion with clinical symptoms, patients who need to puncture drainage or who have received pleural fluid or ascites drainage within 1 month before signing an informed consent, and except patients who only show a small amount of ascites or pleural effusion in an imaging way but are not accompanied by clinical symptoms;

4. in the last 5 years, a2 nd primary malignancy, with the exception of basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix, which has been adequately treated;

5. gastrointestinal stromal tumors with central nervous system metastases;

6. the inability to swallow, chronic diarrhea and intestinal obstruction, the existence of a variety of factors that affect drug administration and absorption;

7. grade 2 bleeding (NCI CTC AE 5.0) occurred within the first 4 weeks of randomization;

8. happened within the first 12 months of randomization: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass surgery, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or an arteriovenous embolic event that has occurred within 6 months (e.g., lower limb deep vein embolism, pulmonary embolism);

9. there are clinical symptoms or diseases of the heart that are not well controlled, such as: (1) heart failure above NYHA2 level (2) unstable angina (3) myocardial infarction occurring within 1 year (4) clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention;

10. hypertension exists, and the good control cannot be obtained by antihypertensive drug treatment (the systolic pressure is more than or equal to 140mmHg or the diastolic pressure is more than or equal to 90mmHg, and after the abnormal patients in the screening period are corrected, the abnormal patients are in accordance with 2 measurements at intervals of more than 24 h); hypertensive crisis or hypertensive encephalopathy has occurred in the past;

11. drug-uncontrollable thyroid dysfunction;

12. acute or chronic active hepatitis is known, HBV virus titer is more than 500IU, HCVRNA detection is more than ULN;

13. a history of immunodeficiency, including positive HIV detection, or other acquired, congenital immunodeficiency diseases, or a history of organ transplantation;

14. receiving exaggerated surgery or radiotherapy within 4 weeks of randomization, or receiving temporary palliative radiotherapy within 1 week of randomization for the purpose of pain relief; molecular targeted therapy (including other oral targeted drugs for clinical trials) patients with a half-life of < 5 drugs from the first study medication;

15. other drug clinical trials were enrolled within the first 4 weeks of randomization;

16. perforation of the digestive tract occurred within the first 3 months at random;

17. at the discretion of the investigator, there are serious concomitant diseases that compromise patient safety or affect the patient's completion of the study (e.g., severe diabetes, a clear history of neurological or psychiatric disorders, such as epilepsy or dementia, etc.).