阅读说明：本技术 阿帕替尼与依托泊苷联合在制备治疗肺癌的药物中的用途 (Application of apatinib and etoposide in preparation of medicine for treating lung cancer ) 是由 蔡晓虹 张芷旋 尹序德 汪闻平 景秋平 于 2019-09-11 设计创作，主要内容包括：本发明涉及阿帕替尼与依托泊苷联合在制备治疗肺癌的药物中的用途。具体而言,本发明涉及阿帕替尼与依托泊苷联合在制备治疗肺癌的药物中的用途,尤其是小细胞肺癌。在本发明的优选实施方案中,小细胞肺癌指的是广泛期的小细胞肺癌,尤其是化疗后广泛期的小细胞肺癌。本发明阿帕替尼联合依托泊苷治疗肺癌的方法,显示了良好的治疗效果。(The invention relates to application of apatinib and etoposide in preparation of a medicine for treating lung cancer. Specifically, the invention relates to an application of the combination of apatinib and etoposide in preparing a medicament for treating lung cancer, in particular to small cell lung cancer. In a preferred embodiment of the invention, small cell lung cancer refers to the extensive stage of small cell lung cancer, especially the extensive stage of small cell lung cancer after chemotherapy. The method for treating the lung cancer by combining apatinib with etoposide has a good treatment effect.)

1. Application of apatinib in combination with etoposide in preparation of drugs for treating lung cancer.

2. The use of claim 1, wherein the lung cancer is small cell lung cancer.

3. The use of claim 1, wherein the lung cancer is a wide-term small cell lung cancer.

4. The use of claim 1, wherein the lung cancer is a wide-ranging small cell lung cancer after chemotherapy.

5. Use according to claim 1, wherein the dose of apatinib is selected from 100-1000mg, preferably from 100-500mg, most preferably 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 500 mg.

6. Use according to claim 1 wherein the dose of etoposide is selected from 10-500mg, preferably 10-200mg, most preferably 10mg, 20mg, 25mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100 mg.

7. The use according to claim 1, wherein the weight ratio of apatinib to etoposide is selected from 0.01-100:1, preferably from 1:12, 1:10, 1:9, 1:8, 2:15, 1:7, 1:6, 1:5, 5:24, 2:9, 1:4, 4:15, 5:18, 2:7, 3:10, 5:16, 1:3, 5:14, 3:8, 2:5, 5:12, 3:7, 4:9, 1:2, 8:15, 5:9, 4:7, 7:12, 3:5, 5:8, 2:3, 7:10, 5:7, 3:4, 7:9, 4:5, 5:6, 6:7, 7:8, 8:9, 9:10, 14:15, 15:16, 1:1, 6:5, 4:5, 3: 9, 2:5, 1:5, 2:5, 3:5, 5:6, 6:7, 7:8, 8:9, 9: 15:16, 1:1, 6:5, 5: 5, 3:5, 2:5, 2 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, more preferably 1:1, 6:5, 5:4, 4:3, 3:2, 8:5, 2:1, 5:2, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10: 1.

8. Use according to any one of claims 1 to 7, wherein the apatinib is provided in the form of a tablet.

9. The use according to claim 8 wherein the etoposide is provided in the form of a soft gel capsule.

10. A pharmaceutical composition comprising apatinib, etoposide, optionally one or more pharmaceutically acceptable carriers, excipients and/or diluents.

Technical Field

The invention belongs to the field of medicines, and relates to an application of apatinib and etoposide in preparation of a medicine for treating lung cancer.

Background

Small Cell Lung Cancer (SCLC), a histological subtype of Lung Cancer, accounts for approximately 15% to 20% of Lung Cancer patients. SCLC grows rapidly, metastasizes rapidly, is highly malignant, and is prone to early metastasis. Current treatment modalities include surgery, chemotherapy, and radiation therapy. The platinum-based combination Etoposide (EP) chemotherapy regimen is a standard first-line chemotherapy regimen, but the recurrence rate after treatment is high. The median survival time of recurrent small cell lung cancer is only 4-5 months, so that it is also a hotspot of current research whether maintenance treatment with the same or a replacement scheme can benefit SCLC patients with stable extensive period after first-line chemotherapy is completed.

