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A Phase 1/2, Multicenter, Dose-Escalation and Expansion Study of Combination Therapy with Venetoclax, Daratumumab and Dexamethasone (With and Without Bortezomib) in Subjects with Relapsed or Refractory Multiple Myeloma
The purpose of this study is to see if the combination of venetoclax, daratumumab, and dexamethasone (with or without bortezomib) is safe and tolerable when given to study participants with relapsed (comes back) or refractory (did not get better) multiple myeloma.
Study Objective: The study will be conducted in two distinct parts, with the following objectives for each: To evaluate combination therapy with venetoclax, daratumumab, and dexamethasone (VenDd) in subjects with t(11;14) positive relapsed/refractory (R/R) multiple myeloma who have received: At least 3 prior lines of multiple myeloma therapy that included a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) OR who are double refractory to a PI and an IMiD. To evaluate combination therapy with venetoclax, daratumumab, bortezomib, and dexamethasone (VenDVd) in subjects with R/R multiple myeloma who are: Considered non-refractory to PIs AND received 1 to 3 prior lines of multiple myeloma therapy. Primary Objectives: The following are the primary objectives for each part of the study: Part 1) VenDd in t(11;14) positive R/R multiple myeloma: a.) Dose Escalation: To evaluate the safety and tolerability of increasing doses of venetoclax when used in combination with daratumumab (16 mg/kg) and dexamethasone (40 mg) to support dose selection for the VenDd expansion phase. b.). Blinded, randomized, placebo-controlled expansion: To evaluate the preliminary efficacy of VenDd relative to placebo + Dd. Efficacy will be evaluated by assessing the objective response rate (ORR), including partial or better response per IMWG. Part 2) VenDVd in R/R multiple myeloma: a.) Dose escalation: To evaluate the safety and tolerability of increasing doses of venetoclax when used in combination with daratumumab (16 mg/kg), bortezomib (1.3 mg/m2) and dexamethasone (20 mg) to support dose selection for the VenDVd expansion. b.) Single-arm, open-label expansion: To evaluate the preliminary efficacy of VenDVd. Efficacy will be evaluated by assessing the complete response or better rate (CR or better rate) per IMWG. Secondary Objectives: To evaluate the safety profiles of VenDd and VenDVd in the expansion phases. To determine VGPR or better rate, ORR (Part 2b), progression-free survival (PFS), duration of response (DOR) and time to progression (TTP). To assess minimal residual disease (MRD) in the bone marrow by next generation sequencing (NGS). To characterize the pharmacokinetic (PK) profile of venetoclax and daratumumab when administered as placebo + Dd, VenDd or VenDVd and to characterize the immunogenicity to daratumumab when administered with venetoclax. Exploratory Objectives: To evaluate pharmacodynamic and predictive biomarkers for association with pharmacokinetic, safety, and efficacy measures.