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International Patent Classification: A61K 31/155 (2006.01) A61K 31

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International Patent Classification: A61K 31/155 (2006.01) A61K 31 ( International Patent Classification: Declarations under Rule 4.17: A61K 31/155 (2006.01) A61K 31/443 (2006.01) — of inventorship (Rule 4.17(iv)) A61K 31/553 (2006.01) A61K 31/4745 (2006.01) A61P 35/00 (2006.01) A61K 31/519 (2006.01) Published: A61K 31/4196 (2006.01) A61K 31/5375 (2006.01) — with international search report (Art. 21(3)) (21) International Application Number: PCT/US20 19/049086 (22) International Filing Date: 30 August 2019 (30.08.2019) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/742,636 08 October 2018 (08. 10.2018) US (71) Applicant (for US only): GENENTECH, INC. [US/US]; 1 DNA Way, South San Francisco, California 94080 (US). (71) Applicant (for all designated States except US): F. HOFF- MANN-LA ROCHE AG [CH/CH]; Grenzacherstrasse 124, Basel, 4070 (CH). (72) Inventors: GREENE, Susan; 1 DNA Way, South San Francisco, California 94080 (US). JOO, Stephanie; 1 DNA Way, South San Francisco, California 94080 (US). SCHUTZMAN, Jennifer; 1 DNA Way, South San Fran¬ cisco, California 94080 (US). (74) Agent: ANDRUS, Alex et al.; 785 1 Metro Parkway, Suite 325, Bloomington, Minnesota 55425 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available) : ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 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, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (54) Title: METHODS OF TREATING CANCER WITH PI3K ALPHA INHIBITORS AND METFORMIN (57) Abstract: Described herein are methods of treating PIK3 CA-mutant cancer patients by administering metformin and a PI3K alpha inhibitor. METHODS OFTREATING CANCER WITH PBK ALPHA INHIBITORS AN METFORMIN 5 CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority benefit of United States Provisional. Application, Serial No. 62/742,636 filed on October 2 , which is incorporated herein n its entirety. FIELD OF THE IN VENTION The invention relates generally to treatment of IK3CA~mutant cancer patients by administering metformin and P 3K alpha inhibitor, BACKGROUND OF THE INVENTION hospha lylin itol 3-kinase (PBK) is a lipid kinase that upon activation by growth factor receptors and integrals regulates cell proliferation, survival, and migration. 3 catalyzes the phosphorylation of phosphatidylinosito!-4,5-bisphospltate (PUT) to generate S ph sphat dy in s -3,4 5- ri phos ha e (PIP;;), a"second messenger involved in the phosphorylation of A T and other components in the AKT/niTQR :pathway (Can e LG Science 20 2 296(5573); 55- 657; Guertin DA, et a 2007) Cancer Cell 2 9 22 PBK and its downstream effectors, AKT and rnTOR, are major nodes in the PBK/AKT.'mTOR signaling pathway and are critical for cell-cycle modulation, cell growth, metabolism, motility, 20 and surv ival (Ratneh, et al ( 1999) Biol Chem, 274:8347-8350; Cantrell DA (20 ) J Cell S 4 ; 1439-1445; ana an D, et al (201 ) Cell 144:646-674; Vanh e e ro k B, et al (20 ) Na( Rev Mol Cell Biol 195-203). RIS is a heterodimer consisting of p85 and p subunits ( s et al (T99.1) Cell 65:91- 04 ; i es et a (1992) Cell 70:419-429). Four distinct Class l PBKs have been identified, 25 designated P 3K (alpha), (beta), (delta), and γ (gamma), each consisting of a dislinet Da catalytic subunit and a regulatory subunit p85. These four Isoforms are the product of four genes; PJK3CA, P 3CB 3C , and K3CG. Three of the catalytic subunits, i.e., p alpha, p beta and pi 0 delta, each teract w th the same regulatory subunit, p ; whereas p i 0 ga ma interacts with a distinct regulatory subunit, The patterns of expression of 30 each of these PBKs n human cells and tissues are distinct. a each of the PBK alpha, beta, and delta subtypes, the p85 subunit acts to localize PBK to the plasma membrane by th interaction of it SH2 domain w th phosphorylated tyrosine residues (present in an appropriate sequence context) in target proteins (Rameh et al (1995) Cell, 83:8:21-30; Vollni et a (1992) Oncogene, 7:789-93). Deregulation of the B /A T/mT R signaling path way through multiple different mechanisms has