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(12) United States Patent (10) Patent No.: US 8,975,248 B2 Zakn0en Et Al

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(12) United States Patent (10) Patent No.: US 8,975,248 B2 Zakn0en Et Al US008975248B2 (12) United States Patent (10) Patent No.: US 8,975,248 B2 Zakn0en et al. (45) Date of Patent: Mar. 10, 2015 (54) COMBINATIONS OF THERAPEUTIC (56) References Cited AGENTS FOR TREATING CANCER U.S. PATENT DOCUMENTS (75) Inventors: Sara Zaknoen, Hoboken, NJ (US); 7,105,492 B2 * 9/2006 Dallavalle et al. .............. 514/25 Margaret Ma Woo, Raritan, NJ (US); 2002/0103141 A1* 8, 2002 McKearnet al. ............... 514,43 Richard William Versace, Wanaque, NJ 2004, OO18988 A1 1/2004 Dallavalle et al. (US); Claudio Pisano, Aprilia (IT): 2004/01 16407 A1* 6/2004 Borisy et al. .................. 514,217 Loredana Vesci, Rome (IT) 2005/0272755 A1* 12/2005 Denis et al. ................... 514,283 FOREIGN PATENT DOCUMENTS (73) Assignee: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Rome (IT) EP O715854 9, 2003 JP 2002-539 128 11, 2002 JP 2004-529150 9, 2004 (*) Notice: Subject to any disclaimer, the term of this JP 2008-1698.25 T 2008 patent is extended or adjusted under 35 WO WOOO,536O7 A1 * 9, 2000 CO7D 491?22 WO WO O2/O85459 10, 2002 U.S.C. 154(b) by 1206 days. WO WO-O3,O13541 2, 2003 WO WO-03/037897 5, 2003 (21) Appl. No.: 11/720,776 WO WO-2004/083214 9, 2004 WO WO-2004,103274 12, 2004 WO WO 2004f103358 12, 2004 (22) PCT Filed: Dec. 13, 2005 WO WO-2006/06578O 6, 2006 OTHER PUBLICATIONS (86). PCT No.: PCT/US2OOS/O44993 Petrangolini et al. (Molecular Cancer Research 2003; 1: 863-870).* S371 (c)(1), Kao et al. (J. Nucl. Med. 2001; 42 : 17-20).* Byers, T. (CA Cancer Journal, vol. 49, No. 6, Nov./Dec. 1999).* (2), (4) Date: Jun. 4, 2007 Doctor's Guide, Personal Edition (FDA Approves Avastin (Bevacizumab, rhuMAB-VEGF) for Treatment of Metastatic Colon (87) PCT Pub. No.: WO2006/065780 or Rectal Cancer, Feb. 27, 2004).* MeSH (ST1481, Sep. 4, 2001).* PCT Pub. Date: Jun. 22, 2006 MeSH (erlotinib, Nov. 22, 1999).* MeSH (everolimus, Aug. 11, 1997).* MeSH (epothilone B, Jun. 28, 1995).* (65) Prior Publication Data PubChem Compound (AEE788 Dec. 8, 2010).* US 201O/OO28338A1 Feb. 4, 2010 Velcade(R) (bortezomib, Takeda Millennium, Aug. 23, 2010).* MeSH (cetuximab, Jul 26, 2000).* Dorland's Medical Dictionary for Healthcare Consumers (glioblastoma, Elsevier, 2007).* Related U.S. Application Data MeSH (bortezomib, Sep. 4, 2001).* Non-small Cell Lung Cancer Collaborative Group(BMJOct. 7, 1995 (60) Provisional application No. 60/636,439, filed on Dec. 311:899-909).* 15, 2004. Langer et al. (Europ. J. Cancer 2000 36: 183-193).* International Search Report and Written Opinion for PCT/US2005/ 044993 mailed Jul. 3, 2006. (51) Int. Cl. Search Report and Written Opinion received for Singapore Applin. A6 IK3I/47 (2006.01) No. 200704032-2 mailed Sep. 30, 2008. A6 IK3I/282 (2006.01) Sekikawa et al., “Combination chemotherapy of a novel A6 IK33/24 (2006.01) pyrazoloacridone derivative, KW-2170, and SN-38: The synergy and mechanisms. Proceedings of the American Association for Cancer A 6LX39/395 (2006.01) Research Annual Meeting, vol. 42, p. 252 (2001) and 92". Annual A6 IK3I/427 (2006.01) Meeting of the American Association for Cancer Research (2001). A6 IK3I/53 (2006.01) A 6LX3/555 (2006.01) (Continued) A6 IK3I/4745 (2006.01) Primary Examiner — Peter J Reddig A6 IK3I/337 (2006.01) (74) Attorney, Agent, or Firm — Foley & Lardner LLP A6 IK 45/06 (2006.01) (57) ABSTRACT (52) U.S. Cl. A combination therapy for treating patients suffering from CPC ............... A61K 45/06 (2013.01); A61 K3I/282 proliferative diseases or diseases associated with persistent (2013.01); A61 K33/24 (2013.01); A61 K angiogenesis is disclosed. The patient is treated with a camp 39/395 (2013.01); A61 K3I/427 (2013.01); tothecin derivative and one or more chemotherapeutic agents A6 IK3I/53 (2013.01); A61 K3I/555 selected from a microtubule active agent; an alkylating agent; (2013.01); A61K3I/4745 (2013.01); A61 K an anti-neoplastic anti-metabolite; a platin compound; a 31/337 (2013.01) topoisomerase II inhibitor; a VEGF inhibitor; a tyrosine USPC ...................................... 514/187: 514/253.06 kinase inhibitor; an EGFR kinase inhibitor; an mTOR kinase (58) Field of Classification Search inhibitor; an insulin-like growth factor I inhibitor; a Raf CPC ... C07D 217/00; C07D 215/00; A61K 31/47; kinase inhibitor, a monoclonal antibody; a proteasome inhibi A61K 31/4745 tor; a HDAC inhibitor; and ionizing radiation. See application file for complete search history. 11 Claims, No Drawings US 8,975,248 B2 Page 2 (56) References Cited longed Inactivation of Ribosomal Protein S6 Kinase 1 in Peripheral Blood Mononuclear Cells.” Cancer Research 2004; 64: 252-261. OTHER PUBLICATIONS Notice of Preliminary Rejection (English Translation) in Korean Sartore-Bianchi et al., “The combination of the novel camptothecin Application No. 10-2007-7013401 dated Apr. 24, 2013. analogue Gimatecan (ST1481) plus the proteasome inhibitor PS341 produces an enhanced pro-apoptotic effect in a malignant Traxler, et al., “AEE788: A Dual Family Epidermal Growth Factor mesothelioma cell line.” Proceedings of the American Association Receptor/ErbB2 and Vascular Endothelial Growth Factor Receptor for Cancer Research Annual Meeting, vol. 44, pp. 742-743 (2003) & Tyrosine Kinase Inhibitor with Antitumor and Antiangiogenic Activ 94'. Annual Meeting of the American Association for Cancer ity.” Cancer Research 2004; 64: 4931-4941. Research (2003). Xu et al., “Progress of the Research on Epothilones as New Natural Perego et al., “511 Potentiation of cell sensitivity to the DNA Anti-tumor Drugs.” Chin Pharm J., Sep. 2003, vol. 38, No. 9, pp. topoisomerase I inhibitor gimatecan by TRAIL in prostate carcinoma 648-651. (English abstract included). cells.” European Journal of Cancer, Supplement, vol. 2(8), p. 156 Second Office Action in Chinese Application No. 200580042979.8 (2004). received Jan. 15, 2010 (English translation included—6 pages. Boulay, et al., “Antitumor Efficacy of Intermittent Treatment Sched ules with the Rapamycin Derivative RAD001 Correlates with Pro * cited by examiner US 8,975,248 B2 1. 2 COMBINATIONS OF THERAPEUTIC (b) a pharmaceutical formulation of one or more chemo AGENTS FOR TREATING CANCER therapeutic agents for simultaneous, concurrent, sepa rate or sequential use. This application claims benefit of U.S. Provisional Appli The Chemotherapeutic Agents cation No. 60/636,439, filed Dec. 15, 2004. The term “chemotherapeutic agents’ is a broad one cover The invention relates to a method of preventing or treating ing many chemotherapeutic agents having different mecha proliferative diseases or diseases that are associated with or nisms of action. Combinations of Some of these with camp triggered by persistent angiogenesis in a mammal, particu tothecin derivatives can result in improvements