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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Dexamethasone
* Drug: Daratumumab
* Drug: Venetoclax
* Drug: Bortezomib


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A, Part 1a: VenDd Dose Escalation<br>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). | Drug: Dexamethasone<br>* Infusion; Intravenous (IV), or Tablet; Oral<br>Drug: Daratumumab<br>* Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)<br>Drug: Venetoclax<br>* Tablet; Oral<br>* Other names: Venclexta;|
| Experimental: Arm B, Part 1b: VenDd Dose Expansion<br>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). | Drug: Dexamethasone<br>* Infusion; Intravenous (IV), or Tablet; Oral<br>Drug: Daratumumab<br>* Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)<br>Drug: Venetoclax<br>* Tablet; Oral<br>* Other names: Venclexta;|
| Experimental: Arm D, Part 2a: VenDVd Dose Escalation<br>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+. | Drug: Dexamethasone<br>* Infusion; Intravenous (IV), or Tablet; Oral<br>Drug: Daratumumab<br>* Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)<br>Drug: Venetoclax<br>* Tablet; Oral<br>* Other names: Venclexta;Drug: Bortezomib<br>* Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)<br>|
| Experimental: Arm E, Part 2b: VenDVd Dose Expansion<br>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+. | Drug: Dexamethasone<br>* Infusion; Intravenous (IV), or Tablet; Oral<br>Drug: Daratumumab<br>* Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)<br>Drug: Venetoclax<br>* Tablet; Oral<br>* Other names: Venclexta;Drug: Bortezomib<br>* Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)<br>|
| Experimental: Arm F: VenDd Dose Expansion<br>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). | Drug: Dexamethasone<br>* Infusion; Intravenous (IV), or Tablet; Oral<br>Drug: Daratumumab<br>* Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)<br>Drug: Venetoclax<br>* Tablet; Oral<br>* Other names: Venclexta;|
| Experimental: Arm G: VenDd Dose Expansion<br>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). | Drug: Dexamethasone<br>* Infusion; Intravenous (IV), or Tablet; Oral<br>Drug: Daratumumab<br>* Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)<br>Drug: Venetoclax<br>* Tablet; Oral<br>* Other names: Venclexta;|
| Active Comparator: Arm H: DVd Dose<br>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 | Drug: Dexamethasone<br>* Infusion; Intravenous (IV), or Tablet; Oral<br>Drug: Daratumumab<br>* Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)<br>Drug: Bortezomib<br>* Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants with documented partial response (PR) or better based on International Myeloma Working Group (IMWG) criteria. | Up to approximately 3.5 years after the last participant is enrolled | 
| Very Good Partial Response or Better Response Rate (VGPR) | 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. | Up to approximately 3.5 years after the last participant is enrolled | 
| Complete Response (CR) or Better Rate | 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. | Up to approximately 3.5 years after the last participant is enrolled | 
| Time to Response (TTR) | 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. | Up to approximately 3.5 years after the last participant is enrolled | 
| Duration of Response (DOR) | 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. | Up to approximately 3.5 years after the last participant is enrolled | 
| Time to Progression (TTP) | 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. | Up to approximately 3.5 years after the last participant is enrolled | 
| Progression-Free Survival (PFS) | 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. | Up to approximately 3.5 years after the last participant is enrolled | 
| Overall Survival (OS) | 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. | Up to approximately 3.5 years after the last participant is enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimal Residual Disease (MRD) | 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. | Up to 12 months after confirmation of Complete Response (CR) or Stringent Complete Response (sCR) | 
| Cmax of Venetoclax | Maximum observed plasma concentration (Cmax) of venetoclax | Up to approximately 1 year | 
| Tmax of Venetoclax | Time to Cmax (Tmax) of Venetoclax | Up to approximately 1 year | 
| AUC0-24 of Venetoclax | Area under the plasma concentration-time curve (AUC) over the dose interval (AUC0-24) of venetoclax. | Up to approximately 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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