described in solid tumor malignancies, including activating and transforming mutations, s well as i o , of PIK3CA that encodes the pl 1 alph subunit of P K G stin i,P et al (2008) Curr Cancer Drug Targets 8:733-740; Yuan L, (2008) Oncogene 27:5497-55 Courtney D, et a (20 ) J Clin Oncol 28: 075- 1 83) Activating mutations in. the P C gene occur primarily in exons 9 and 20 (“hotspot” regions), which encode the helical and kinase domains of Ρ0 alpha protein (Bachman et a (2004) Cancer Biol Ther 3:772-5: Samuels Y, et al (2004) Science 304:$$4). Up to 70% of breast cancers have some form of molecular aberration of the 3 /A T/ T R pathway (Cancer Genome Atlas Network 2012). Myperactivatfom of the P B /A T/n T R signaling pathway was shown to promote both de novo and acquired resistance to endocrine therapy in ER-f breast cancer cell lines and xenograft models (Sab i , et al (2007) Clin Cancer Res 13:2751-2757), and simultaneous blocking of the PBK/AKT/mTOR pathway enhances anti-tumor activity (B u ay A et at (2005) Clin Cancer R ί :53 9-5328), indicating blocking PBK/AKT/mTOR pathway signaling may have a therapeutic benefit in patients with ER-f breast cancer. The P 3K/AKT/PT pathway is an attractive target for cancer drag development since such agents would be expected to inhibit cellular pro eration, to repress signals fro stromal cells that provide for survi val and iem r sistan e of cancer cells, to reverse t e repression of apoptosis and surmount intrinsic resistance of cancer cells to cytotoxic agents. There is a need for additional modulators of P 3K. (alpha isoform) that re useful for treating cancers, particularly a inhibitor of P 3 that is selective r mutant P13KO. expressing tumors relative to non-mutant PB expressing cells. There i especially a need tor such an agent that selectively inhibits the P13 iso relative to the Ρ Κβ, P 3K , an P 3 isoforms, which may be expected to result in an enhanced therapeutic window. Hyperglycemia is a dos -li ti g toxicity associated with treatment with 13K alpha inhibitors (Jun , et al (2 3) Proceedings of the 04 h Annual :Meeting of the American Association f r Cancer Research; 2013 Apr 6- : Washington, DC, Philadelphia (PA): AACR; Cancer Re 20 3 73(8 Suppl):Abstract nr LB-64). Management guidelines for hyperglycemia with PI3K pathway inhibitors have recommended metformin as the first- ne treatment: - osta ek , et al (2 5) Drugs 75:107 - 1 94 ; sa dy et al (2 ) J C in Oncol 30 :2 9 9- ), Mitigation or management of a hyperglycemic effect may provide additional opportunities for treatmentof cancer w ith P 3K alpha inhibitors. Maximizing therapeutic benefit, while minimizing treatment-related toxicides, is particularly important in +/H 2 negative breast cancer where treatment times can belong. SUMMARY OF THE INVENTION The invention: provides methods of treating patients wit cancer with a BK alpha inhibitor, after treatment with the ant -hyperglycemic medication metformin to mitigate or ge hyperg em a. i aspect of the inven tio n is method for the treatment of cancer in a patient comprising administering therapeutically effec tive amount of a P alpha Inhibitor selected from the group consisting of a pe isib YL I ), taselisih GDC 032), buparlisih B 2 da t ii ib (BEZ235), pi ti isib (GDC0941), g dat i s b (PF-052 12384, K 587), - 3, P K -75 b, YM2 1636, omipalisib 2 4 8, GSK458), GSK 05961 , copanlislb (BAY 80-6946), apii ri b GD 09 0), vox al si (XL765, SAR245409), sera e isib (MEN , TAK- 1 , i 7), and TK474, or a pharmaceutically acceptable salt thereof wherein the patient ha been previously treated with metformin. DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS Reference will now be ade in detail to certain embodiments of the invention, examples of which illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it wi l be understood that they are not intended to limit the invention to those embodi ments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope Of the present invention as defined by the claims, One skilled in the art wi l recognize many methods materials similar or equivalent to those described herein, which coul be used in the practice of the present invention.
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