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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03314181
Registration number
NCT03314181
Ethics application status
Date submitted
11/10/2017
Date registered
19/10/2017
Date last updated
16/02/2023
Titles & IDs
Public title
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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Scientific 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
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Secondary ID [1]
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2017-002099-26
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Secondary ID [2]
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M15-654
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Multiple Myeloma
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Condition category
Condition code
Cancer
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Other cancer types
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Intervention/exposure
Study type
Interventional(has expanded access)
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Description of intervention(s) / exposure
Treatment: Drugs - Dexamethasone
Treatment: Drugs - Daratumumab
Treatment: Drugs - Venetoclax
Treatment: Drugs - Bortezomib
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).
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).
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+.
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+.
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).
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).
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
Treatment: Drugs: Dexamethasone
Infusion; Intravenous (IV), or Tablet; Oral
Treatment: Drugs: Daratumumab
Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)
Treatment: Drugs: Venetoclax
Tablet; Oral
Treatment: Drugs: Bortezomib
Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Overall Response Rate (ORR)
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Assessment method [1]
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ORR is defined as the percentage of participants with documented partial response (PR) or better based on International Myeloma Working Group (IMWG) criteria.
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Timepoint [1]
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Up to approximately 3.5 years after the last participant is enrolled
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Primary outcome [2]
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Very Good Partial Response or Better Response Rate (VGPR)
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Assessment method [2]
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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.
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Timepoint [2]
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Up to approximately 3.5 years after the last participant is enrolled
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Primary outcome [3]
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Complete Response (CR) or Better Rate
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Assessment method [3]
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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.
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Timepoint [3]
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Up to approximately 3.5 years after the last participant is enrolled
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Primary outcome [4]
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Time to Response (TTR)
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Assessment method [4]
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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.
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Timepoint [4]
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Up to approximately 3.5 years after the last participant is enrolled
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Primary outcome [5]
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Duration of Response (DOR)
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Assessment method [5]
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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.
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Timepoint [5]
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Up to approximately 3.5 years after the last participant is enrolled
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Primary outcome [6]
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Time to Progression (TTP)
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Assessment method [6]
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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.
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Timepoint [6]
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Up to approximately 3.5 years after the last participant is enrolled
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Primary outcome [7]
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Progression-Free Survival (PFS)
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Assessment method [7]
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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.
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Timepoint [7]
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Up to approximately 3.5 years after the last participant is enrolled
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Primary outcome [8]
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Overall Survival (OS)
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Assessment method [8]
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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.
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Timepoint [8]
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Up to approximately 3.5 years after the last participant is enrolled
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Secondary outcome [1]
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Minimal Residual Disease (MRD)
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Assessment method [1]
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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.
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Timepoint [1]
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Up to 12 months after confirmation of Complete Response (CR) or Stringent Complete Response (sCR)
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Secondary outcome [2]
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Cmax of Venetoclax
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Assessment method [2]
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Maximum observed plasma concentration (Cmax) of venetoclax
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Timepoint [2]
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Up to approximately 1 year
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Secondary outcome [3]
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Tmax of Venetoclax
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Assessment method [3]
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Time to Cmax (Tmax) of Venetoclax
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Timepoint [3]
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Up to approximately 1 year
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Secondary outcome [4]
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AUC0-24 of Venetoclax
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Assessment method [4]
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Area under the plasma concentration-time curve (AUC) over the dose interval (AUC0-24) of venetoclax.
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Timepoint [4]
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Up to approximately 1 year
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Eligibility
Key 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.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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).
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Active, not recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
2/04/2018
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
28/08/2025
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Actual
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Sample size
Target
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Accrual to date
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Final
156
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Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC,WA
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Recruitment hospital [1]
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The Kinghorn Cancer Centre /ID# 165431 - Darlinghurst
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Recruitment hospital [2]
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St George Hospital /ID# 171063 - Kogarah
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Recruitment hospital [3]
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Royal Adelaide Hospital /ID# 171060 - Adelaide
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Recruitment hospital [4]
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Eastern Health /ID# 165850 - Box Hill
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Recruitment hospital [5]
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St Vincent's Hospital Melbourne /ID# 165853 - Fitzroy Melbourne
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Recruitment hospital [6]
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Peter MacCallum Cancer Ctr /ID# 164742 - Melbourne
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Recruitment hospital [7]
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Royal Perth Hospital /ID# 224895 - Perth
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Recruitment postcode(s) [1]
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2010 - Darlinghurst
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Recruitment postcode(s) [2]
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2217 - Kogarah
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Recruitment postcode(s) [3]
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5000 - Adelaide
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Recruitment postcode(s) [4]
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3128 - Box Hill
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Recruitment postcode(s) [5]
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3065 - Fitzroy Melbourne
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Recruitment postcode(s) [6]
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3000 - Melbourne
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Recruitment postcode(s) [7]
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6000 - Perth
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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Colorado
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United States of America
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Florida
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United States of America
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Georgia
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United States of America
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Illinois
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United States of America
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Massachusetts
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United States of America
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New Jersey
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United States of America
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New York
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United States of America
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North Carolina
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Oregon
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Washington
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Canada
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Alberta
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Canada
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Quebec
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Denmark
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Hovedstaden
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Denmark
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Midtjylland
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Denmark
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Syddanmark
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France
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Franche-Comte
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France
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Indre-et-Loire
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France
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Pays-de-la-Loire
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France
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Poitou-Charentes
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France
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Val-de-Marne
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France
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Paris
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Germany
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Baden-Wuerttemberg
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Germany
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Cologne
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Japan
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Aichi
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Japan
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Chiba
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Japan
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Ehime
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Japan
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Gifu
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
AbbVie
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Address
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Other collaborator category [1]
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Commercial sector/Industry
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Name [1]
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Janssen Research & Development, LLC
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Ethics approval
Ethics application status
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Summary
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).
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03314181
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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ABBVIE INC.
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Address
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AbbVie
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Contact person for public queries
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03314181
Download to PDF