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(12) Patent Application Publication (10) Pub. No.: US 2005/0037090 A1 Mckearn Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2005/0037090 A1 Mckearn Et Al US 20050O37090A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0037090 A1 McKearn et al. (43) Pub. Date: Feb. 17, 2005 (54) COMBINATION THERAPY INCLUDING A Related U.S. Application Data CYCLOOXYGENASE-2 INHIBITOR AND AN ANTINEOPLASTICAGENT (63) Continuation of application No. 09/857,873, filed on Oct. 5, 2001, filed as 371 of international application No. PCT/US99/30693, filed on Dec. 22, 1999. (76) Inventors: JohnGary P.Gordon, McKearn, Highland, Glencoe, IL (US);MO (US); (60) Provisional application No. 60/113,786, filed on Dec. James J. Cunningham, Chicago, IL 23, 1998. (US); Stephen T. Gately, Palatine, IL (US); Alane T. Koki, Beaufort, MO Publication Classification (US); Jaime L. Masferrer, Ballwin, MO (US) (51) Int. Cl." .................. A61K 31/7072; A61K 31/704; A61K 31/415; A61K 33/24 (52) U.S. Cl. .............................. 424/649; 514/27; 514/49; Correspondence Address: 514/283; 514/34, 514/406; Harness, Dickey & Pierce, P.L.C. 514/602; 514/559; 514/649; Suite 400 514/492; 514/411 7700 Bonhomme St. Louis, MO 63105 (US) (57) ABSTRACT (21) Appl. No.: 10/945,422 The present invention provides methods to treat or prevent neoplasia disorders in a mammal using a combination of a (22) Filed: Sep. 20, 2004 cyclooxygenase-2 inhibitor and an antineoplastic agent. US 2005/0037090 A1 Feb. 17, 2005 COMBINATION THERAPY INCLUDING A 0007. The adverse effects of systemic chemotherapy used CYCLOOXYGENASE-2 INHIBITOR AND AN in the treatment of neoplastic disease is most feared by ANTINEOPLASTICAGENT patients undergoing treatment for cancer. Of these adverse effects nausea and vomiting are the most common and FIELD OF THE INVENTION severe side effects. Other adverse side effects include cytopenia, infection, cachexia, mucositis in patients receiv 0001. The present invention relates to combinations and ing high doses of chemotherapy with bone marrow rescue or methods for treatment or prevention of neoplasia disorders radiation therapy; alopecia (hair loss); cutaneous complica in a mammal using two or more components with at least tions (see M. D. Abeloff, et al: Alopecia and Cutaneous one component being a cyclooxygenase-2 inhibitor. Complications. P. 755-56. In Abeloff, M.D., Armitage, J. O., Lichter, A. S., and Niederhuber, J. E. (eds) Clinical Oncol BACKGROUND OF THE INVENTION ogy. Churchill Livingston, N.Y., 1992, for cutaneous reac tions to chemotherapy agents), Such as pruritis, urticaria, and 0002. A neoplasm, or tumor, is an abnormal, unregulated, angioedema, neurological complications, pulmonary and and disorganized proliferation of cell growth. A neoplasm is cardiac complications in patients receiving radiation or malignant, or cancerous, if it has properties of destructive chemotherapy; and reproductive and endocrine complica growth, invasiveness and metastasis. Invasiveness refers to tions. the local spread of a neoplasm by infiltration or destruction of Surrounding tissue, typically breaking through the basal 0008 Chemotherapy-induced side effects significantly laminas that define the boundaries of the tissues, thereby impact the quality of life of the patient and may dramatically often entering the body's circulatory System. Metastasis influence patient compliance with treatment. typically refers to the dissemination of tumor cells by 0009 Additionally, adverse side effects associated with lymphotics or blood vessels. Metastasis also refers to the chemotherapeutic agents are generally the major dose-lim migration of tumor cells by direct extension through Serous iting toxicity (DLT) in the administration of these drugs. For cavities, or Subarachnoid or other Spaces. Through the example, mucositis, is one of the major dose limiting process of metastasis, tumor cell migration to other areas of toxicity for Several anticancer agents, including the antime the body establishes neoplasms in areas away from the Site tabolite cytotoxic agents 5-FU, methotrexate, and antitumor of initial appearance. antibiotics, Such as doxorubicin. Many of these chemo 0003 Cancer is now the second leading cause of death in therapy-induced side effects if Severe, may lead to hospital the United States and over 8,000,000 persons in the United ization, or require treatment with analgesics for the treat States have been diagnosed with cancer. In 1995, cancer ment of pain. accounted for 23.3% of all deaths in the United States. (See 0010. The adverse side effects induced by chemothera U.S. Dept. of Health and Human Services, National Center peutic agents and radiation therapy have become of major for Health Statistics, Health United States 1996-97 and importance to the clinical management of cancer patients. Injury Chartbook 117 (1997)). 