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WO 2017/187156 Al 02 November 2017 (02.11.2017) W !P O PCT (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 2017/187156 Al 02 November 2017 (02.11.2017) W !P O PCT (51) International Patent Classification: EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, A61K 38/04 (2006.01) A61P 35/00 (2006.01) MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, A61K 38/12 (2006.01) A61K 38/06 (2006.01) TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, A61K 31/365 {2006.01) A61K 45/06 {2006.01) KM, ML, MR, NE, SN, TD, TG). A61K 31/69 (2006.01) A61K 31/4015 (2006.01) C07D 303/36 (2006.01) Published: — with international search report (Art. 21(3)) (21) International Application Number: PCT/GB2017/05 1148 (22) International Filing Date: 25 April 2017 (25.04.2017) (25) Filing Language: English (26) Publication Langi English (30) Priority Data: 1607279.5 26 April 2016 (26.04.2016) GB (71) Applicant: BIG DNA LTD [GB/GB]; Wallace Building, Roslin Biocentre, Roslin, Midlothian EH25 9PP (GB). (72) Inventors: MARCH, John, Bernard; c/o Big DNA Ltd, Wallace Building, Roslin BioCentre, Roslin Midlothian EH25 9PP (GB). CLARK, Ewan, Mcintosh; c/o Big DNA Ltd, Wallace Building, Roslin BioCentre, Roslin Midlothi an EH25 9PP (GB). (74) Agent: HGF LIMITED (LEEDS); 1 City Walk, Leeds West Yorkshire LSI 1 9DX (GB). (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, 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, (54) Title: COMBINATION THERAPY (57) Abstract: The present invention relates to a combination comprising a proteasome inhibitor and a cyclic peptide that comprisesan exposed Arg-Gly-Asp (RGD)moiety;wherein the combination is formulated for oral administration of both the proteasome inhibitor and cyclic peptide components. In particular, the present invention relates to a combination comprising a proteasome inhibitor selected from the group consisting of: a boronate, anepoxyketone, a peptide aldehydeand a β-lactone protease inhibitor; and a cyclic peptidethat comprisesan exposed Arg-Gly-Asp (RGD)moiety; wherein the combination is formulated for oral administration of both the proteasome inhibitor and cyclic peptide components. More particularly, the present invention relates to a combination comprising a proteasome inhibitor selected from the group consisting ofbortezomib, delanzomib,ixazomib, carfilzomib, oprozomib, MG132and marizomib; and a cyclic peptidethat comprisesan exposed Arg-Gly-Asp (RGD)moiety; wherein the combination is formulated for oral administration of both the proteasome inhibitor and cyclic peptide components. COMBINATION THERAPY FIELD OF THE INVENTION [01] The present invention relates to a combination comprising a proteasome inhibitor and a cyclic peptide that comprises an exposed Arg-Gly-Asp (RGD) moiety; wherein the combination is formulated for oral administration of both the proteasome inhibitor and cyclic peptide components. In particular, the present invention relates to a combination comprising a proteasome inhibitor selected from the group consisting of: a boronate, an epoxyketone, a peptide aldehyde and a β-lactone protease inhibitor; and a cyclic peptide that comprises an exposed Arg-Gly-Asp (RGD) moiety; wherein the combination is formulated for oral administration of both the proteasome inhibitor and cyclic peptide components. More particularly, the present invention relates to a combination comprising a proteasome inhibitor selected from the group consisting of: bortezomib, delanzomib, ixazomib, carfilzomib, oprozomib, MG1 32 and marizomib; and a cyclic peptide that comprises an exposed Arg-Gly-Asp (RGD) moiety; wherein the combination is formulated for oral administration of both the proteasome inhibitor and cyclic peptide components. [02] The present invention relates to an oral combination that is useful as a medicament, for example in the treatment of hyper proliferative diseases, such as cancer. [03] The present invention also relates to a pharmaceutical composition formulated for oral administration comprising the combination and to kits comprising each component of the combination wherein each component of the kit is formulated for oral administration. BACKGROUND OF THE INVENTION [04] Bortezomib (BTZ) is an anti-neoplastic agent which is licensed for intravenous injection (IV) or