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303 Phase 2 Study of Venetoclax Plus Carfilzomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Novel Targeted Combinations in Myeloma
Hematology Disease Topics & Pathways:
Diseases, Adult, apoptosis, Non-Biological, Therapies, Biological Processes, Study Population, Clinically relevant, Myeloid Malignancies
Sunday, December 2, 2018: 8:00 AM
Grand Ballroom 7 (Marriott Marquis San Diego Marina)

Luciano J Costa, MD, PhD1, Edward A. Stadtmauer, MD, FACP2*, Gareth Morgan, MD3, Gregory Monohan, MD4, Tibor Kovacsovics, MD5, Nicholas Burwick, MD6, Andrzej Jakubowiak, MD, PhD7, Jonathan L Kaufman, MD8, Mehrdad Mobasher, MD, MPH9, Kevin J. Freise, PhD10, Jeremy A. Ross, PhD10*, John Pesko, PhD10*, Wijith Munasinghe, PhD10*, Saketh Gudipati, MD10*, Sarah Mudd, PhD10*, Orlando Bueno, MD, PhD10 and Shaji K. Kumar, MD11

1University of Alabama at Birmingham, Vestavia, AL
2Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
3University of Arkansas for Medical Sciences, Little Rock, AR
4University of Kentucky, Lexington, KY
5Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT
6VA Puget Sound Health Care System, Seattle, WA
7University of Chicago, Chicago, IL
8Winship Cancer Institute, Emory University, Atlanta, GA
9Genentech Inc, South San Francisco, CA
10AbbVie, Inc., North Chicago, IL
11Department of Hematology, Mayo Clinic, Rochester, MN

Introduction: Venetoclax (Ven), an oral agent that targets the antiapoptotic protein, BCL-2, has demonstrated efficacy, as monotherapy and combined with proteasome inhibitor (PI) bortezomib, in relapsed/refractory (R/R) multiple myeloma (MM). We report preliminary safety and efficacy data for Ven combined with the second generation PI carfilzomib (K) and dexamethasone (VenKd) in R/R MM.

Methods: In this ongoing phase 2, dose escalation study (NCT02899052), patients with R/R MM and no prior K exposure received VenKd on 28-d cycles in 4 dose finding and one expansion cohorts: Ven 400 mg/day + K 27 mg/m2 Day 1, 2, 8, 9, 15, 16 + dex 40 mg Day 1, 8, 15, 22 (Cohort 1), same regimen but with Ven 800 mg/day (Cohort 2), Ven 800 mg/day + K 70 mg/m2 Day 1, 8, 15 + dex 40 mg Day 1, 8, 15, 22 (Cohort 3/expansion cohort), or Ven 800 mg + K 56 mg/m2 Day 1, 2, 8, 9, 15, 16 + dex 40 mg Day 1, 2, 8, 9, 15, 16, 22, 23 (Cohort 4). Treatment continued until progressive disease (PD) or unacceptable toxicity.

Results: As of June 11, 2018, 42 patients were enrolled. The median age was 66.5 years (min, max: 37, 79), 63% had ISS II/III disease, and 8 patients (19%) had t(11;14). Patients received a median of 2 prior therapies (range: 1 – 3), 93% had received prior PI (50% refractory), 62% were refractory to immunomodulatory therapies, and 33% double refractory.

At the data cut off, 29 patients were still active and had completed ≥2 cycles and 13 patients discontinued with the primary reason being disease progression (n=4), death (n=3), physician decision (n=2), withdrawal of consent (n=2), lack of efficacy (n=1), and AE (n=1). All patients experienced at least one AE, and grade 3/4 AEs experienced by >10% of subjects included: decreased lymphocyte count (26%), decreased neutrophil count (14%), and hypertension (12%). Thirteen subjects experienced at least one serious AE. Maximum tolerated dose was not reached and Ven 800 mg/day + K 70 mg/m2 was selected for expansion. Ven mean (% coefficient of variation) maximum plasma concentration (Cmax) and area under the plasma concentration-time curve over 24 hours (AUC24) on Cycle 1 Day 15 were 2.7 (57) mg/mL and 33.1 (54) mg×h/mL, respectively, at 400 mg venetoclax (n=4); and were 2.42 (53) mg/mL and 38.7 (51) mg×h/mL, respectively, at 800 mg venetoclax (n=13) in the dose escalation cohorts.

The overall response rate (ORR) was 78% and the very good partial response (VGPR) or better rate was 56% (Table). Median time from first dose to the data cut or discontinuation was 5.7 months (range: 0.9 - 16.3) and the median time to first response was 1.9 months (95% CI: 0.9, 9.2). ORRs for subgroups of interest are reported in the Table.

Conclusions: The combination of VenKd appears tolerable with no new safety signals or changes in Ven pharmacokinetics. VenKd shows promising preliminary efficacy in R/R MM patient subgroups. Response rates were comparable in all high risk subgroups and overall population. However, the subset of patients with t(11;14) had the highest response. Overall, these results demonstrate that VenKd is a safe and efficacious regimen in R/R MM and support the continued study of VenKd.

Disclosures: Costa: Abbvie: Research Funding; BMS: Research Funding; Karyopharm: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Research Funding. Stadtmauer: Celgene: Consultancy; AbbVie, Inc: Research Funding; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Morgan: Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Research Funding; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Kovacsovics: Amgen: Honoraria, Research Funding; Abbvie: Research Funding. Jakubowiak: Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Kaufman: Roche: Consultancy; BMS: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; Abbvie: Consultancy; Celgene: Consultancy. Mobasher: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests non-PLC; Genentech Inc: Employment. Freise: AbbVie, Inc: Employment, Equity Ownership. Ross: AbbVie, Inc: Employment, Equity Ownership. Pesko: AbbVie, Inc: Employment, Equity Ownership. Munasinghe: AbbVie, Inc: Employment, Equity Ownership. Gudipati: AbbVie, Inc: Employment, Equity Ownership. Mudd: AbbVie, Inc: Employment, Equity Ownership. Bueno: AbbVie, Inc: Employment, Equity Ownership. Kumar: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

*signifies non-member of ASH