0011 FR 2771 005 describes compositions containing a 0004 Cancer is not fully understood on the molecular cyclooxygenase-2 inhibitor and a N-methyl-d-aspartate level. It is known that exposure of a cell to a carcinogen Such as certain viruses, certain chemicals, or radiation, leads to (NMDA) antagonist used to treat cancer and other diseases. DNA alteration that inactivates a “Suppressive' gene or 0012 WO99/18960 describes a combination comprising activates an “oncogene'. Suppressive genes are growth a cyclooxygenase-2 inhibitor and an induced nitric-oxide regulatory genes, which upon mutation, can no longer synthase inhibitor (iNOS) that can be used to treat colorectal control cell growth. Oncogenes are initially normal genes and breast cancer. (called proto-oncogenes) that by mutation or altered context 0013 WO 99/13799 describes the combination of a of expression become transforming genes. The products of cyclooxygenase-2 inhibitor and an opioid analgesic. transforming genes cause inappropriate cell growth. More than twenty different normal cellular genes can become 0014 WO 98/41511 describes 5-(4-sulphunyl-phenyl)- oncogenes by genetic alteration. Transformed cells differ pyridaZinone derivatives used for treating cancer. from normal cells in many ways, including cell morphology, 0.015 WO 98/41516 describes (methylsulphonyl)phenyl cell-to-cell interactions, membrane content, cytoskeletal 2-(5H)-furanone derivatives that can be used in the treat Structure, protein Secretion, gene expression and mortality ment of cancer. (transformed cells can grow indefinitely). 0016 WO 98/16227 describes the use of cyclooxyge 0005 Cancer is now primarily treated with one or a nase-2 inhibitors in the treatment or prevention of neoplasia. combination of three types of therapies: Surgery, radiation, and chemotherapy. Surgery involves the bulk removal of 0017 WO97/36497 describes a combination comprising diseased tissue. While Surgery is Sometimes effective in a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor removing tumors located at certain Sites, for example, in the useful in treating cancer. breast, colon, and Skin, it cannot be used in the treatment of 0018 WO97/29776 describes a composition comprising tumors located in other areas, Such as the backbone, nor in a cyclooxygenase-2 inhibitor in combination with a leukot the treatment of disseminated neoplastic conditions Such as riene B4 receptor antagonist and an immunosuppressive leukemia. drug. 0006 Chemotherapy involves the disruption of cell rep 0019 WO 97/29775 describes the use of a cyclooxyge lication or cell metabolism. It is used most often in the nase-2 inhibitor in combination with a leukotriene A4 hydro treatment of breast, lung, and testicular cancer. lase inhibitor and an immunosuppressive drug. US 2005/0037090 A1 Feb. 17, 2005 0020 WO 97/29774 describes the combination of a 0037 Stadler, W. M. et al. describes the response rate and cyclooxygenase-2 inhibitor and protStaglandin or antiulcer toxicity of oral 13-cis-retinoic acid added to an outpatient agent useful in treating cancer. regimen of Subcutaneous interleukin-2 and interferon alpha 0021 WO97/11701 describes a combination comprising in patients with metastatic renal cell carcinoma. a cyclooxygenase-2 inhibitor and a leukotriene B4 receptor 0038 Rosenbeg, S. A. et al. describes treatment of antagonist useful in treating colorectal cancer. patients with metastatic melanoma using chemotherapy with 0022 WO96/41645 describes a combination comprising cisplatin, dacarbazine, and tamoxifen alone or in combina a cyclooxygenase-2 inhibitor and a leukotriene A hydrolase tion with interleukin-2 and interferon alpha-2b. inhibitor. 0039 Elias, L. et al. describes the use of infusional 0023 WO 96/03385 describes 3,4-Di substituted pyra 5-fluorouracil, interleukin-2, and Subcutaneous interferon Zole compounds given alone or in combination with alpha to treat advanced renal cell carcinoma. NSAIDs, steroids, 5-LO inhibitors, LTB4 antagonists, or 0040 Tourani, J-M. et al describes treatment of renal cell LTA4 hydrolase inhibitors that may be useful in the treat carcinoma using interleukin-2, and interferon alpha-2a ment of cancer. administered in combination with fluorouracil. 0024 WO 98/47890 describes substituted benzopyran 0041 Majewski, S. describes the anticancer action of derivatives that may be used alone or in combination with retinoids, Vitamin D3 and cytokines (interferons and inter other active principles. leukin-12) as related to the antiangiogenic and antiprolif 0025 WO 98/16227 describes a method of using erative effects. cyclooxygenase-2 inhibitors in the treatment and prevention 0042 Ryan, C. W. describes treatment of patients with of neoplasia. metastatic renal cell cancer with GM-CSF, Interleukin-2, 0026 U.S. Pat. No. 5,854.205 describes an isolated and
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