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

• ClinicalTrials.gov Identifier: NCT03314181
• Recruitment Status: Active, not recruiting
• First Posted: October 19, 2017
• Last Update Posted: February 16, 2023
• Sponsor: AbbVie
• Collaborator: Janssen Research & Development, LLC
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: October 11, 2017
• First Posted Date: October 19, 2017
• Last Update Posted Date: February 16, 2023
• Actual Study Start Date: April 2, 2018
• Estimated Primary Completion Date: August 28, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 14, 2020)

• 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.

Original Primary Outcome Measures (submitted: October 17, 2017)

• Part 1: Number of Participants with Dose Limiting Toxicities (DLT) [ Time Frame: Up to Day 28 ]
  Adverse events occurring following Cycle 1 and evaluated by the Investigator and the sponsor; events that are considered to have a reasonable possibility of relationship to the administration of venetoclax, daratumumab, bortezomib, or dexamethasone, which cannot be attributed by the investigator to a clearly identifiable cause such as disease progression, concurrent illness, or concomitant medication, will be considered a DLT.
• Part 1: Objective Response Rate (ORR) [ Time Frame: Up to 3 months ]
  ORR is defined as the proportion of participants with documented partial response (PR) or better based on International Myeloma Working Group (IMWG) criteria.
• Part 2: Number of Participants with Dose Limiting Toxicities (DLT) [ Time Frame: Up to Day 21 ]
  Adverse events occurring following Cycle 1 and evaluated by the Investigator and the sponsor; events that are considered to have a reasonable possibility of relationship to the administration of venetoclax, daratumumab, bortezomib, or dexamethasone, which cannot be attributed by the investigator to a clearly identifiable cause such as disease progression, concurrent illness, or concomitant medication, will be considered a DLT.
• Part 2: Complete Response (CR) [ Time Frame: Up to 5 months ]
  CR is defined as the proportion of participants with documented response of CR or better (stringent complete response [sCR] or CR) based on IMWG criteria.

Current Secondary Outcome Measures (submitted: December 14, 2020)

• 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.

Original Secondary Outcome Measures (submitted: October 17, 2017)

• Very Good Partial Response or Better Response Rate (VGPR) [ Time Frame: Up to 5 months ]
  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.
• ORR (Part 2b VenDVd Expansion) [ Time Frame: UP to 3 months ]
  ORR is defined as the proportion of participants with a documented response PR or better based on IMWG.
• Progression-Free Survival (PFS) [ Time Frame: Up to 2 years ]
  PFS is defined as the number of days from the date of the first dose of study drug (for Arms A, D and E) or date of randomization (for Arms B and C) to the date of the first documented disease progression or death due to any cause, whichever occurs first.
• Duration of Response (DOR) [ Time Frame: Up to 20 months ]
  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 20 months ]
  TTP is defined as the number of days from the date of the first dose of study drug (Arms A, D and E) or date of randomization (Arms B and C) to the date of first documented disease progression or death due to multiple myeloma, whichever occurs first.
• Minimal Residual Disease (MRD) [ Time Frame: Up to 12 months ]
  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 Day 29 ]
  Maximum observed plasma concentration (Cmax) of venetoclax
• Tmax of Venetoclax [ Time Frame: Up to Day 29 ]
  Time to Cmax (Tmax) of Venetoclax
• AUC0-24 of Venetoclax [ Time Frame: Up to Day 29 ]
  Area under the plasma concentration-time curve (AUC) over the dose interval (AUC0-24) of venetoclax.
• Cmax of Daratumumab [ Time Frame: Up to 48 weeks ]
  Maximum observed plasma concentration (Cmax) of daratumumab
• Trough Concentration (Ctrough) of Daratumumab [ Time Frame: Up to 48 weeks ]
  Observed plasma concentration at trough (Ctrough) of Daratumumab

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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 Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• Drug: Dexamethasone
  Infusion; Intravenous (IV), or Tablet; Oral
• Drug: Daratumumab
  Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)
• Drug: Venetoclax
  Tablet; Oral
  Other Names:

  • ABT-199
  • Venclexta
• Drug: Bortezomib
  Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)

Study Arms

• 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).
  Interventions:

  • Drug: Dexamethasone
  • Drug: Daratumumab
  • Drug: Venetoclax
• 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).
  Interventions:

  • Drug: Dexamethasone
  • Drug: Daratumumab
  • Drug: Venetoclax
• 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+.
  Interventions:

  • Drug: Dexamethasone
  • Drug: Daratumumab
  • Drug: Venetoclax
  • Drug: Bortezomib
• 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+.
  Interventions:

  • Drug: Dexamethasone
  • Drug: Daratumumab
  • Drug: Venetoclax
  • Drug: Bortezomib
• 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).
  Interventions:

  • Drug: Dexamethasone
  • Drug: Daratumumab
  • Drug: Venetoclax
• 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).
  Interventions:

  • Drug: Dexamethasone
  • Drug: Daratumumab
  • Drug: Venetoclax
• 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
  Interventions:

  • Drug: Dexamethasone
  • Drug: Daratumumab
  • Drug: Bortezomib

• Publications *: Bahlis NJ, Baz R, Harrison SJ, Quach H, Ho SJ, Vangsted AJ, Plesner T, Moreau P, Gibbs SD, Coppola S, Yang X, Al Masud A, Ross JA, Bueno O, Kaufman JL. Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14). J Clin Oncol. 2021 Nov 10;39(32):3602-3612. doi: 10.1200/JCO.21.00443. Epub 2021 Aug 13.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 2, 2022): 156
• Original Estimated Enrollment (submitted: October 17, 2017): 90
• Estimated Study Completion Date: August 28, 2025
• Estimated Primary Completion Date: August 28, 2025 (Final data collection date for primary outcome measure)

Eligibility 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

• 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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Denmark, France, Germany, Japan, United States

Administrative Information

• NCT Number: NCT03314181
• Other Study ID Numbers: M15-654; 2017-002099-26 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• 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

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
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: 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/

• Current Responsible Party: AbbVie
• Original Responsible Party: Same as current
• Current Study Sponsor: AbbVie
• Original Study Sponsor: Same as current
• Collaborators: Janssen Research & Development, LLC

Investigators

• Study Director: ABBVIE INC.; AbbVie

• PRS Account: AbbVie
• Verification Date: February 2023