Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/1078-0432.CCR-18-3728 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 A Phase 1b/2 Study of Oprozomib in Patients With Advanced Multiple Myeloma and Waldenström 2 Macroglobulinemia 3 4 Running title: Oprozomib in myeloma and macroglobulinemia 5 6 Irene M. Ghobrial,1 Ravi Vij,2 David Siegel,3 Ashraf Badros,4 Jonathan Kaufman,5 Noopur Raje,6 Andrzej 7 Jakubowiak,7 Michael R. Savona,8 Mihaela Obreja,9 and Jesus G. Berdeja10 8 9 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 2Department of Medicine, 10 Washington University School of Medicine, St Louis, MO; 3Myeloma Division, John Theurer Cancer 11 Center at Hackensack University Medical Center, Hackensack, NJ; 4 Multiple Myeloma Service, University 12 of Maryland School of Medicine, Baltimore, MD; 5Department of Hematology and Medical Oncology, 13 Winship Cancer Institute of Emory University, Emory University, Atlanta, GA; 6Department of 14 Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, 15 MA; 7Myeloma Program, University of Chicago Medical Center, Chicago, IL; 8Department of Medicine, 16 Vanderbilt University School of Medicine, Nashville, TN; 9 Department of Biostatistics, Amgen Inc., 17 Thousand Oaks, CA; and 10Myeloma Research, Sarah Cannon Research Institute, Nashville, TN 18 Financial support: This study was supported by Amgen Inc. 19 20 Correspondence: Irene M. Ghobrial; Dana-Farber Cancer Institute; 450 Brookline Avenue, Boston, MA 21 02215; Phone: 617-632-4218; Email: [email protected] 22 Keywords: Oprozomib, multiple myeloma, Waldenström macroglobulinemia. 23 1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/1078-0432.CCR-18-3728 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 24 Conflicts of interest: I.M.G. reports advisory board roles for Amgen, Celgene, Takeda, BMS, and Janssen. 25 R.V. reports consultancy fees from Amgen, Celgene, Takeda, BMS, and Janssen, and research funding 26 grants from Amgen, Takeda, BMS, and Celgene. D.S. reports speakers’ bureau and honoraria fees from 27 Amgen, Celgene, Takeda, Novartis, BMS, and Janssen. A.B. has no conflicts to disclose. J.K. reports 28 research funding grants from Merck, and consultancy fees from Karyopharm, BMS, Janssen, Takeda, 29 Abbvie, Incyte, and TG Therapeutics. N.R. reports research funding grants from Astra Zeneca, and 30 consultancy fees from Celgene, Takeda, Amgen, Janssen, and BMS. A.J. reports consultancy, honoraria, 31 and membership on an entity's Board of Directors or Advisory Committees fees from Amgen, ABBVIE, 32 BMS, Celgene, Janssen, Karyopharm, Millennium, Takeda, Sanofi, and SkylineDx. M.R.S. reports equity in 33 Karyopharm, received consultancy fees and research funding from Astex, Celgene, Incyte, Karyopharm, 34 Merck, Millenium, Sunesis, and TG Therapeutics, and serves on advisory boards from Celgene and 35 Karyopharm Therapeutics. M.O. reports employment with and stock holdings for Amgen. J.G.B. reports 36 research funding grants from Abbvie, Amgen, Bluebird, BMS, Celgene, Genentech, Glenmark, Janssen, 37 Novartis, Poseida, Takeda, and Teva. 38 39 Manuscript word count: (4334/4000 word limit) 40 Tables/figures: 6/6 (4 tables, 2 figures) 41 References: 25/50 42 2 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/1078-0432.CCR-18-3728 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 43 Statement of translational relevance 44 This study is the first to evaluate single-agent oprozomib, an oral proteasome inhibitor, in patients with 45 relapsed multiple myeloma (MM) and Waldenström macroglobulinemia (WM). The data from this study 46 demonstrated that oprozomib had promising antitumor activity in patients with relapsed MM or WM, 47 including responses observed in patients refractory to other proteasome inhibitors (bortezomib or 48 carfilzomib). Gastrointestinal tolerability was a concern with the formulation of oprozomib used in this 49 study, and alternative formulations are currently being investigated to improve tolerability. Overall, the 50 findings from this study provide proof of principle for the single-agent activity of oprozomib in relapsed 51 MM or WM and provide rationale for the evaluation of new oprozomib formulations and oprozomib- 52 based combination therapy for the treatment of patients with MM or WM. 3 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/1078-0432.CCR-18-3728 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 53 Abstract 54 Background: The oral proteasome inhibitor oprozomib has shown preclinical antitumor activity. Here, 55 we report phase 1b/2 study results investigating single-agent oprozomib in relapsed multiple myeloma 56 (MM) and Waldenström macroglobulinemia (WM) patients. 