Final Results of Phase 1 MMRC Trial of Selinexor, Carfilzomib, and Dexamethasone in Relapsed/Refractory Multiple Myeloma (RRMM)

作者：Andrzej Jakubowiak, Jagoda Jasielec, Cara A. Rosenbaum, Craig E. Cole, Ajai Chari, Jennifer Nam, Erica Severson, Leonor A Stephens, Kathryn McDonnell, Shaun Rosebeck, Todd M. Zimmerman, Theodore Karrison, Jeffrey A. Zonder · 发表于：Blood · 年份：2016 · DOI：10.1182/blood.v128.22.973.973 · 被引用次数：13 · 研究领域：Multiple Myeloma Research and Treatments、HIV/AIDS drug development and treatment

Abstract Background There are an increasing number of multiple myeloma (MM) patients (pts) refractory to currently available drugs, including the proteasome inhibitors bortezomib and carfilzomib (CFZ), necessitating development of novel therapeutics. Pre-clinical evaluation of selinexor (SEL), an orally available Selective Inhibitor of Nuclear Export (SINE) compound, demonstrated synergistic myeloma cell death with CFZ and mechanistic rationale for overcoming resistance to CFZ (Rosebeck et al., 2016), providing support for this phase 1 trial. Aims The primary objectives were to assess the maximum tolerated dose (MTD) of a SEL, CFZ and dexamethasone (DEX) combination and to obtain preliminary efficacy data for this novel regimen in RRMM pts. Methods Pts with RRMM who progressed after at least two prior treatment regimens of myeloma therapy were eligible for enrollment. Dose escalation followed the 3+3 design with pts receiving 30 mg/m2 - 40 mg/m2 SEL PO on days (D) 1, 3, 8, 10, 15, 17; 20 mg/m2 - 56 mg/m2 CFZ IV on D 1, 2, 8, 9, 15, 16, and DEX PO (20mg cycles 1-4/ 10mg cycles 5+) in 28-day cycles (C) in up to 5 dose levels. An expansion cohort has enrolled additional pts to a total of 12 CFZ-refractory pts treated at the recommended Phase 2 dose (RP2D). Dose Limiting Toxicities (DLTs) were evaluated through C2D1. Responses were assessed by IMWG criteria plus near complete response (nCR). Results As of July 1st, 2016, the study has completed dose escalation and enrolled a tota...