Combinational compositions and methods for treatment of cancer

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.

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.