57 Methods: The primary objectives were to determine the maximum tolerated dose (MTD), safety and 58 tolerability of oprozomib (phase 1b) as well as overall response rate (ORR) (phase 2). Oprozomib was 59 administered once daily on days 1, 2, 8, and 9 (2/7 schedule) or days 1–5 (5/14 schedule) of a 14-day 60 cycle. 61 Results: In patients with MM or WM (n = 71), the determined MTDs were 300 mg/day (2/7 schedule) 62 and 240 mg/day (5/14 schedule). Median oprozomib treatment duration for MM patients was 11.4 63 weeks (2/7 schedule, 240/300-mg/day), 5.4 weeks (5/14, 240-mg/day), and 10.1 weeks (5/14, 150/180- 64 mg/day). For WM patients, these values were 34.6 weeks (2/7 schedule, 240/300-mg/day) and 8.1 65 weeks (5/14 schedule, 240-mg/day). The most common grade ≥3 adverse events (AEs) in phase 1b 66 included gastrointestinal and hematologic AEs. Three AE-related deaths in phase 2 prompted enrollment 67 into 2/7 and 5/14 step-up dosing schedules (240/300 mg/day and 150/180 mg/day, respectively). In 68 phase 2, ORRs in 95 response-eligible MM patients were 41.0%, 28.1%, and 25.0% in the 2/7, 240/300- 69 mg/day; 5/14, 150/180-mg/day; and 5/14, 240-mg/day cohorts, respectively. ORRs in 31 response- 70 eligible WM patients were 71.4% and 47.1% for the 2/7 and 5/14 cohorts, respectively. 71 Conclusion: This study demonstrated promising efficacy of single-agent oprozomib in relapsed MM and 72 WM patients. 73 74 4 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/1078-0432.CCR-18-3728 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 75 Introduction 76 Proteasome inhibitors (PIs), including carfilzomib, bortezomib, and ixazomib, have become validated 77 strategies for treating patients with multiple myeloma (MM). Bortezomib has demonstrated efficacy in 78 MM patients, but is associated with peripheral neuropathy and must be administered intravenously (IV) 79 or subcutaneously, limiting its use in some patients.(1-5) Given the challenges of IV administration, 80 subcutaneous treatment with bortezomib is now the preferred administration route.(6) Carfilzomib, an 81 epoxyketone PI, is approved in the United States and other countries for the treatment of relapsed or 82 refractory MM.(7) In the ENDEAVOR trial, carfilzomib demonstrated superiority over bortezomib in 83 patients with relapsed or refractory MM.(8) One challenge associated with carfilzomib treatment is the 84 need for twice-weekly IV administration.(7,9) Once-weekly carfilzomib has recently been approved for 85 the treatment of relapsed or refractory MM based on results from the phase 3 A.R.R.O.W. trial, which 86 demonstrated prolonged progression-free survival with once-weekly carfilzomib at 70 mg/m2 vs twice- 87 weekly carfilzomib at 27 mg/m2.(7, 10) 88 Oral administration of PIs can enhance accessibility and feasibility of MM treatment. Ixazomib is the only 89 oral PI that is currently approved in the United States for the treatment of MM.(11) In the phase 3 90 TOURMALINE-MM1 trial, the addition of ixazomib to lenalidomide and dexamethasone significantly 91 improved progression-free survival (PFS) compared with lenalidomide-dexamethasone.(12) In a 92 subgroup analysis of TOURMALINE-MM1, however, patients with 1 prior therapy and transplant did not 93 have a PFS improvement with ixazomib-lenalidomide-dexamethasone.(13) 94 Due to the limitations and challenges of the 3 PIs currently approved for MM treatment, there is a need 95 for additional PIs that are effective, tolerable, and convenient. Oprozomib is an oral tripeptide 96 epoxyketone PI that is structurally analogous to carfilzomib and binds selectively and irreversibly to the 97 proteasome.(14) Oprozomib has shown antitumor activity similar to carfilzomib in preclinical models 5 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/1078-0432.CCR-18-3728 Author manuscripts have