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

• r 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. Shain8

1Medical College of Wisconsin, Milwaukee, WI; 2Washington University School of Medicine

in St. Louis, St. Louis, MO; 3Berenson Oncology, West Hollywood, CA; 4University of Chicago Medical Center, Chicago, IL; 5Winship Cancer Institute of Emory University, Emory University, Atlanta, GA; 6Levine Cancer Institute, Charlotte, NC; 7Amgen Inc., Thousand Oaks, CA;

• 8H. 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

• n 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 disease1

• Oprozomib is an oral, selective, and irreversible inhibitor of the

chymotrypsin-like activity of the constitutive proteasome and the immunoproteosome2

• Oprozomib has been associated with poor gastrointestinal tolerability3;

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

Odex

Oprozomib was administered on days 1 and 2 each week in a 4-week cycle (Mon–Tues); Dexamethasone was administered on each

• prozomib dosing day

Formulations IR (150 mg) + dexamethasone (20 mg) GR (150 mg) + dexamethasone (20 mg) BAYESIAN DOSE ESCALATION

OPomD

Oprozomib was administered on days 1 and 2 each week in a 4-week cycle (Mon–Tues); Dexamethasone was administered on each oprozomib dosing day; Pomalidomide was administered on days 1 to 21 of 28-week cycle Formulations IR (150 mg) + dexamethasone (20 mg) + pomalidomide (4 mg) GR (150 mg) + dexamethasone (20 mg) + pomalidomide (4 mg) *GR formulation administered after IR formulation was proven tolerable Escalation by 25- or 50-mg increments based on available data and algorithm recommendation Escalation includes a step-up after 150 mg/day × 2 for a week

The starting dose of the GR formulation will be determined based on the safety and pharmacokinetic data observed in the first cohorts 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.

150 mg 200 mg 250 mg 300 mg × 2/wk

IR GR*

225 mg 150 mg 200 mg 150 mg × 2/wk

GR IR

150 mg × 2/wk

The study was conducted in approximately 25 sites in the United States, Australia, Canada, and Europe

GR=gastroretentive; IR=immediate release; Odex=oprozomib plus dexamethasone; OPomD=oprozomib plus dexamethasone plus pomalidomide

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

Characteristic All Patients (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 (%) 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

Regimen* Number of Cycles, Median (IQR) DLTs,† n DLT Events

IR 150 mg/day (n = 5) 2.0 (1.0–11.0) – GR 150 mg/day (n = 8) 3.5 (1.5–5.0) – 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 IR 200 mg/day (n = 8) 5.0 (3.0–9.5) 1 Acute kidney injury GR 200 mg/day (n = 5) 2.0 (2.0–3.0) 3 Thrombocytopenia (3 events in 2 patients) IR 225 mg/day (n = 5) 6.0 (5.0–6.0) – IR 250 mg/day (n = 8) 3.0 (3.0–3.0) 1 Lipase increased

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

Odex OPomD

• MTD has been reached (IR 250 mg/day)

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) Neutropenia 7 (14.9) 5 (10.6) Pneumonia 7 (14.9) 6 (12.8)

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

• One fatal AE was observed (OPomD GR 200 mg, gastrointestinal hemorrhage)

Common Adverse Events of Interest by Treatment Cohort

GR=gastroretentive; IR=immediate release; Odex=oprozomib plus dexamethasone; OPomD=oprozomib plus dexamethasone plus pomalidomide

Nausea Vomiting Diarrhea

O d e x G R 1 5 0 m g (n = 8 ) O P o m D G R 1 5 0 m g (n = 4 ) O P o m D G R 2 0 0 m g (n = 5 )

2 0 4 0 6 0 8 0 1 0 0

P a tie n ts , %

2 0 4 0 6 0 8 0 1 0 0

P a tie n ts , %

2 0 4 0 6 0 8 0 1 0 0

P a tie n ts , % O P o m D IR 1 5 0 m g (n = 4 ) O P o m D IR 2 0 0 m g (n = 8 ) O P o m D IR 2 2 5 m g (n = 5 ) O P o m D IR 2 5 0 m g (n = 8 ) O d e x IR 1 5 0 m g (n = 5 ) G ra d e ≥ 3

G R O d e x a n d O P o m D IR O d e x a n d O P o m D G R O d e x a n d O P o m D IR O d e x a n d O P o m D G R O d e x a n d O P o m D IR O d e x a n d O P o m D

Strategies to Reduce GI Toxicities in the Trial

• Lansoprazole or another oral proton-pump inhibitor (PPI) was

required (H2 antagonists were recommended if patient had intolerance or hypersensitivity to PPI for the duration of treatment to prevent GI toxicities)

