Combination therapy

Patent metadata

Field	Value
Publication number	US-10195208-B2
Application number	US-201515328710-A
Country	US
Kind code	B2
Filing date	Jul 29, 2015
Priority date	Jul 31, 2014
Publication date	Feb 5, 2019
Grant date	Feb 5, 2019

Abstract

The present disclosure relates to pharmaceutical products comprising a combination of (i) a MET inhibitor which is INC280 or a pharmaceutically acceptable salt or hydrate thereof and (ii) an EGFR inhibitor described herein, which are jointly active in the treatment of proliferative diseases, corresponding pharmaceutical formulations, uses, methods, processes, commercial packages and related embodiments.

First claim

The invention claimed is:

1. A pharmaceutical combination comprising
(i) a MET tyrosine kinase inhibitor which is 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide having the formula

or a pharmaceutically acceptable salt or hydrate thereof,
(ii) an EGFR tyrosine kinase inhibitor which is (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide, or a pharmaceutically acceptable salt thereof.

2. The combination of claim 1 , wherein the MET tyrosine kinase inhibitor is in the dihydrochloric acid salt form of 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide.

3. The combination of claim 1 , wherein the MET tyrosine kinase inhibitor is in the form of a dihydrochloric monohydrate salt of 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide.

4. The combination of claim 1 , wherein the EGFR tyrosine kinase inhibitor is the hydrochloride salt or the mesylate salt of (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide.

5. The combination of claim 1 , further comprising of at least one pharmaceutically acceptable carrier.

6. A method of treating an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, which comprises simultaneous, separate or sequential administration to a subject in need of such treatment,
(i) a MET tyrosine kinase inhibitor which is 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide having the formula

or a pharmaceutically acceptable salt or hydrate thereof, and
(ii) an EGFR tyrosine kinase inhibitor which is (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide, or a pharmaceutically acceptable salt thereof, wherein treatment refers to ameliorating the disease or disorder, alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient, or modulating the disease or disorder, either physically, physiologically, or both.

7. The method of claim 6 wherein the EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease is cancer.

8. The method of claim 7 , wherein the cancer is a carcinoma, a musculoskeletal sarcoma, a soft tissue sarcoma, a hematopoietic malignancy, or another neoplasm.

9. The method of claim 7 , wherein the cancer is an EGFR resistant tumor with a c-MET activation/amplification.

10. The method of claim 7 , wherein the cancer is non-small cell lung cancer (NSCLC).

11. The method of claim 7 , wherein the cancer is metastatic non-small cell lung cancer.

12. The method of claim 7 , wherein the cancer is resistant to treatment with erlotinib, gefitinib or afatinib.

13. The method of claim 7 , wherein the cancer is resistant to treatment with (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide as monotherapy.

14. The method of claim 7 , wherein the cancer is colorectal cancer (CRC) or metastatic colorectal cancer (mCRC).

15. The method of claim 7 , wherein the cancer is head and neck cancer or metastatic head and neck cancer or head and neck squamous cell carcinoma (HNSCC).

16. The method of claim 8 , wherein the carcinoma is bladder, breast, cervical, cholangiocarcinoma, colorectal, esophageal, gastric, head and neck, kidney, liver, lung, nasopharygeal, ovarian, pancreas, prostate, or thyroid carcinoma.

17. The method of claim 8 , wherein the musculoskeletal sarcoma is osteosarcaoma, synovial sarcoma, or rhabdomyosarcoma.

18. The method of claim 8 , wherein the soft tissue sarcoma is MFH/fibrosarcoma, leiomyosarcoma, or Kaposi's sarcoma.

19. The method of claim 8 , wherein the hematopoietic malignancy is multiple myeloma, lymphomas, adult T cell leukemia, acute myelogenous leukemia, or chronic myeloid leukemia.

20. The method of claim 8 , wherein the another neoplasm is glioblastomas, astrocytomas, melanoma, mesothelioma or Wilm's tumor.

21. The method of claim 7 , wherein the cancer is EGFR mutated non-small cell lung cancer.

22. The method of claim 7 , wherein the cancer is EGFR mutant L858R non-small cell lung cancer.

23. The method of claim 7 , wherein the cancer is EGFR mutant ex19del non-small cell lung cancer.

24. The method of claim 6 , wherein 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide or a pharmaceutically acceptable salt and (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide, or a pharmaceutically acceptable salt thereof are administered simultaneously.

25. The method of claim 6 , wherein 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide or a pharmaceutically acceptable salt and (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide, or a pharmaceutically acceptable salt thereof are administered separately.

26. The method of claim 6 , wherein 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide or a pharmaceutically acceptable salt and (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide, or a pharmaceutically acceptable salt thereof are administered sequentially.

Assignees

• Novartis Ag

Inventors

• Hao Huaixiang
• Huang Xizhong
• Tam Angela
• Kasibhatla Shailaja

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/53 Primary

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title