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WO 2013/169611 Al 14 November 2013 (14.11.2013) P O P C T

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WO 2013/169611 Al 14 November 2013 (14.11.2013) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/169611 Al 14 November 2013 (14.11.2013) P O P C T (51) International Patent Classification: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, A61K 39/395 (2006.01) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, (21) International Application Number: RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, PCT/US20 13/0396 12 TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (22) International Filing Date: ZM, ZW. 6 May 2013 (06.05.2013) (84) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (26) Publication Language: English UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (30) Priority Data: TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 61/644,484 ' May 2012 (09.05.2012) US EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (71) Applicant: MERCK SHARP & DOHME CORP. TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, [US/US]; 126 East Lincoln Avenue, Rahway, New Jersey ML, MR, NE, SN, TD, TG). 07065-0907 (US). Declarations under Rule 4.17 : (72) Inventor; and — as to applicant's entitlement to apply for and be granted a (71) Applicant (for US only): SATHYANARAYANAN, Sri- patent (Rule 4.1 7(H)) ram [US/US]; 33 Avenue Louis Pasteur, Boston, Mas sachusetts 021 15-5727 (US). — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.1 7(in)) (74) Common Representative: MERCK SHARP & DOHME CORP.; 126 East Lincoln Avenue, Rahway, New Jersey Published: 07065-0907 (US). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every — before the expiration of the time limit for amending the kind of national protection available): AE, AG, AL, AM, claims and to be republished in the event of receipt of AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, amendments (Rule 48.2(h)) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, — with sequence listing part of description (Rule 5.2(a)) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (54) Title: COMPOSITIONS AND METHODS FOR TREATING BREAST CANCER FIG. 1 (57) Abstract: The instant invention provides methods of treating breast cancer in a subject suffering there from comprising admin o istering a therapeutically effective amount of an mTor inhibitor, an anti-IGF-IR antibody and an aromatase inhibitor. In one embodi - ment of the methods of the invention, the mTOR inhibitor is rapamycin, a rapamycin analog selected from ridaforolimus, ever - olimus, or temsirohmus, or a combination thereof. In another embodiment of the methods of the invention, the anti-IGF-1 R anti o body is selected from dalotuzumab, robatumumab, figitumumab, cixutumumab, ganitumab, Roche RI507 and EM164. In a further embodiment, the aromatase inhibitor is selected from letrozole, exemestane, fulvestrant or anastrozole. COMPOSITIONS AND METHODS FOR TREATING BREAST CANCER BACKGROUND OF THE INVENTION The phosphatidylinositol-3 -kinase (PI3K) signaling pathway is important for the growth and survival of cancer cells in many different types of human malignancy (see, Granville, C.A. et al, 2006, Clin. Cancer Res. 12:679-89). This pathway receives upstream input from ligand-receptor interactions, such as the epidermal growth factor receptor and insulin-like growth factor receptor, and signals through downstream effectors, such as the mammalian target of rapamycin (mTOR). Dysregulation of the PI3K axis is common in human cancer due to overactive growth factor receptor signaling, activating mutations of PI3K, loss of function of the PTEN tumor suppressor, and several other mechanisms that result in activation of mTOR kinase activity. Clinically, successful pharmacological inhibition of the PI3K axis has focused on the upstream growth factor receptors and the downstream effectors of PI3 kinase. The role of the PI3K signaling pathway has been well established in the cellular processes of breast cancer (see, e.g., Lopez-Knowles, E. et al, 2010, Int. J. Cancer 126:1 121-1 131). mTOR is a crucial downstream effector molecule that regulates the production of proteins critical for cell cycle progression and many other important cellular growth processes (see, e.g., Abraham, R.T. and Gibbons, J.J., 2007, Clin. Cancer Res. 13:3109-14. It receives signaling inputs from a number of important growth factor receptors that use the PI3K signaling axis, serving as an effector molecule of those signals by controlling the translation of a number of proteins that are critical for cell cycle progression, nutrient transport, tumor angiogenesis, and many other