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Clinical Trial 19428

Cancer Type: Malignant Hematology
Study Type: Treatment
NCT#: NCT03314181

Phase: Phase I/II
Principal Investigator: Baz, Rachid

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or 1-800-679-0775 Learn More

Overview

Study Title

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

Summary

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.

Objective

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.

Treatments

Therapies

Immunotherapy; Therapy (NOS)

Medications

Bortezomib (); Daratumumab (Darzalex); Dexamethasone (); GDC-0199 (Venetoclax); PS-341 (Bortezomib); Velcade (Bortezomib); Venetoclax ()

Inclusion Criteria

Eastern Cooperative Oncology Group (ECOG) performance status > Participant has relapsed or refractory multiple myeloma with documented evidence of progression that occurred during or after the participant's last treatment regimen based on investigator's determination of International Myeloma Working Group (IMWG) criteria.

Measurable disease confirmed by central lab at Screening, defined by at least 1 of the following: Serum M-protein >= 1.0 g/dL (>= 10 g/L), OR Urine M-protein >= 200 mg/24 hours, OR Serum free light chain (FLC) >= 10 mg/dL, provided serum FLC ratio is abnormal in participants who do not have measurable disease by Serum Protein Electrophoresis (SPEP) or Urine Protein Electrophoresis (UPEP) criteria.

Participant has received previous multiple myeloma treatment as defined in the protocol.

Bone marrow aspirate samples have been collected.

To qualify for Part 1 and 3, the participant must be t(11;14) positive as determined by an analytically validated Fluorescent In Situ Hybridization (FISH) assay per central laboratory testing.

Participants must have adequate hematologic, renal and hepatic function.

Exclusion Criteria

Previous treatment with venetoclax or other B-Cell Lymphoma 2 (BCL-2) inhibitor

For participants in Parts 1 and 2: Previous treatment with daratumumab or other anti-CD38 therapy. For participants in Part 3: Prior daratumumab or other anti-CD38 antibody therapy exposure that meets ANY of the following criteria:

Failure to achieve at least a PR to most recent therapy with daratumumab or other anti-CD38 therapy.

Daratumumab or other anti-CD38 antibody therapy was discontinued due to toxicity.

Relapse within 60 days of intensive treatment (at least every other week) of daratumumab or other anti-CD38 antibody therapy.

Prior treatment with daratumumab or other anti-CD38 antibody within 6 months prior to first dose of study drug.

For participants in Part 2 and 3:

Participant is refractory to any proteasome inhibitor, defined as progression on or within 60 days of the last dose of a proteasome inhibitor-containing regimen.

Participant has had prior treatment with proteasome inhibitor within 60 days prior to first dose of study drug.

Treatment with anti-myeloma chemotherapy, radiotherapy, biological, immunotherapy or an investigational therapy, including targeted small molecule agents within 2 weeks or 5 half-lives (whichever is longer and/or applicable) before first dose.

Treatment with anti-myeloma monoclonal antibodies within 6 weeks prior to first dose.

Recent corticosteroid therapy at a cumulative dose equivalent to >= 140 mg of prednisone, cumulative dose equivalent to >= 40 mg of dexamethasone, or a single dose equivalent to >= 40 mg of dexamethasone within 2 weeks prior the first dose of study drug.

Known central nervous system involvement of multiple myeloma.

Significant history of medical conditions as listed in the protocol.

History of other active malignancies including myelodysplatic syndromes (MDS) within the past 3 years with the exceptions of:

Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin.

Prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels off treatment

Previous malignancy with no evidence of disease confirmed and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study.

Known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Has a hypersensitivity or allergy to any of the components of study therapy, excipient or boron.

Known allergies, hypersensitivities, or intolerance to monoclonal antibodies or human proteins, or their excipients, or known sensitivity to mammalian-derived products (see daratumumab prescribing information).

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