in cancer larly a human, with a combination of pharmaceutical agents therapy. Generally, chemotherapeutic agents are classified 10 according to the mechanism of action. Many of the available which comprises: agents are anti-metabolites of development pathways of vari (a) a camptothecin derivative; and ous tumors, or react with the DNA of the tumor cells. (b) one or more chemotherapeutic agents. By the term “chemotherapeutic agent' is meant especially The invention further relates to pharmaceutical composi any chemotherapeutic agent other than a topoisomerase I tions comprising: 15 inhibitor or a derivative thereof. It includes, but is not limited (a) a camptothecin derivative; to one or more of the following: (b) one or more chemotherapeutic agents; and i.a microtubule active agent; (c) a pharmaceutically acceptable carrier. ii. an alkylating agent; The present invention further relates to a commercial pack iii. an anti-neoplastic anti-metabolite; age or product comprising: iv. a platin compound; (a) a pharmaceutical formulation of a camptothecin deriva v. topoisomerase II inhibitor; tive; and vi. a compound targeting/decreasing a protein or lipid (b) a pharmaceutical formulation of one or more chemo kinase activity or a protein or lipid phosphatase activity; therapeutic agents for simultaneous, concurrent, sepa vii. monoclonal antibodies; rate or sequential use. 25 viii. proteasome inhibitors; The combination partners (a) and (b) can be administered ix. HDAC inhibitors; and together, one after the other or separately in one combined X. tumor cell damaging approaches, such as ionizing radia unit dosage form or in two separate unit dosage forms. The tion. unit dosage form may also be a fixed combination. The term “microtubule active agent, as used herein, 30 relates to microtubule stabilizing, microtubule destabilizing BACKGROUND OF THE INVENTION agents and microtublin polymerization inhibitors including, but not limited to, taxanes, e.g., pacilitaxel and docetaxel; Camptothecin and derivatives thereofare cytotoxic agents, Vinca alkaloids, e.g., vinblastine, especially vinblastine Sul which exhibit antitumor activity primarily by inhibiting fate; Vincristine, especially Vincristine Sulfate and vinorel 35 bine; discodermolides; cochicine and epothilones and deriva topoisomerase I, a clinically validated drug target which is tives thereof, e.g., epothilone B or a derivative thereof. usually overexpressed in malignant cells. Camptothecin and Paclitaxel is marketed as TAXOL: docetaxel as TAXOTERE: its derivatives act by interfering with the unwinding of super vinblastine sulfate as VINBLASTINR.P; and vincristine sul coiled DNA by the cellular enzyme topoisomerase I which fate as FARMISTIN. Also included are the generic forms of triggers events leading to apoptosis and programmed death in 40 paclitaxel, as well as various dosage forms of paclitaxel. malignant cells. Generic forms of paclitaxel include, but are not limited to, betaxolol hydrochloride. Various dosage forms of paclitaxel SUMMARY OF THE INVENTION include, but are not limited to albumin nanoparticle paclitaxel marketed as ABRAXANE; ONXOL, CYTOTAX. Discoder It has now been found that Surprisingly camptothecin 45 mollide can be obtained, e.g., as disclosed in U.S. Pat. No. derivatives are even more efficacious when used in combina 5,010.099. Also included are Epotholine derivatives which tion with other chemotherapeutic agents.
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