The trial is taking place at:
D

Dana-Farber Cancer Institute | Pediatric Hematologic Malignancy

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A Study of Combination Therapy With Venetoclax, Daratumumab and Dexamethasone (With and Without Bortezomib) in Participants With Relapsed or Refractory Multiple Myeloma

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AbbVie

Status and phase

Active, not recruiting
Phase 2

Conditions

Multiple Myeloma

Treatments

Drug: Bortezomib
Drug: Daratumumab
Drug: Dexamethasone
Drug: Venetoclax

Study type

Interventional

Funder types

Industry

Identifiers

NCT03314181
M15-654
2017-002099-26 (EudraCT Number)

Details and patient eligibility

About

This is a study of venetoclax, daratumumab, and dexamethasone with and without bortezomib combination therapy to evaluate safety, tolerability, and efficacy of these combinations in participants with relapsed or refractory multiple myeloma. The study will consist of 3 distinct parts: Part 1 includes participants with t(11;14) positive relapsed/refractory (R/R) multiple myeloma who will receive venetoclax in combination with daratumumab and dexamethasone (VenDd); Part 2 includes participants with R/R multiple myeloma who will receive venetoclax in combination with daratumumab, bortezomib, and dexamethasone (VenDVd); Part 3 includes participants with t(11;14) positive R/R multiple myeloma who will receive venetoclax in combination with daratumumab and dexamethasone (VenDd) or daratumumab, bortezomib, and dexamethasone (DVd). Part 1 and Part 2 are non-randomized and will be initiated with a dose-escalation phase in which increasing doses of venetoclax will be given with fixed doses of daratumumab and dexamethasone (Part 1a) or with fixed doses of daratumumab, bortezomib, and dexamethasone (Part 2a). Each dose escalation phase will be followed by a single-arm, open-label expansion phase. Part 3 will include a randomized, open-label expansion phase with participants receiving venetoclax in combination with daratumumab and dexamethasone (VenDd) or daratumumab, bortezomib, and dexamethasone (DVd).

Enrollment

156 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

* Eastern Cooperative Oncology Group (ECOG) performance status \<= 2. * 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).

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

156 participants in 7 patient groups

Arm A, Part 1a: VenDd Dose Escalation
Experimental group
Description:
Venetoclax (Ven) various doses administered orally, once daily (QD) in combination with daratumumab (D) (1800 mg subcutaneous injection (preferred) or 16 mg/kg intravenous [IV]) administered in accordance with prescribing information and dexamethasone (d) (oral or IV) 40 mg weekly (or 20 mg weekly, if necessary, as described in the protocol).
Treatment:
Drug: Venetoclax
Drug: Dexamethasone
Drug: Daratumumab
Arm B, Part 1b: VenDd Dose Expansion
Experimental group
Description:
Venetoclax at a dose determined by the dose-escalation phase, administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information and dexamethasone (oral or IV) 40 mg weekly (or 20 mg weekly, if necessary, as described in the protocol).
Treatment:
Drug: Venetoclax
Drug: Dexamethasone
Drug: Daratumumab
Arm D, Part 2a: VenDVd Dose Escalation
Experimental group
Description:
Venetoclax at various doses administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information, bortezomib (1.3 mg/m2 subcutaneous injection [preferred] or IV) Cycles 1-8, Days 1, 4, 8 and 11), and dexamethasone (oral or IV) 20 mg Cycles 1 - 3, Days 1, 2, 4, 5, 8, 9, 11,12 and 15; 20 mg Cycles 4-8, Days 1,2,4,5,8,9,11 and 12; 40 mg weekly (or 20 mg weekly, if necessary as described in the protocol) Cycle 9+.
Treatment:
Drug: Venetoclax
Drug: Dexamethasone
Drug: Daratumumab
Drug: Bortezomib
Arm E, Part 2b: VenDVd Dose Expansion
Experimental group
Description:
Venetoclax at dose determined by the dose-escalation phase, administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information, bortezomib (1.3 mg/m2 subcutaneous injection) Cycles 1-8, Days 1, 4, 8 and 11, and dexamethasone (oral or IV) 20 mg Cycles 1 - 3, Days 1, 2, 4, 5, 8, 9, 11,12 and 15; 20 mg Cycles 4-8, Days 1,2,4,5,8,9,11 and 12; 40 mg weekly (or 20 mg weekly, if necessary as described in the protocol) Cycle 9+.
Treatment:
Drug: Venetoclax
Drug: Dexamethasone
Drug: Daratumumab
Drug: Bortezomib
Arm F: VenDd Dose Expansion
Experimental group
Description:
Venetoclax at a pre-determined dose, administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information and dexamethasone (oral or IV) 40 mg weekly (or 20 mg weekly, if necessary, as described in the protocol).
Treatment:
Drug: Venetoclax
Drug: Dexamethasone
Drug: Daratumumab
Arm G: VenDd Dose Expansion
Experimental group
Description:
Venetoclax at a pre-determined dose, administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information and dexamethasone (oral or IV) 40 mg weekly (or 20 mg weekly, if necessary, as described in the protocol).
Treatment:
Drug: Venetoclax
Drug: Dexamethasone
Drug: Daratumumab
Arm H: DVd Dose
Active Comparator group
Description:
Daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information, bortezomib (1.3 mg/m2 subcutaneous injection) Cycles 1-8: Days 1, 4, 8 and 11, and dexamethasone (oral or IV) 20 mg on Cycles 1 - 3: Days 1, 2, 4, 5, 8, 9, 11,12 and 15; 40 mg weekly (or 20 mg weekly, if necessary as described in the protocol) on Cycles 4-8: Days 1,2,4,5,8,9,11 and 12; 20 mg monthly for Cycles 9+: Day 1
Treatment:
Drug: Dexamethasone
Drug: Daratumumab
Drug: Bortezomib

Trial contacts and locations

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Data sourced from clinicaltrials.gov

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