In recent years, the treatment of small cell lung cancer is advanced mainly based on mek gene and immunotherapy targeted therapy, but the treatment of small cell lung cancer is mainly chemotherapy, the treatment scheme is not changed in decades, and although new chemotherapeutic drugs are developed as substitutes, the overall survival rate is not improved significantly. There are many abnormal gene mutations in small cell lung cancer, such as TP53, RB gene mutation are closely related to small cell lung cancer, but there is no specific medicine aiming at these targets at present. Many clinical studies have explored small molecule drugs targeting other targets, such as those targeting Bcl-2, mTOR, EGFR, C-kit, etc., but all have failed. Anti-angiogenic therapies have been explored in small cell lung cancer studies, such as E3501, SALUTE studies, etc., and the results show that combination anti-angiogenic therapy can prolong PFS in patients, but not translate into OS benefits. In recent years, the only targeted drug with obvious influence is sunitinib, a multi-target small-molecule tyrosine kinase inhibitor mainly used for resisting angiogenesis, sunitinib serving as maintenance therapy of small-cell lung cancer can prolong PFS (3.7vs 2.1, P is 0.037) which is prolonged by 1.6 months compared with a placebo group, and OS (oxygen system) is also prolonged but does not reach statistical difference. This study suggests that it is not absolutely impossible to attempt targeted drugs in small cell lung cancer.

Both the persistence of tumor blood vessels and immune escape are implicated in the ten major characteristics of tumors. The interaction and complex mechanisms among cells, cytokines and other molecules in the tumor microenvironment, where the VEGF/VFGFR pathway plays an important role in multiple links of tumor immune escape, such as maturation of Dendritic Cells (DCs), induction of the mature DCs to express PD-L1, thereby affecting T cell activation, and affecting the production of cytotoxic lymphocytes (CTLs). Kailas et al suggested that Cabozantinib (Cabozantinib) significantly increased the number of effector T cells surrounding tumor tissue. Hodi et al, who used bevacizumab in combination with ipilimumab to treat 46 patients with metastatic melanoma, found that the combination therapy could improve the phenotype of tumor-invading lymphocytes (TIL) and circulating memory cells compared to ipilimumab alone, thereby regulating the body immunity. The above studies indicate that the anti-angiogenesis therapy has the function of enhancing the anti-tumor immunity of the organism while preventing the tumor angiogenesis.

Apatinib is a newly developed oral anti-angiogenesis drug, and is highly selectively combined with VEGFR-2 sites, downstream signal conduction is blocked, tumor angiogenesis is strongly inhibited, and the functions of VEGFR-2 restorable DC cells are blocked, so that the anti-tumor immune function of an organism is enhanced. The apatinib can effectively inhibit VEGFR2 at a very low concentration, and can also inhibit kinases such as platelet-derived growth factor receptor (PDGFR), c-Kit and c-Src at a higher concentration, and the acting part of the apatinib is an intracellular ATP binding site of a protein tyrosine receptor. Pharmacodynamic studies show that apatinib can inhibit VEGFR tyrosine kinase activity, block signal conduction after VEGF combination, and inhibit tumor angiogenesis. Preclinical research shows that apatinib has strong inhibitory effect on the growth of various human nude mouse transplantable tumors such as sarcoma, colorectal cancer, non-small cell lung cancer, gastric cancer, liver cancer and the like, and is a broad-spectrum antitumor drug. And in the tumor species with multiple drug resistance, apatinib can reverse the multiple drug resistance. The existing clinical test results show that the apatinib has obvious effects on various tumors such as colorectal cancer, non-squamous non-small cell lung cancer, hepatocellular carcinoma, breast cancer and the like.

Apatinib has been shown in phase III trials for treatment of advanced gastric cancer to significantly prolong progression-free survival (PFS) and Overall Survival (OS) of patients with advanced gastric cancer, and based on the results of phase I-III clinical trials, the chinese food and drug administration approved apatinib for marketing for treatment of advanced gastric cancer 11/17/2014. In addition, apatinib also shows good curative effect in II-stage clinical tests for treating advanced non-squamous non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer and triple-negative/non-triple-negative breast cancer, can remarkably prolong the progression-free survival time (PFS) of a patient, and currently carries out III-stage clinical tests on various malignant tumors such as non-squamous non-small cell lung cancer, hepatocellular carcinoma and the like.

The invention provides a method for treating lung cancer by combining apatinib with etoposide, and shows good treatment effect.

Disclosure of Invention

The invention provides application of apatinib combined with etoposide in preparation of a medicine for treating lung cancer.

The lung cancer is selected from small cell lung cancer, non-small cell lung cancer and mixed small cell cancer, the non-small cell lung cancer is selected from squamous cell carcinoma, lung adenocarcinoma, large cell lung cancer, adenosquamous carcinoma, sarcomatoid carcinoma, carcinoid tumor and salivary gland carcinoma, and small cell lung cancer is preferred. In a preferred embodiment, the lung cancer of the present invention refers to a wide-term small cell lung cancer, especially a wide-term small cell lung cancer after chemotherapy. The chemotherapy comprises platinum-containing chemotherapy regimen, especially combined chemotherapy of platinum and etoposide.

