A Study of Combination Therapy With Venetoclax, Daratumumab and Dexamethasone (With and Without Bortezomib) in Participants With Relapsed or Refractory Multiple Myeloma
- Conditions
- Multiple Myeloma
- Interventions
- Registration Number
- NCT03314181
- Lead Sponsor
- AbbVie
- Brief Summary
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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 156
- 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
-
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).
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) Up to approximately 3.5 years after the last participant is enrolled ORR is defined as the percentage of participants with documented partial response (PR) or better based on International Myeloma Working Group (IMWG) criteria.
Duration of Response (DOR) Up to approximately 3.5 years after the last participant is enrolled DOR is defined as the number of days from the participant's date of first documented response (PR or better) to the date of first documented disease progression or death due to multiple myeloma, whichever occurs first.
Very Good Partial Response or Better Response Rate (VGPR) Up to approximately 3.5 years after the last participant is enrolled VGPR or better response rate is defined as the proportion of participants with documented VGPR or better (sCR, CR. or VGPR) based on IMWG criteria.
Complete Response (CR) or Better Rate Up to approximately 3.5 years after the last participant is enrolled CR or better response is defined as the percentage of participants with documented response of CR or better (stringent complete response \[sCR\] or CR) based on IMWG criteria.
Time to Response (TTR) Up to approximately 3.5 years after the last participant is enrolled TTR is defined as the number of days from the date of treatment start (for subjects enrolled prior to randomization start) or randomization (for randomized subjects) to the date of first documented response of PR or better.
Time to Progression (TTP) Up to approximately 3.5 years after the last participant is enrolled TTP is defined as the number of days from the date of treatment start (for subjects enrolled prior to randomization start) or randomization (for randomized subjects) to the date of first documented PD or death due to MM, whichever occurs first.
Progression-Free Survival (PFS) Up to approximately 3.5 years after the last participant is enrolled PFS is defined as the number of days from the date of treatment start (for subjects enrolled prior to randomization start) or randomization (for randomized subjects) to the date of the first documented PD or death due to any cause, whichever occurs first.
Overall Survival (OS) Up to approximately 3.5 years after the last participant is enrolled OS is defined as the number of days from the date of treatment start (for subjects enrolled prior to randomization start) or randomization (for randomized subjects) to the date of death.
- Secondary Outcome Measures
Name Time Method AUC0-24 of Venetoclax Up to approximately 1 year Area under the plasma concentration-time curve (AUC) over the dose interval (AUC0-24) of venetoclax.
Minimal Residual Disease (MRD) Up to 12 months after confirmation of Complete Response (CR) or Stringent Complete Response (sCR) MRD negativity in bone marrow aspirates is defined at 10\^-5 threshold as assessed by next generation sequencing (NGS) in participants at the time of suspected CR/sCR, and at 6 and 12 months post confirmation of CR/sCR for participants who maintained this response.
Tmax of Venetoclax Up to approximately 1 year Time to Cmax (Tmax) of Venetoclax
Cmax of Venetoclax Up to approximately 1 year Maximum observed plasma concentration (Cmax) of venetoclax
Trial Locations
- Locations (40)
Eastern Health /ID# 165850
🇦🇺Box Hill, Victoria, Australia
Cross Cancer Institute /ID# 203114
🇨🇦Edmonton, Alberta, Canada
Kameda General Hospital /ID# 225246
🇯🇵Kamogawa-shi, Chiba, Japan
Oregon Health and Science University /ID# 166822
🇺🇸Portland, Oregon, United States
Dana-Farber Cancer Institute /ID# 166886
🇺🇸Boston, Massachusetts, United States
Univ of Colorado Cancer Center /ID# 167331
🇺🇸Aurora, Colorado, United States
Beth Israel Deaconess Medical Center /ID# 210904
🇺🇸Boston, Massachusetts, United States
Emory University, Winship Cancer Institute /ID# 165427
🇺🇸Atlanta, Georgia, United States
The University of Chicago Medical Center /ID# 165429
🇺🇸Chicago, Illinois, United States
Atrium Health Carolinas Medical Center /ID# 164948
🇺🇸Charlotte, North Carolina, United States
Duke Cancer Center /ID# 165104
🇺🇸Durham, North Carolina, United States
Sygehus Lillebalt, Vejle /ID# 164418
🇩🇰Vejle, Syddanmark, Denmark
CHU Limoges - Dupuytren 1 /ID# 224759
🇫🇷Limoges CEDEX 1, Franche-Comte, France
The Kinghorn Cancer Centre /ID# 165431
🇦🇺Darlinghurst, New South Wales, Australia
Tom Baker Cancer Centre /ID# 167822
🇨🇦Calgary, Alberta, Canada
Odense University Hospital /ID# 164417
🇩🇰Odense, Syddanmark, Denmark
University Hospital Cologne /ID# 166037
🇩🇪Cologne, Germany
AP-HP - Hopital Saint-Louis /ID# 224758
🇫🇷Paris, France
Gifu Municipal Hospital /ID# 240381
🇯🇵Gifu-shi, Gifu, Japan
St George Hospital /ID# 171063
🇦🇺Kogarah, New South Wales, Australia
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
University of Washington /ID# 164884
🇺🇸Seattle, Washington, United States
Royal Adelaide Hospital /ID# 171060
🇦🇺Adelaide, South Australia, Australia
Moffitt Cancer Center /ID# 169614
🇺🇸Tampa, Florida, United States
Wake Forest Baptist Health /ID# 224447
🇺🇸Winston-Salem, North Carolina, United States
Duplicate_Royal Perth Hospital /ID# 224895
🇦🇺Perth, Western Australia, Australia
Duplicate_Aarhus University Hospital /ID# 164509
🇩🇰Aarhus N, Midtjylland, Denmark
Rigshospitalet /ID# 164420
🇩🇰Copenhagen Ø, Hovedstaden, Denmark
St Vincent's Hospital Melbourne /ID# 165853
🇦🇺Fitzroy Melbourne, Victoria, Australia
Universitaetsklinikum Freiburg /ID# 166036
🇩🇪Freiburg, Baden-Wuerttemberg, Germany
Institut Gustave Roussy /ID# 164807
🇫🇷Villejuif Cedex, Val-de-Marne, France
Royal Victoria Hospital / McGill University Health Centre /ID# 167824
🇨🇦Montreal, Quebec, Canada
CHU Poitiers - La miletrie /ID# 164806
🇫🇷Poitiers, Vienne, France
Hackensack Univ Med Ctr /ID# 225111
🇺🇸Hackensack, New Jersey, United States
Peter MacCallum Cancer Ctr /ID# 164742
🇦🇺Melbourne, Victoria, Australia
CHRU Tours - Hopital Bretonneau /ID# 164795
🇫🇷Tours CEDEX 9, Indre-et-Loire, France
Nagoya City University Hospital /ID# 225273
🇯🇵Nagoya shi, Aichi, Japan
Matsuyama Red Cross Hospital /ID# 225196
🇯🇵Matsuyama-shi, Ehime, Japan
CHU de Nantes, Hotel Dieu -HME /ID# 164767
🇫🇷Nantes, Pays-de-la-Loire, France