COMBINATIONAL COMPOSITIONS AND METHODS FOR TREATMENT OF CANCER

• US 20100297075A1
• Filed: 02/11/2010
• Published: 11/25/2010
• Est. Priority Date: 02/12/2009
• Status: Abandoned Application

• Current Assignee: Kyowa Hakko Kirin Company Limited (Kirin Holdings Company Limited), ArQule, Inc. (Merck & Co., Inc.)
• Original Assignee: Kyowa Hakko Kirin Company Limited (Kirin Holdings Company Limited), ArQule, Inc. (Merck & Co., Inc.)
• Inventors: Ishii, Kenichi, Pucci, Paolo, Chan, Thomas C.K., France, Dennis S.
• Application Number:
  US12/704,361
• Publication Number:
  US 20100297075A1
• Time in Patent Office: Days
• US Class Current: 424/85.4
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides methods of treating a cell proliferative disorder, such as a cancer, by administering to a subject in need thereof a therapeutically effective amount of a pyrroloquinolinyl-pyrrole-2,5-dione compound or a pyrroloquinolinyl-pyrrolidine-2,5-dione compound in combination with a therapeutically effective amount of a second anti-proliferative agent.

Claims

1. A method of treating a cell proliferative disorder, said method comprising administering, to a subject in need thereof, a therapeutically effective amount of a composition comprising (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, in combination with a therapeutically effective amount of a second anti-proliferative agent, wherein said cell proliferation disorder is treated.

2. The method of claim 1, wherein the second anti-proliferative agent is a kinase inhibitor, an alkylating agent, an antibiotic, an anti-metabolite, a detoxifying agent, an interferon, a polyclonal or monoclonal antibody, a HER2 inhibitor, a histone deacetylase inhibitor, a hormone, a mitotic inhibitor, an MTOR inhibitor, a taxane or taxane derivative, an aromatase inhibitor, an anthracycline, a microtubule targeting drug, a topoisomerase poison drug, or a cytidine analogue drug.

3. The method of claim 2, wherein the kinase inhibitor is a serine/threonine kinase inhibitor.

4. The method of claim 2, wherein the kinase inhibitor is a tyrosine kinase inhibitor.

5. The method of claim 2, wherein said kinase inhibitor is sorafenib, sunitinib, erlotinib, imatinib or gefitinib.

6. The method of claim 2, wherein said alkylating agent is cisplatin or carboplatin.

7. The method of claim 2, wherein said anti-metabolite is gemcitabine, fluorouracil, TS-1 or capecitabine.

8. The method of claim 2, wherein said mitotic inhibitor is camptothecin or irinotecan.

9. The method of claim 2, wherein said taxane or taxane derivative is paclitaxel or docetaxel.

10. The method of claim 1, wherein said cell proliferative disorder is a precancerous condition.

11. The method of claim 1, wherein said cell proliferative disorder is a cancer.

12. The method of claim 1, wherein said cell proliferative disorder is a hematologic tumor or malignancy.

13. The method of claim 1, wherein said cell proliferative disorder is a solid tumor (or tumors).

14. The method of claim 11, wherein said cancer is lung cancer, small cell lung cell cancer, non-small cell lung cancer, colon cancer, breast cancer, pancreatic cancer, prostate cancer, renal cancer, cervical cancer, brain cancer, gastric/stomach cancer, uterine cancer, intestinal cancer, hepatic cancer, chronic myelogenous leukemia, melanoma, ovarian cancer, translocation-associated renal cell carcinoma (RCC), alveolar soft part sarcoma (ASPS), clear cell sarcoma (CCS), or hepatocellular carcinoma.

15. The method of claim 11, wherein said treating cancer comprises a reduction in tumor size.

16. The method of claim 11, wherein the cancer is metastatic cancer.

17. The method of claim 11, wherein said treating cancer comprises inhibition of metastatic cancer cell invasion.

18. The method of claim 1, further comprising administering radiation therapy.

19. The method of claim 1, wherein the cells with proliferative disorder contain DNA encoding c-Met.

20. The method of claim 19, wherein the cells have a constitutively enhanced c-Met activity.

21. The method of claim 1, wherein the (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione is administered at a dose range between 0.1 mg/day to 10 g/day.

22. The method of claim 21, wherein the (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione is administered at a dose range between 0.1 mg/day to 5 g/day.

23. The method of claim 22, wherein the (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione is administered at a dose range between 10 mg/day to 1 g/day.

24. The method of claim 23, wherein the (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione is administered at a maximal daily dose of 720 mg.

25. The method of claim 24, wherein the (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione is administered at a dose of 360 mg, provided twice a day.

26. The method of claim 1, wherein the composition comprising (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione, and the second anti-proliferative agent are administered intravenously, orally or intraperitoneally.

27. The method of claim 1, wherein the second anti-proliferative agent is administered simultaneously with, preceding administration of, or following administration of the composition comprising (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.

28. The method of claim 27, wherein the second anti-proliferative agent is administered within 24 hours after the composition comprising (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione is administered.

29. The method of claim 1, wherein said composition further comprises one or more pharmaceutically acceptable carriers or excipients.

30. The method of claim 1, wherein said second anti-proliferative agent comprises one or more pharmaceutically acceptable carriers or excipients.

31. The method of claim 1, wherein the subject is a human.

32. A kit for the treatment of a cell proliferative disorder in a subject comprising separate vials containing a composition comprising (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, and a second anti-proliferative agent, with instructions for administering said composition and second anti-proliferative agent.