In a preferred embodiment of the invention, the weight ratio of apatinib to etoposide is selected from 0.01-100:1, preferably from 1:12, 1:10, 1:9, 1:8, 2:15, 1:7, 1:6, 1:5, 5:24, 2:9, 1:4, 4:15, 5:18, 2:7, 3:10, 5:16, 1:3, 5:14, 3:8, 2:5, 5:12, 3:7, 4:9, 1:2, 8:15, 5:9, 4:7, 7:12, 3:5, 5:8, 2:3, 7:10, 5:7, 3:4, 7:9, 4:5, 5:6, 6:7, 7:8, 8:9, 9:10, 14:15, 15:16, 1:1, 6:5, 5:4, 3:8, 3:5, 1:5, 2:5, 1:5, 5:8, 1:5, 5:8, 1:5, 5:8, 5: 5, 1:8, 5, 6:1, 7:1, 8:1, 9:1, 10:1, more preferably 1:1, 6:5, 5:4, 4:3, 3:2, 8:5, 2:1, 5:2, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10: 1.

In certain embodiments, the dose of apatinib is selected from 100-1000mg, preferably from 100-500mg, most preferably 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 500 mg.

In certain embodiments, the dose of etoposide is selected from 10-500mg, preferably 10-200mg, most preferably 10mg, 20mg, 25mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100 mg.

In an embodiment of the invention, the route of administration is selected from oral, parenteral, transdermal, including but not limited to intravenous, subcutaneous, intramuscular, preferably oral. In a preferred embodiment of the invention, apatinib and etoposide are both administered orally. In a preferred embodiment of the invention, apatinib is administered in the form of a tablet and etoposide is administered in the form of a soft capsule.

The invention further relates to the application of the combination of apatinib and etoposide in preparing a medicament for treating lung cancer, wherein the administration frequency of apatinib can be once a day, once every two days, once every three days, five days for two days, seven days for seven days. The administration frequency of the etoposide can be once a day, once every two days, once every three days, five days for two days, seven days for seven days, fourteen days for seven days.

In a preferred embodiment of the invention, apatinib is administered orally once daily at 250mg and etoposide is administered orally once daily at 50 mg. Further, apatinib was administered orally once daily, 250mg, daily; etoposide is administered on days 1-14, with 21 days as a course of treatment, until disease progression or development of intolerable toxicity. .

The invention also relates to a pharmaceutical composition containing apatinib and etoposide, which comprises one or more optional pharmaceutical carriers, excipients and/or diluents. The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. For example, the pharmaceutical preparation containing apatinib and etoposide can be prepared into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection, sterile powder for injection and concentrated solution for injection), suppositories, inhalants or sprays.

The apatinib and etoposide of the invention can be administered alone or in combination with one or more therapeutic agents.

The ingredients to be combined (e.g., apatinib and etoposide, with any of the other component drugs) may be administered simultaneously or separately in sequential order. Furthermore, the components to be combined may also be administered in combination in the same formulation or in separate and distinct formulations.

The invention also provides a medicine packaging box, wherein the medicine composition of apatinib and etoposide is packaged.

The invention provides a method for treating lung cancer by combining apatinib and etoposide, which has a good treatment effect and has advantages in PFS (lung cancer treatment).

Detailed Description

In the invention, the apatinib refers to a pharmaceutical composition containing all the apatinib in a pharmaceutical form, such as apatinib or a pharmaceutical salt thereof. Etoposide refers to a pharmaceutical composition containing all the pharmaceutically acceptable forms of etoposide such as etoposide or pharmaceutically acceptable salts thereof.

The invention relates to a "combination" which is a mode of administration and means that at least one dose of apatinib and at least one dose of etoposide are administered over a period of time, wherein both substances show a pharmacological effect. The time period may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. Apatinib and etoposide may be administered simultaneously or sequentially. Such terms include treatments wherein apatinib and etoposide are administered by the same route of administration or by different routes of administration. The mode of administration of the combinations of the invention is selected from simultaneous administration, separate formulation and co-administration or separate formulation and sequential administration. In a preferred embodiment, apatinib is administered after a meal, e.g. half an hour after a meal, and etoposide is taken before a meal.

