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WO 2016/179306 Al 10 November 2016 (10.11.2016) P O P C T

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WO 2016/179306 Al 10 November 2016 (10.11.2016) 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 2016/179306 Al 10 November 2016 (10.11.2016) P O P C T (51) International Patent Classification: 358508 (SG). RASHID, Masturah Mohd Abdul; BLK A61K 31/706 (2006.01) A61K 31/573 (2006.01) 456, Hougang Ave. 10, #04-445, Singapore 530456 (SG). A61K 31/407 (2006.01) A61K 31/404 (2006.01) (74) Agents: LIU, Cliff Z. et al; Foley & Lardner LLP, 3000 K A61K 31/69 (2006.01) A61P 35/00 (2006.01) Street N.W., Suite 600, Washington, District of Columbia A61K 31/13 (2006.01) 20007-5 109 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US20 16/0308 19 kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 4 May 2016 (04.05.2016) 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, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (26) Publication Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (30) Priority Data: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/157,348 5 May 2015 (05.05.2015) US SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (71) Applicants: THE REGENTS OF THE UNIVERSITY TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. OF CALIFORNIA [US/US]; 1111 Franklin Street, (84) Designated States (unless otherwise indicated, for every Twelfth Floor, Oakland, California 94607-5200 (US). NA¬ kind of regional protection available): ARIPO (BW, GH, TIONAL UNIVERSITY OF SINGAPORE [SG/SG]; 2 1 GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Lower Kent Ridge Road, Singapore 119077 (SG). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (72) Inventors: HO, Dean; 11826 Dorothy Street, #101, Los 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, Angeles, California 90049 (US). HO, Chin-Ming; 11959 LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Mayfield Ave., #5, Los Angeles, California 90049 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, VITE, Aleidy Marlene Silva; 10588 Ashton Avenue, Los GW, KM, ML, MR, NE, SN, TD, TG). Angeles, California 90024 (US). ZHANG, Kangyi; 1390 Veteran Ave., #4, Los Angeles, California 90024 (US). Declarations under Rule 4.17 : CHOW, Edward Kai-Hua; 119 Clementi Road, Block I — as to applicant's entitlement to apply for and be granted a #09-18, Singapore 129801 (SG). TOH, Tan Boon; BLK patent (Rule 4.1 7(H)) 88, Bedok North Street 4, #02-129, Singapore 460088 (SG). CHNG, Wee Joo; 12 Melrose Drive, Singapore [Continued on next page] (54) Title: IMPROVED DRUG COMBINATIONS FOR DRUG-RESISTANT AND DRUG-SENSITIVE MULTIPLE MYELOMA of drug combinations Data analysis a d optimization In vitro cellular assay Figure 1 (57) Abstract: Disclosed are pharmaceutical compositions and methods of treating multiple myeloma by providing a pharmaceutic - © ally effective amount of each drug in a combination of drugs. w o 2016/179306 Al III II II 111 I Illlll 111 III III 111 I I II 111 Hill 111 llll 111 llll — as to the applicant's entitlement to claim the priority of — before the expiration of the time limit for amending the the earlier application (Rule 4.17(Hi)) claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) Published: IMPROVED DRUG COMBINATIONS FOR DRUG-RESISTANT AND DRUG- SENSITIVE MULTIPLE MYELOMA Cross-Reference to Related Application [0001] This application claims the benefit of U.S. Provisional Application No. 62/157,348, filed on May 5, 2015, the disclosure of which is incorporated herein by reference in its entirety. Technical Field [0002] This disclosure generally relates to multi-drug therapies for multiple myeloma. Background [0003] The use of drug combinations possesses an important advantage over single drug therapy. Monotherapies often lead to disease recurrence and subsequent ineffectiveness of standard treatment due to drug resistance development. Multi-drug therapies are now the standard treatment for multiple diseases, but their development has involved arduous empirical testing. The design of such therapies is quite challenging since the interactions between drugs are not well understood, as the crossover between the affected cellular pathways is quite difficult to comprehend. Furthermore, combining several drugs at different possible concentrations or dosages yields a large testing parametric space, which makes the search of an optimal combination a major challenge. Therefore, there is a need to use a different approach to develop multi-drug therapies. [0004] It is against this background that a need arose to develop the embodiments described in this