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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

NCT03314181

Description:

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).

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Combination Therapy With Venetoclax, Daratumumab and Dexamethasone (With and Without Bortezomib) in Subjects 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

Clinical Trial IDs

  • ORG STUDY ID: M15-654
  • SECONDARY ID: 2017-002099-26
  • NCT ID: NCT03314181

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
DexamethasoneArm A, Part 1a: VenDd Dose Escalation
DaratumumabArm A, Part 1a: VenDd Dose Escalation
VenetoclaxABT-199, VenclextaArm A, Part 1a: VenDd Dose Escalation
BortezomibArm D, Part 2a: VenDVd Dose Escalation

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Arm A, Part 1a: VenDd Dose EscalationExperimentalVenetoclax (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).
  • Dexamethasone
  • Daratumumab
  • Venetoclax
Arm B, Part 1b: VenDd Dose ExpansionExperimentalVenetoclax 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).
  • Dexamethasone
  • Daratumumab
  • Venetoclax
Arm D, Part 2a: VenDVd Dose EscalationExperimentalVenetoclax 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+.
  • Dexamethasone
  • Daratumumab
  • Venetoclax
  • Bortezomib
Arm E, Part 2b: VenDVd Dose ExpansionExperimentalVenetoclax 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+.
  • Dexamethasone
  • Daratumumab
  • Venetoclax
  • Bortezomib
Arm F: VenDd Dose ExpansionExperimentalVenetoclax 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).
  • Dexamethasone
  • Daratumumab
  • Venetoclax
Arm G: VenDd Dose ExpansionExperimentalVenetoclax 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).
  • Dexamethasone
  • Daratumumab
  • Venetoclax
Arm H: DVd DoseActive ComparatorDaratumumab (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
  • Dexamethasone
  • Daratumumab
  • Bortezomib

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 OR
             previous treatment with daratumumab or other anti-CD38 therapy.

          -  For participants in Part 2 and 3:

               1. 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.

               2. 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 first dose.

          -  Recent corticosteroid therapy at a cumulative dose equivalent to >= 140 mg of
             prednisone or a single dose equivalent to >= 40 mg of dexamethasone within 2 weeks
             prior the first dose of study drug.

          -  Known meningeal 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:

               1. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the
                  skin.

               2. Prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific
                  Antigen (PSA) levels off treatment

               3. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:Up to approximately 3.5 years after the last participant is enrolled
Safety Issue:
Description:ORR is defined as the percentage of participants with documented partial response (PR) or better based on International Myeloma Working Group (IMWG) criteria.

Secondary Outcome Measures

Measure:Time to Progression (TTP)
Time Frame:Up to approximately 3.5 years after the last participant is enrolled
Safety Issue:
Description: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.
Measure:Duration of Response (DOR)
Time Frame:Up to approximately 3.5 years after the last participant is enrolled
Safety Issue:
Description: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.
Measure:Progression-Free Survival (PFS)
Time Frame:Up to approximately 3.5 years after the last participant is enrolled
Safety Issue:
Description: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.
Measure:Cmax of Venetoclax
Time Frame:Up to approximately 1 year
Safety Issue:
Description:Maximum observed plasma concentration (Cmax) of venetoclax
Measure:AUC0-24 of Venetoclax
Time Frame:Up to approximately 1 year
Safety Issue:
Description:Area under the plasma concentration-time curve (AUC) over the dose interval (AUC0-24) of venetoclax.
Measure:Tmax of Venetoclax
Time Frame:Up to approximately 1 year
Safety Issue:
Description:Time to Cmax (Tmax) of Venetoclax
Measure:Minimal Residual Disease (MRD)
Time Frame:Up to 12 months after confirmation of Complete Response (CR) or Stringent Complete Response (sCR)
Safety Issue:
Description: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.
Measure:Time to Response (TTR)
Time Frame:Up to approximately 3.5 years after the last participant is enrolled
Safety Issue:
Description: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.
Measure:Overall Survival (OS)
Time Frame:Up to approximately 3.5 years after the last participant is enrolled
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AbbVie

Trial Keywords

  • 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

Last Updated

May 7, 2020