A Phase 1b Study of Oprozomib With Dexamethasone or Pomalidomide and - PowerPoint PPT Presentation

A Phase 1b Study of Oprozomib With Dexamethasone or Pomalidomide and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma Parameswaran Hari, 1 Mark A. Schroeder, 2 James R. Berenson, 3 Andrzej Jakubowiak, 4 Jonathan L. Kaufman, 5 Peter M. Voorhees, 6 Hisaki Fujii, 7 Zhao Yang, 7 Francesco Galimi, 7 Kenneth H. Shain 8 1 Medical College of Wisconsin, Milwaukee, WI; 2 Washington University School of Medicine in St. Louis, St. Louis, MO; 3 Berenson Oncology, West Hollywood, CA; 4 University of Chicago Medical Center, Chicago, IL; 5 Winship Cancer Institute of Emory University, Emory University, Atlanta, GA; 6 Levine Cancer Institute, Charlotte, NC; 7 Amgen Inc., Thousand Oaks, CA; 8 H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

Conflict of Interest Disclosures Parameswaran Hari Received research funding and served as a consultant for Amgen and Celgene Mark A. Schroeder Served on an advisory board and as a consultant for Amgen James R. Berenson Served as a consultant for Amgen and received research funding and honoraria from Amgen Andrzej Jakubowiak Reports consultancy, honoraria, and membership on an entity's board of directors or advisory committees fees from Amgen, AbbVie, BMS, Celgene, Janssen, Karyopharm, Millennium, Takeda, Sanofi, and SkylineDx Jonathan L. Kaufman Served as a consultant for BMS and Janssen and served on data monitoring committees for Karyopharm and Incyte Peter M. Voorhees Served as a consultant for BMS, Celgene, Novartis, Janssen, Oncopeptides, and TeneoBio; served on an advisory board for BMS, Celgene, Janssen, Oncopeptides, and TeneoBio; served on an IRC for Celgene, Novartis, and Oncopeptides; and served on a speakers bureau for Amgen and Janssen Hisaki Fujii Is an employee of and owns stock in Amgen Zhao Yang Is an employee of and owns stock in Amgen Francesco Galimi Is an employee of and owns stock in Amgen Kenneth H. Shain Served as a consultant for and received research funding from AbbVie and served as a consultant for and received speakers honoraria from Celgene, Amgen, Takeda, and Janssen

Background • Despite advances in the treatment of MM, relapse is common and is associated with more aggressive disease 1 • Oprozomib is an oral, selective, and irreversible inhibitor of the chymotrypsin-like activity of the constitutive proteasome and the immunoproteosome 2 • Oprozomib has been associated with poor gastrointestinal tolerability 3 ; new formulations of oprozomib may have an improved safety profile MM=multiple myeloma 1. Dimopoulos MA, et al. Nat Rev Clin Oncol. 2015;12;42-54 2. Zhou HJ, et al. J Med Chem. 2009;52:3028-3038 3. Vij R, et al. Abstract presented at EHA Annual Meeting, June 2015

Background • This phase 1b study evaluated the safety and tolerability of 2 new formulations of oprozomib, immediate release (IR) and extended- release gastroretentive (GR), in combination with dexamethasone (Odex) or pomalidomide and dexamethasone (OPomD) in patients with RRMM Primary Objective • To identify the maximum tolerated dose (MTD) and to evaluate the safety and tolerability of OPomD in patients with RRMM RR=relapsed or refractory multiple myeloma

INTREPID-1: Trial Schema The study was conducted in approximately 25 sites in the United States, Australia, Canada, and Europe BAYESIAN DOSE ESCALATION Odex OPomD Oprozomib was administered on days 1 and Oprozomib was administered on days 1 and 2 each week in a 2 each week in a 4-week cycle (Mon – Tues); 4-week cycle (Mon – Tues); Dexamethasone was administered on each Dexamethasone was administered on each oprozomib dosing day; oprozomib dosing day Pomalidomide was administered on days 1 to 21 of 28-week cycle Formulations Formulations IR (150 mg) + dexamethasone (20 mg) IR (150 mg) + dexamethasone (20 mg) + pomalidomide (4 mg) GR (150 mg) + dexamethasone (20 mg) GR (150 mg) + dexamethasone (20 mg) + pomalidomide (4 mg) 300 mg × 2/wk IR IR 250 mg 150 mg × 2/wk 225 mg 200 mg GR* GR 150 mg 150 mg × 2/wk 200 mg 150 mg GR=gastroretentive; IR=immediate release; *GR formulation administered after IR formulation was proven tolerable Odex=oprozomib plus dexamethasone; Escalation by 25- or 50-mg increments based on available data and algorithm recommendation OPomD=oprozomib plus dexamethasone plus Escalation includes a step-up after 150 mg/day × 2 for a week pomalidomide The starting dose of the GR formulation will be determined based on the safety and pharmacokinetic data observed in the first co horts of the IR dose escalation, and it will be ≥ 1 dose level lower that the highest dose tested of the IR formulation. INTREPID- 1 is registered at ClinicalTrials.gov with Identifier NCT02939183.