disclosure. Summary of Disclosure [0005] In certain aspects, some embodiments of this disclosure are directed to a pharmaceutical composition comprising a pharmaceutically effective amount of each drug in a drug combination selected from the group consisting of: decitabine and mitomycin C; bortezomib and mechlorethamine hydrochloride; decitabine and mechlorethamine hydrochloride; decitabine, mechlorethamine hydrochloride, and mitomycin C; bortezomib, decitabine, and mitomycin C; bortezomib, mechlorethamine hydrochloride, and decitabine; and bortezomib, mechlorethamine hydrochloride, decitabine, and mitomycin C. In some embodiments, the drug combination comprises, or alternatively consists essentially of, or yet further consists of decitabine and mitomycin C. In some embodiments, the drug combination comprises, or alternatively consists essentially of, or yet further consists of bortezomib and mechlorethamine hydrochloride. In some embodiments, the drug combination comprises, or alternatively consists essentially of, or yet further consists of decitabine and mechlorethamine hydrochloride. In some embodiments, the drug combination comprises, or alternatively consists essentially of, or yet further consists of decitabine, mechlorethamine hydrochloride, and mitomycin C. In some embodiments, the drug combination comprises, or alternatively consists essentially of, or yet further consists of bortezomib, decitabine, and mitomycin C. In some embodiments, the drug combination comprises, or alternatively consists essentially of, or yet further consists of bortezomib, mechlorethamine hydrochloride, and decitabine. In some embodiments, the drug combination comprises, or alternatively consists essentially of, or yet further consists of bortezomib, mechlorethamine hydrochloride, decitabine, and mitomycin C. In some embodiments, the pharmaceutically effective amount, or dosage, of each respective drug in the drug combination is below a maximum tolerated dosage of that respective drug. In some embodiments, the pharmaceutical composition consists essentially of, or consists of, the drug combination. In some embodiments, the pharmaceutical composition comprises, or alternatively consists essentially of, or yet further consists of the drug combination and a pharmaceutical acceptable carrier or excipient. [0006] In other aspects, some embodiments of this disclosure are directed to a pharmaceutical composition comprising a pharmaceutically effective amount of each drug in a drug combination selected from the group consisting of: bortezomib and dexamethasone; bortezomib, panobinostat, and dexamethasone; bortezomib, mechloroethamine hydrochloride, and dexamethasone; and bortezomib, mechloroethamine hydrochloride, panobinostat, and dexamethasone. In some embodiments, the drug combination comprises, or alternatively consists essentially of, or yet further consists of bortezomib and dexamethasone. In some embodiments, the drug combination comprises, or alternatively consists essentially of, or yet further consists of bortezomib, panobinostat, and dexamethasone. In some embodiments, the drug combination comprises, or alternatively consists essentially of, or yet further consists of bortezomib, mechloroethamine hydrochloride, and dexamethasone. In some embodiments, the drug combination comprises, or alternatively consists essentially of, or yet further consists of bortezomib, mechloroethamine hydrochloride, panobinostat, and dexamethasone. In some embodiments, the pharmaceutically effective amount, or dosage, of each respective drug in the drug combination is below a maximum tolerated dosage of that respective drug. In some embodiments, the pharmaceutical composition consists essentially of, or consists of, the drug combination. In some embodiments, the pharmaceutical composition comprises, or alternatively consists essentially of, or yet further consists of the drug combination and a pharmaceutical acceptable carrier or excipient. [0007] In other aspects, some embodiments of this disclosure are directed to a method of treating bortezomib-resistant multiple myeloma in a subject in need thereof, comprising, or alternatively consisting essentially of, or yet further consisting of administering to the subject a pharmaceutically effective amount of each drug in a drug combination selected from the group consisting of: decitabine and mitomycin C; bortezomib and mechlorethamine hydrochloride; decitabine and mechlorethamine hydrochloride; decitabine, mechlorethamine hydrochloride, and mitomycin C; bortezomib, decitabine, and mitomycin C; bortezomib, mechlorethamine hydrochloride,
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