• Oral hydration of 1.5–2 liters per 24 hours was required for all

patients 24 hours before initiation of therapy for every cycle and throughout every day of oprozomib dosing

• Patients who experienced any grade of GI hemorrhage

during the study were not re-challenged with oprozomib

GI=gastrointestinal

Best Tumor Response

GR=gastroretentive; IR=immediate release; Odex=oprozomib plus dexamethasone; OPomD=oprozomib plus dexamethasone plus pomalidomide; ORR=objective response rate; PR=partial response Dose listed is for oprozomib; data cutoff, September 24, 2018

Odex

Responses in Patients Refractory to Previous Therapies

• Among 7 patients who were refractory to daratumumab,

2 responses were observed

– OPomD: IR 225 mg/day, n=1; IR 250 mg/day, n=1

• Among 19 patients who were refractory to bortezomib,

5 responses were observed

– Odex: GR 150 mg/day, n=1; IR 150 mg/day, n=1 – OPomD: IR 200 mg/day, n=1; IR 250 mg/day, n=2

• Among 12 patients who were refractory to carfilzomib,

3 responses were observed

– OPomD: IR 150 mg/day, IR 225 mg/day, IR 250 mg/day; n=1 each

GR=gastroretentive; IR=immediate release; Odex=oprozomib plus dexamethasone; OPomD=oprozomib plus dexamethasone plus pomalidomide

Serum M-Protein Change From Baseline

GR=gastroretentive; IR=immediate release; Odex=oprozomib plus dexamethasone; OPomD=oprozomib plus dexamethasone plus pomalidomide Dose listed is for oprozomib; data cutoff, September 24, 2018

Reasons for Oprozomib Discontinuation

IR 150 mg/day (n=5) GR 150 mg/day (n=8) IR 150 mg/day (n=3) GR 150 mg/day (n=4) IR 200 mg/day (n=9) GR 200 mg/day (n=5) IR 225 mg/day (n=5) IR 250 mg/day (n=8) Total (N=47)

Patients who discontinued

• prozomib, n (%)

5 (100.0) 6 (75.0) 2 (66.7) 2 (50.0) 6 (66.7) 2 (40.0) 1 (12.5) 24 (51.1) Death 1 (20.0) 1 (2.1) Adverse event 2 (22.2) 2 (4.3) Patient request 1 (12.5) 1 (12.5) 2 (4.3) Disease progression 3 (60.0) 4 (50.0) 1 (33.3) 2 (50.0) 3 (33.3) 1 (20.0) 14 (29.8) Other 2 (40.0) 1 (12.5) 1 (33.3) 1 (11.1) 5 (10.6)

GR=gastroretentive; IR=immediate release

Preliminary Pharmacokinetics of Oprozomib

• Lower peak exposures (Cmax) and longer median tmax of GR tablet compared with IR tablet,

consistent with release profile of GR tablet

• Relative bioavailability of GR tablet compared with IR tablet was approximately 80% based
• n mean AUC ratios

AUC=area under the concentration-time curve; Cmax=maximum concentration; GR=gastroretentive; IR=immediate release; tmax=time to Cmax Data presented following day 8 dosing of 150 mg oprozomib, pomalidomide, and dexamethasone

6 1 2 1 8 2 4 0 .1 1 1 0 1 0 0 1 0 0 0

T im e (h o u rs ) O p ro z o m ib P la s m a C o n c . (n g /m L ; M e a n + S D ) IR (n = 3 ) G R (n = 4 )

Conclusions

• Preliminary results indicate oprozomib IR administered in combination

with pomalidomide and dexamethasone is safe up to 225 mg/day

• A fatal AE (GI hemorrhage) was observed in the GR 200-mg/day cohort,

and the oprozomib GR formulation has been put on hold

• Therapy with OPomD showed promising efficacy, with an objective

response rate of 67% for patients in the IR 200-mg/day cohort

• Additional investigation is needed to determine a recommended

phase 3 dose

AE=adverse event; GI=gastrointestinal; GR=gastroretentive; IR=immediate release; OPomD=oprozomib plus dexamethasone plus pomalidomide

Acknowledgments

• The authors thank the patients and their families and the

study staff who participated in the trial

• The authors acknowledge Jesse Potash, PhD (Amgen Inc.),

Lee B. Hohaia, PharmD, and Meghan Johnson, PhD (Complete Healthcare Communications, Inc., North Wales, PA), whose work was funded by Amgen Inc., for assistance in preparing this presentation

• This study was sponsored and funded by Amgen Inc.