processes. mTOR can be activated in cancer cells by abnormal or inappropriate growth factor signaling, mutation or activation of signaling molecules such as PI3K or Akt, or the loss of the PTEN tumor suppressor molecule. There is now substantial clinical evidence showing that mTOR inhibitors can provide clinical benefit to patients with advanced malignancies (see, e.g., Polunovsky, V. A., and Peter J. Houghton, eds. mTOR Pathway and mTOR Inhibitors in Cancer Therapy, New York: Humana Press, 2010). Insulin-like growth factor receptor 1 (IGF-1R), a receptor tyrosine kinase of the insulin receptor family that sits upstream of mTOR in the PI3K pathway, is involved in cell proliferation and differentiation and plays an important role in the transformation and maintenance of malignant cells in many types of cancer. See, Baselga, R, et al., 2003, Int. J. Cancer 107:873-77. IGR-1R and its ligand IGF-2 are over-expressed in many types of advanced cancer, and ligand-stimulated receptor signaling promotes the proliferation of cancer cells in vitro. IGF-IR signaling is closely linked to the PI3K axis (see, e.g., Riedemann, J. and Macaulay, V.M., 2006, Endocrine-Related Cancer 13:S33-S43). IGF-IR inhibition has shown potent anti-cancer effects in preclinical studies, and a number of IGF-IR inhibitors are currently in clinical development (see, e.g., Weroha, S.J. and Haluska, P., 2009, J. Mammary Gland Biol. Neoplasia 13:471-483). Studies have demonstrated the IGFR pathway plays an important role in the signal transduction pathways involved in breast cancer (see, e.g., Hartog, H. et al, 2012, Anticancer Res. 32:1309-1318). The inhibition of mTOR leads to activation of a feedback loop that activates the Akt oncogene, as shown by increased levels of phosphorylated Akt in both tumor cells in vitro after rapamycin inhibition and tumor biopsies taken from patients treated with mTOR inhibitors (see, Sun, S-Y et al, 2005, Cancer Res. 65:7052-58; and Gardner, H et al, "Biomarker analysis of a phase II double-blind randomized trial of daily oral RADOOl (everolimus) plus letrozole or placebo plus letrozole as neoadjuvant therapy for patients with estrogen receptor positive breast cancer," Abstract 4006, San Antonio Breast Cancer Symposium, San Antonio, TX, December 13-16, 2007). This feedback loop can involve signaling through IGF-IR and the insulin receptor substrate, and is inhibited by IGF-IR inhibitors. Preclinical studies have shown that the combination of IGF-IR inhibitors and mTOR inhibitors leads to additive or synergistic anti- tumor activity in vitro, inhibiting both upstream and downstream molecular targets in the PI3K axis. Two groups independently reported results of combining rapamycin with anti-IGF-lR antibodies in xenograft models of human sarcomas (see, Kurmasheva ,R.T. et al., "Combination of CP-751871, a human monoclonal antibody against the IGF-1 receptor with rapamycin results in highly effective therapy for xenografts derived from childhood sarcomas," Abstract CI72, AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, October 22-26, 2007, San Francisco, CA; and Darko, LA. et al., "Evaluation of combined insulin-like growth factor receptor type I (IGF-IR) and mTOR pathway blockade in sarcoma xenograft models," Abstract 4760, 98th AACR Annual Meeting, April 14-18, 2007, Los Angeles, CA). Additionally, the combination of an mTOR inhibitor, ridaforolimus, and an anti- IGF-1R antibody, dalotuzumab, in human lung cancer cell lines was more effective in blocking PI3K signaling than either agent alone (see, PCT International Patent Application serial no. PCT/US20 10/030074, published as WO 2010/120599 on October 21, 2010). RNA interference enhancer screens have also identified the combination of IGF- IR and mTOR inhibitors as one of high interest for the potential treatment of human cancers. A short-hairpin (sh)RNA kinome library screen identified mTOR (also known as FRAPl) as a top hit to mediate the ability of an anti-IGF-lR antibody, dalotuzumab, to suppress proliferation in HT-29 cells. Conversely, a short-interfering (si)R A genomic screen using HT-1080 cells treated with an mTOR inhibitor, ridaforolimus, identified IGF-IR and several components of the IGF-IR signaling pathway, as the primary mediator of the A t feedback activation noted with ridaforolimus treatment. These results underscore the centrality of the IGFlR-mTOR relationship in tumor proliferation and feedback regulation of Akt. There is also accumulating evidence suggesting that the crosstalk between the PI3K pathway and the estrogen receptor (ER) pathway is a major determinant of endocrine sensitivity, (Perez-Tenorio et al, 2007, Clin.
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