subcutaneous (SC) use. The structure of bortezomib is: [05] Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis which can affect multiple signalling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumour growth in vivo in nonclinical tumour models, including multiple myeloma. [06] Data from in vitro, ex-vivo, and animal models with bortezomib suggest that it increases osteoblast differentiation and activity and inhibits osteoclast function. These effects have been observed in patients with multiple myeloma affected by an advanced osteolytic disease and treated with bortezomib. [07] Dorsey et al. J . Med Chem. 2008; 5 1 :1068-72 assessed the pharmacokinetics of bortezomib in CD-1 mice. Bortezomib was dosed at 4mg/kg PO was comparable to about half the AUC values compared with delivery of 0.8mg/kg intravenously. The estimated oral bioavailability of bortezomib was approximately 11% . Zhu et al. J . Med Chem 201 0 ; 53: 1990-9 also assessed the pharmacokinetics of bortezomib in Sprague-Dawley rats. The authors report oral Tmax, Cmax, AUC and other pharmacokinetic parameters for bortezomib. The calculated bioavailability of bortezomib in this study was 46% by comparison of the AUC for intravenous versus intra-gastric administration. [08] Delanzomib (DLZ), ([(1 R)-1 -[[(2S,3R)-3-Hydroxy-2-[[(6-phenylpyridin-2-yl)carbonyl]amino]- 1- oxobutyl]amino]-3-methylbutyl]boronic acid), is an anti-neoplastic agent for intravenous injection (IV), oral or subcutaneous (SC) use. The structure of delanzomib is: [09] Delanzomib is also a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. Experiments have demonstrated that delanzomib is cytotoxic to multiple myeloma cell lines in vitro (Piva et al. Blood 2008;1 11:2765-75, Dorsey et al. , J . Med Chem 2008;51 :1068-72). Delanzomib causes a reduction in tumour growth in vivo in nonclinical tumour models, including multiple myeloma (Sanchez et al., Br. J . Haematol 201 0 ;148:569-81 ) . The estimated oral bioavailability of bortezomib was approximately 39% (Dorsey et al). [01 0] Ixazomib (IXZ) is an anti-neoplastic agent for intravenous injection (IV), oral or subcutaneous use. Ixazomib is formulated with citric acid for clinical use: the citrate hydrolyses immediately on contact with plasma or aqueous solutions (Kupperman et al., Cancer Res. 201 0;70: 1970-80). The final formulation is termed ixazomib citrate, originally designated 'MLN9708', which contains the active drug component 'MLN2238' (ixazomib) and a citric acid moiety. [01 1] The structure of Ixazomib (MLN2238) ([(1 R)-1 -[[2-[(2,5- dichlorobenzoyl)amino]acetyl]amino]-3-methyl-butyl]boronic acid) is provided below: [01 2] The structure of Ixazomib citrate (MLN9708) (2,2'-{2-[(1 R)-1 -{[N-(2,5- Dichlorobenzoyl)glycyl]amino}-3-methylbutyl]-5-oxo-1 ,3,2-dioxaborolane-4,4-diyl} diacetic acid) is provided below: [01 3] Ixazomib is also a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. [01 4] Kupperman and co-workers (Kupperman et al. , Cancer Res. 201 0;70:1 970-80) describe the physiochemical, phamocokinetic, pharmacodynamic, antitumoral activity and interactions of ixazomib with the proteasome compared with bortezomib. Both bortezomib and ixazomib bind preferentially to the β5 site of the 20S proteasome, also binding to the β2 and β1 sites at higher concentrations. Although the affinity for the active sites in the proteasome is approximately equal for ixazomib and bortezomib, ixazomib was found to remain bound to the proteasome for a shorter time period. The proteasome dissociation half-life of ixazomib is approximately 18 minutes, whereas the dissociation half-life of bortezomib is approximately 110 minutes, i.e. ixazomib is released approximately 6-fold faster than bortezomib. Ixazomib is cytotoxic to a variety of cancer cell lines in vitro including melanoma, lung cancer and colorectal cancer cell lines. Ixazomib also exhibited antitumoral activity in vivo in several preclinical models. In CWR22 human prostate cancer xenografts, both bortezomib and ixazomib showed effective anti-tumoral activity at their maximum tolerated dose (MTD). Ixazomib proved more effective than bortezomib at half the MTD. In WSU-DLCL2 lymphoma xenograft model, ixazomib showed significant anti-tumoral activity whereas bortezomib was ineffective at its MTD.
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