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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| ClinicalTrials.gov Identifier: NCT03314181 |
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Recruitment Status :
Active, not recruiting
First Posted : October 19, 2017
Last Update Posted : February 16, 2023
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Sponsor:
AbbVie
Collaborator:
Janssen Research & Development, LLC
Information provided by (Responsible Party):
AbbVie
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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).
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Multiple Myeloma | Drug: Dexamethasone Drug: Daratumumab Drug: Venetoclax Drug: Bortezomib | Phase 2 |
Expanded Access : An investigational treatment associated with this study is available outside the clinical trial. More info ...
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 156 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official 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 |
| Actual Study Start Date : | April 2, 2018 |
| Estimated Primary Completion Date : | August 28, 2025 |
| Estimated Study Completion Date : | August 28, 2025 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Multiple myeloma
MedlinePlus related topics:
Multiple Myeloma
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm A, Part 1a: VenDd Dose Escalation
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).
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Drug: Dexamethasone
Infusion; Intravenous (IV), or Tablet; Oral Drug: Daratumumab Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) Drug: Venetoclax Tablet; Oral
Other Names:
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Experimental: Arm B, Part 1b: VenDd Dose Expansion
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).
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Drug: Dexamethasone
Infusion; Intravenous (IV), or Tablet; Oral Drug: Daratumumab Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) Drug: Venetoclax Tablet; Oral
Other Names:
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Experimental: Arm D, Part 2a: VenDVd Dose Escalation
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+.
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Drug: Dexamethasone
Infusion; Intravenous (IV), or Tablet; Oral Drug: Daratumumab Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) Drug: Venetoclax Tablet; Oral
Other Names:
Drug: Bortezomib Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) |
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Experimental: Arm E, Part 2b: VenDVd Dose Expansion
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+.
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Drug: Dexamethasone
Infusion; Intravenous (IV), or Tablet; Oral Drug: Daratumumab Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) Drug: Venetoclax Tablet; Oral
Other Names:
Drug: Bortezomib Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) |
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Experimental: Arm F: VenDd Dose Expansion
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).
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Drug: Dexamethasone
Infusion; Intravenous (IV), or Tablet; Oral Drug: Daratumumab Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) Drug: Venetoclax Tablet; Oral
Other Names:
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Experimental: Arm G: VenDd Dose Expansion
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).
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Drug: Dexamethasone
Infusion; Intravenous (IV), or Tablet; Oral Drug: Daratumumab Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) Drug: Venetoclax Tablet; Oral
Other Names:
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Active Comparator: Arm H: DVd Dose
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
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Drug: Dexamethasone
Infusion; Intravenous (IV), or Tablet; Oral Drug: Daratumumab Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) Drug: Bortezomib Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) |
Primary Outcome Measures :
- Overall Response Rate (ORR) [ Time Frame: 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.
- Very Good Partial Response or Better Response Rate (VGPR) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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.
- Duration of Response (DOR) [ Time Frame: 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.
- Time to Progression (TTP) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 :
- Minimal Residual Disease (MRD) [ Time Frame: 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.
- Cmax of Venetoclax [ Time Frame: Up to approximately 1 year ]Maximum observed plasma concentration (Cmax) of venetoclax
- Tmax of Venetoclax [ Time Frame: Up to approximately 1 year ]Time to Cmax (Tmax) of Venetoclax
- AUC0-24 of Venetoclax [ Time Frame: Up to approximately 1 year ]Area under the plasma concentration-time curve (AUC) over the dose interval (AUC0-24) of venetoclax.
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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
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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.
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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.
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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).
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03314181
Locations
Show 40 study locations
Sponsors and Collaborators
AbbVie
Janssen Research & Development, LLC
Investigators
| Study Director: | ABBVIE INC. | AbbVie |
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | AbbVie |
| ClinicalTrials.gov Identifier: | NCT03314181 |
| Other Study ID Numbers: |
M15-654 2017-002099-26 ( EudraCT Number ) |
| First Posted: | October 19, 2017 Key Record Dates |
| Last Update Posted: | February 16, 2023 |
| Last Verified: | February 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols, analyses plans, clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. |
| Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Clinical Study Report (CSR) |
| Time Frame: | For details on when studies are available for sharing visit https://vivli.org/ourmember/abbvie/ |
| Access Criteria: | Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous independent scientific research, and will be provided following review and approval of a research proposal and statistical analysis plan and execution of a data sharing statement. Data requests can be submitted at any time after approval in the US and/or EU and a primary manuscript is accepted for publication. For more information on the process, or to submit a request, visit the following link https://www.abbvieclinicaltrials.com/hcp/data-sharing/ |
| URL: | https://vivli.org/ourmember/abbvie/ |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
| Product Manufactured in and Exported from the U.S.: | No |
Keywords provided by AbbVie:
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t(11,14) positive relapsed/refractory (R/R) multiple myeloma Non-refractory Relapsed Multiple Myeloma Non-refractory Refractory Multiple Myeloma Relapsed Multiple Myeloma Refractory Multiple Myeloma |
Multiple Myeloma Cancer Venetoclax Venclexta |
Additional relevant MeSH terms:
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Multiple Myeloma Neoplasms, Plasma Cell Neoplasms by Histologic Type Neoplasms Hemostatic Disorders Vascular Diseases Cardiovascular Diseases Paraproteinemias Blood Protein Disorders Hematologic Diseases Hemorrhagic Disorders Lymphoproliferative Disorders Immunoproliferative Disorders Immune System Diseases Dexamethasone |
Bortezomib Venetoclax Daratumumab Anti-Inflammatory Agents Antiemetics Autonomic Agents Peripheral Nervous System Agents Physiological Effects of Drugs Gastrointestinal Agents Glucocorticoids Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Antineoplastic Agents, Hormonal Antineoplastic Agents |