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
- Conditions
- Multiple Myeloma
- Interventions
- Registration Number
- 2023-506110-43-00
- Lead Sponsor
- AbbVie Deutschland GmbH & Co. KG
- Brief Summary
1. 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 one prior line of multiple myeloma therapy that included a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD)
2. 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.
3. To evaluate combination therapy with venetoclax, daratumumab, and dexamethasone (VenDd) in subjects with t(11;14) positive R/R multiple myeloma who are:
- Considered non-refractory to PIs AND received at least one prior line of multiple myeloma therapy that included an IMiD
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Not specified
- Target Recruitment
- 19
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.
Previous treatment with venetoclax or other B-Cell Lymphoma 2 (BCL-2) inhibitor
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).
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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A, Part 1a: VenDd Dose Escalation Daratumumab 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). Arm A, Part 1a: VenDd Dose Escalation Dexamethasone 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). Arm A, Part 1a: VenDd Dose Escalation Venetoclax 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). Arm B, Part 1b: VenDd Dose Expansion Dexamethasone 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). Arm B, Part 1b: VenDd Dose Expansion Daratumumab 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). Arm B, Part 1b: VenDd Dose Expansion Venetoclax 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). Arm D, Part 2a: VenDVd Dose Escalation Dexamethasone 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+. Arm D, Part 2a: VenDVd Dose Escalation Daratumumab 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+. Arm D, Part 2a: VenDVd Dose Escalation Venetoclax 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+. Arm D, Part 2a: VenDVd Dose Escalation Bortezomib 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+. Arm E, Part 2b: VenDVd Dose Expansion Dexamethasone 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+. Arm E, Part 2b: VenDVd Dose Expansion Daratumumab 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+. Arm E, Part 2b: VenDVd Dose Expansion Venetoclax 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+. Arm E, Part 2b: VenDVd Dose Expansion Bortezomib 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+. Arm F: VenDd Dose Expansion Dexamethasone 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). Arm F: VenDd Dose Expansion Daratumumab 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). Arm F: VenDd Dose Expansion Venetoclax 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). Arm G: VenDd Dose Expansion Daratumumab 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). Arm G: VenDd Dose Expansion Venetoclax 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). Arm G: VenDd Dose Expansion Dexamethasone 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). Arm H: DVd Dose Daratumumab 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 Arm H: DVd Dose Dexamethasone 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 Arm H: DVd Dose Bortezomib 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
- Primary Outcome Measures
Name Time Method Overall response rate (ORR) Overall response rate (ORR)
Very good partial response (VGPR) or better rate Very good partial response (VGPR) or better rate
Complete response (CR) or better rate Complete response (CR) or better rate
Time to response (TTR) Time to response (TTR)
Duration of response (DOR) Duration of response (DOR)
Time to progression (TTP) Time to progression (TTP)
Progression-free survival (PFS) Progression-free survival (PFS)
Overall survival (OS) Overall survival (OS)
- Secondary Outcome Measures
Name Time Method Safety, Pharmacokinetic (PK) and Biomarker Research Variables Safety, Pharmacokinetic (PK) and Biomarker Research Variables
Minimal Residual Disease (MRD) Minimal Residual Disease (MRD)
Trial Locations
- Locations (40)
Univ of Colorado Cancer Center /ID# 167331
🇺🇸Aurora, Colorado, United States
Moffitt Cancer Center /ID# 169614
🇺🇸Tampa, Florida, United States
Winship Cancer Institute of Emory University /ID# 165427
🇺🇸Atlanta, Georgia, United States
The University of Chicago Medical Center /ID# 165429
🇺🇸Chicago, Illinois, United States
Beth Israel Deaconess Medical Center /ID# 210904
🇺🇸Boston, Massachusetts, United States
Dana-Farber Cancer Institute /ID# 166886
🇺🇸Boston, Massachusetts, United States
Hackensack Univ Med Ctr /ID# 225111
🇺🇸Hackensack, New Jersey, United States
Duplicate_Roswell Park Comprehensive Cancer Center /ID# 169615
🇺🇸Buffalo, New York, United States
Weill Cornell Medicine/NYP /ID# 167605
🇺🇸New York, New York, United States
Atrium Health Carolinas Medical Center /ID# 164948
🇺🇸Charlotte, North Carolina, United States
Scroll for more (30 remaining)Univ of Colorado Cancer Center /ID# 167331🇺🇸Aurora, Colorado, United States