The combination of the invention may refer to the administration of apatinib and etoposide simultaneously, said "simultaneously" as used herein means that the administration of apatinib and etoposide at least partially overlap in time. Thus, concurrent administration includes dosing regimens in which administration of one drug continues after administration of another drug is stopped. For example, administration of apatinib continues after administration of etoposide is stopped.

The term "effective amount" refers to an amount of a drug effective to treat a disease or disorder in a mammal. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the size of the tumor; inhibit (i.e., slow to some extent and preferably prevent) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably prevent) tumor metastasis; inhibit tumor growth to some extent; and/or to alleviate one or more symptoms associated with the condition to some extent. Depending on the extent to which the drug can prevent growth and/or kill existing cancer cells, it can be cytostatic and/or cytotoxic. For cancer treatment, in vivo efficacy can be measured by assessing survival duration, Progression Free Survival (PFS) duration, Response Rate (RR), response duration, and/or quality of life.

By "platinum-containing chemotherapeutic regimen" is meant a chemotherapeutic regimen comprising a platinum-based antineoplastic agent, optionally in combination with other chemotherapeutic agents. The platinum antineoplastic agent is selected from cisplatin, carboplatin, oxaliplatin, Nedaplatin, lobaplatin, satraplatin, cycloplatin, Miboplatin, Enloplatin, Iproplatin, Dicycloplatin and the like. Examples of chemotherapeutic agents include alkylating agents (alkylating agents), such as thiotepa (thiotepa) and cyclophosphamide (cyclophosphamide); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines (aziridines), such as benzotepa (benzodepa), carboquone (carboquone), metoclopramide (meteredepa), and uretepa (uredepa); ethyleneimines and methylmelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimetalmamine; annonaceous acetogenins (especially bullatacin and bullatacin); camptothecin (camptothecin); bryostatin; callystatin; CC-1065 (including its adozelesin (adozelesin), carvelesin (carzelesin), and bizelesin (bizelesin) synthetic analogs); cryptophycins (especially cryptophycins 1 and 8); dolastatin (dolastatin); duocarmycins (including synthetic analogs, KW-2189 and CB1-TM 1); eiscosahol (eleutherobin); pancratistatin; sarcodictyin; spongistatin (spongistatin); nitrogen mustards (nitrosgen mustards), such as chlorambucil (chlorambucil), chlorambucil (chlorenaphazine), cholorophosphamide (cholorophosphamide), estramustine (estramustine), ifosfamide (ifosfamide), mechlorethamine (mechlorethamine), mechlorethamine hydrochloride (mechlorethamine oxydichloride), melphalan (melphalan), neomustard (novembichin), benzene mustard cholesterol (phenosterine), prednimustine (prednimustine), triamcinolone (trofosfamide), uracil mustard (uracil mustard); nitrosoureas such as carmustine (carmustine), chlorouretocin (chlorozotocin), fotemustine (fotemustine), lomustine (lomustine), nimustine (nimustine) and ramustine (ranimustine); antibiotics such as enediynes antibiotics (enediynes) (e.g. calicheamicins, especially calicheamicin gamma 1I and calicheamicin omega I1; anthracyclines (dynemicins), including dynemicin A; bisphosphonates (bisphosphates), such as clodronate (clodronate), epothilones (esperamicins), and neocarzinostatin (neocarzinostatin) and related chromoprotein enediynes antibiotic chromophores), aclacinomycin (aclacinomycin), pingomycin, actinomycin (actinomycin), anthranomycin (antrhramycin), azaserine (azaserine), bleomycin (ubomycin), actinomycin C (cactinomycin), carmycinin, carminomycin (carmycin), carminomycin (carminomycin), doxorubicin (neomycin), doxorubicin (rubicin), doxorubicin (doxorubicin), doxorubicin (5), doxorubicin (doxorubicin), doxorubicin (doxorubicin-6), doxorubicin (doxorubicin-D), doxorubicin (doxorubicin ), doxorubicin (doxorubicin), doxorubicin (E), doxorubicin (D), and a pharmaceutically acceptable salt (such as an antibiotic, doxorubicin derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt, cyanomorpholinodoxorubicin, 2-pyrrolodoxorubicin and deoxydoxorubicin), epirubicin (epirubicin), esorubicin (esorubicin), idarubicin (idarubicin), marijucin (marcelomycin), mitomycins (mitomycins), such as mitomycin C, mycophenolic acid (mycophenolic acid), norramycin (nogalamycin), olivomycin (olivomycin), pelomycin (polyplomycin), pofiomycin (potfiromycin), puromycin (puromycin), triiron doxorubicin (quelamycin), rodobicin (rodorubicin), streptonigrin (streptonigrogrin), streptozotocin (streptozostacin), tubercidin (tubulicin), ubenimex (enomycin), stastatin (pararubicin), zorubicin (zorubicin); antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteroyltriglutamic acid (pteropterin), trimetrexate (trimetrexate); purine analogs such as fludarabine (fludarabine), 6-mercaptopurine (mercaptoprine), thiamiprine (thiamiprine), thioguanine (thioguanine); pyrimidine analogs such as ancitabine (ancitabine), azacitidine (azacitidine), 6-azauridine, carmofur (carmofur), cytarabine (cytarabine), dideoxyuridine (dideoxyuridine), deoxyfluorouridine (doxifluridine), enocitabine (enocitabine), floxuridine (floxuridine); androgens such as carotinone (calusterone), dromostanolone propionate, epitioandrostanol (epitiostanol), mepiquitane (mepiquitane), testolactone (testolactone); anti-adrenal agents such as aminoglutethimide (aminoglutethimide), mitotane (mitotane), trilostane (trilostane); folic acid supplements such as folinic acid (folinic acid); acetoglucurolactone (acegultone); an aldophosphamide glycoside (aldophosphamideglycoside); aminolevulinic acid (aminolevulinic acid); eniluracil (eniluracil); amsacrine (amsacrine); bestrabuucil; bisantrene; edatrexate (edatraxate); desphosphamide (defosfamide); dimecorsine (demecolcine); diazaquinone (diaziqutone); elfornitine; ammonium etitanium acetate; epothilone (epothilone); etoglut (etoglucid); gallium nitrate; hydroxyurea (hydroxyurea); lentinan (lentinan); lonidamine (lonidamine); maytansinoids (maytansinoids), such as maytansine (maytansine) and ansamitocins (ansamitocins); mitoguazone (mitoguzone); mitoxantrone (mitoxantrone); mopidamol (mopidamol); diamine nitracridine (nitrarine); pentostatin (pentostatin); methionine mustard (phenamett); pirarubicin (pirarubicin); losoxantrone (losoxantrone); podophyllinic acid (podophyllic acid); 2-ethyl hydrazide (ethylhydrazide); procarbazine (procarbazine); polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane (rizoxane); rhizomycin (rhizoxin); sisofilan (sizofiran); helical germanium (spirogermanium); tenuazonic acid (tenuazonic acid); triimine quinone (triaziquone); 2,2',2 "-trichlorotriethylamine; trichothecenes (trichothecenes), especially the T-2 toxin, verrucin A, rorodin A and snake-fish (anguidin); urethane (urethan); vindesine (vindesine); dacarbazine (dacarbazine); mannitol mustard (mannomustine); dibromomannitol (mitobronitol); dibromodulcitol (mitolactol); pipobromane (pipobroman); a polycytidysine; cytarabine (arabinoside); cyclophosphamide; thiotepa (thiotepa); paclitaxel (taxoids), such as paclitaxel, ABRAXANE, Cremophor, albumin engineered nanoparticle dosage forms paclitaxel and docetaxel (doxetaxel); chlorambucil (chlorambucil); gemcitabine (gemcitabine); 6-thioguanine (thioguanine); mercaptopurine (mercaptoprine); methotrexate (methotrexate); vinblastine (vinblastine); etoposide (VP-16); topotecan; ifosfamide (ifosfamide); mitoxantrone (mitoxantrone); vincristine (vincristine); vinorelbine (vinorelbine); oncostatin (novantrone); teniposide (teniposide); edatrexate (edatrexate); daunomycin (daunomycin); aminopterin (aminopterin); xeloda; ibandronate (ibandronate); irinotecan (irinotecan) (Camptosar, CPT-11) (treatment regimens involving irinotecan with 5-FU and folinic acid); topoisomerase inhibitor RFS 2000; difluoromethyl ornithine (DMFO); tretinoin (retinoids), such as tretinoin (retinocacid); capecitabine (capecitabine); combretastatin; folinic acid (LV); lapatinib (lapatinib) ([ image ]); inhibitors of PKC-alpha, Raf, H-Ras, EGFR (e.g., erlotinib and VEGF-A) that reduce cell proliferation, and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing.

Small cell lung cancer is divided into a local and an extensive phase. By limited term, it is meant that the tumor is confined to one thoracic cavity, including patients with existing mediastinal, ipsilateral supraclavicular and anterior oblique horn lymph node metastases. By extensive stage is meant that the development of the tumor is beyond the range of the limited stage.

Detailed Description