INTREPID-1: Patients Key Eligibility Criteria • Age ≥ 18 years, with definitively diagnosed RRMM with measurable disease • Received ≥ 2 prior lines of therapy, including lenalidomide and a proteasome inhibitor • Willing to undergo bone marrow aspiration • ECOG performance status ≤ 2 • Adequate renal and hepatic function • Provided informed consent ECOG=Eastern Cooperative Oncology Group; RR=relapsed or refractory multiple myeloma

INTREPID-1: Dose Escalation Criteria for Dose-Limiting Toxicities • The DLT window was the initial 28 days of study treatment - Was extended for AEs starting within window - Severe or frequent AEs occurring outside window were included upon unanimous DLRT decision • DLTs were treatment-related AEs occurring within DLT window meeting these criteria: - Required permanent discontinuation of oprozomib - Resulted in a delay of first dose of cycle 2 that persisted for ≥ 14 days after end of cycle 1 - Grade ≥ 3 nonhematologic AEs - Excluding asymptomatic electrolyte abnormalities, asymptomatic hyposphosphatemia, and nausea, vomiting, or diarrhea persisting ≤ 3 days - Hematologic toxicities, including - Grade 4 neutropenia - Febrile neutropenia - Grade 4 thrombocytopenia for ≥ 7 days or grade ≥ 3 with clinically significant bleeding AE=adverse event; DLT=dose-limiting toxicity; DLRT=dose level review team

Baseline Demographics and Disease Characteristics All Patients Characteristic (N = 47) Median (range) age, y 65.0 (39–84) Men, n (%) 31 (66.0) Race, n (%) White 36 (76.6) Black 9 (19.1) Other 2 (4.3) ECOG performance status, n (%) 0 19 (40.4) 1 26 (55.3) Prior lines of therapy, median (range) 4.0 (1–17) Prior therapy [refractory to prior therapy] , n (%) Bortezomib 40 (85.1) [19 (40.4)] Carfilzomib 19 (40.4) [12 (25.5)] Daratumumab 13 (27.7) [7 (14.9)] Lenalidomide and bortezomib 37 (78.7) [13 (27.7)] Lenalidomide, bortezomib, and carfilzomib 15 (31.9 ) [1 (2.1)] ECOG=Eastern Cooperative Oncology Group

Dosing and Dose-Limiting Toxicities Number of Cycles, Regimen* Median (IQR) DLTs, † n DLT Events Odex IR 150 mg/day (n = 5) 2.0 (1.0–11.0) 0 – GR 150 mg/day (n = 8) 3.5 (1.5–5.0) 0 – IR 150 mg/day (n = 4) 6.5 (2.5–11.0) 1 Lipase increased GR 150 mg/day (n = 4) 3.5 (1.5–5.0) 1 Febrile neutropenia OPomD IR 200 mg/day (n = 8) 5.0 (3.0–9.5) 1 Acute kidney injury Thrombocytopenia GR 200 mg/day (n = 5) 2.0 (2.0–3.0) 3 (3 events in 2 patients) IR 225 mg/day (n = 5) 6.0 (5.0–6.0) 0 – IR 250 mg/day (n = 8) 3.0 (3.0–3.0) 1 Lipase increased • MTD has been reached (IR 250 mg/day) DLT=dose-limiting toxicity; GR=gastroretentive; IQR=interquartile range; IR=immediate release; MTD=maximum tolerated dose; Odex=oprozomib plus dexamethasone; OPomD=oprozomib plus dexamethasone plus pomalidomide. *Dose listed is for oprozomib. † Data cutoff, September 24, 2018

Summary of Adverse Events All Patients (N = 47) Any Grade Grade ≥ 3 All treatment-emergent AEs, n (%) 46 (97.9) 37 (78.7) Common treatment-emergent AEs,* n (%) Nausea 36 (76.6) 2 (4.3) Diarrhea 29 (61.7) 7 (14.9) Vomiting 26 (55.3) 4 (8.5) Constipation 19 (40.4) 1 (2.1) Fatigue 19 (40.4) 2 (4.3) Insomnia 12 (25.5) 1 (2.1) Anemia 10 (21.3) 9 (19.1) Dyspnea 10 (21.3) 1 (2.1) Upper respiratory tract infection 10 (21.3) 0 Neutropenia 7 (14.9) 5 (10.6) Pneumonia 7 (14.9) 6 (12.8) • One fatal AE was observed (OPomD GR 200 mg, gastrointestinal hemorrhage) AE=adverse event; GR=gastroretentive; OPomD=oprozomib plus dexamethasone plus pomalidomide *Included AEs of any grade that occurred in ≥ 20% of patients or grade ≥ 3 AEs that occurred in ≥ 10% of patients

Common Adverse Events of Interest by Treatment Cohort Nausea Vomiting Diarrhea 1 0 0 1 0 0 1 0 0 8 0 8 0 8 0 P a tie n ts , % P a tie n ts , % P a tie n ts , % 6 0 6 0 6 0 4 0 4 0 4 0 2 0 2 0 2 0 0 0 0 G R IR G R IR G R IR O d e x a n d O P o m D O d e x a n d O P o m D O d e x a n d O P o m D O d e x a n d O P o m D O d e x a n d O P o m D O d e x a n d O P o m D O d e x G R 1 5 0 m g (n = 8 ) O P o m D G R 2 0 0 m g (n = 5 ) O P o m D IR 1 5 0 m g (n = 4 ) O P o m D IR 2 2 5 m g (n = 5 ) O P o m D G R 1 5 0 m g (n = 4 ) O d e x IR 1 5 0 m g (n = 5 ) O P o m D IR 2 0 0 m g (n = 8 ) O P o m D IR 2 5 0 m g (n = 8 ) G ra d e ≥ 3 GR=gastroretentive; IR=immediate release; Odex=oprozomib plus dexamethasone; OPomD=oprozomib plus dexamethasone plus pomalidomide