Study of Venetoclax in Combination With Carfilzomib and Dexamethasone in Participants With Relapsed or Refractory Multiple Myeloma (MM)

Study Overview
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Brief Summary
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A Phase 2, open-label, dose escalation study to evaluate the safety and efficacy of venetoclax in combination with carfilzomib-dexamethasone (Kd) in participants with relapsed or refractory MM and have received 1 to 3 prior lines of therapy. Part 4 of this study is currently enrolling.

Official Title
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A Phase 2, Open-Label, Multi-Center Study of Venetoclax in Combination With Carfilzomib and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: Venetoclax
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Collaborative Oncology Group (ECOG) performance score of less than or equal to 2. Documented relapsed or progressive Multiple Myeloma (MM) on or after any regimen or is refractory to the most recent line of therapy. Positive for translocation t(11;14) as determined by an analytically validated Fluorescent In Situ Hybridization (FISH) assay per central laboratory testing. Received prior treatment with at least 1 prior line of therapy for MM. Measurable disease on Screening per International Myeloma Working Group (IMWG) criteria. Meets absolute neutrophil count, platelet count, hemoglobin, liver and kidney function laboratory values within 2 weeks prior to first dose of study drug. Exclusion Criteria: Has a pre-existing condition that is contraindicated including. Non-secretory or oligo-secretory MM Active plasma cell leukemia. Waldenström's macroglobulinemia. Primary amyloidosis. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes). Active hepatitis B or C infection based on screening blood testing. Known active Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Significant cardiovascular disease. Major surgery within 4 weeks prior to first dose. Acute infections requiring antibiotic, antifungal or antiviral therapy within14 days prior to first dose. Peripheral neuropathy ≥ Grade 3 or ≥ Grade 2 with pain within 2 weeks prior to first dose. Uncontrolled diabetes or uncontrolled hypertension within 14 days prior to first dose. Any other medical condition that, in the opinion of the Investigator, would adversely affect the participant's participation in the study. History of other active malignancies, including myelodysplastic syndrome (MDS), within the past 3 years prior to study entry Other protocol defined inclusion/exclusion criteria could apply

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Venetoclax + Carfilzomib + Dexamethasone<br>Part 1: Evaluate the safety and pharmacokinetic profiles while providing information to determine the appropriate doses of venetoclax and carfilzomib (VenKd) to be used in the VenKd combination in approximately 18 participants. The dose levels are Venetoclax 400 mg or 800 mg; Carfilzomib 20/27 mg/m2, 20/70 mg/m2, and/or 20/56 mg/m2; Dexamethasone 40 mg Part 2: Further evaluate the safety and efficacy profile of the VenKd combination selected after completion of Part 1 in approximately 22 additional participants. Participants may discontinue Kd but may continue receiving venetoclax once daily (QD) as monotherapy. Part 3: Further evaluation of the efficacy of the VenKd combination after completion of Part 1 and Part 2 in 7 additional participants. Part 4, An additional 65 participants t(11;14) positive will receive varying doses of the VenKd combination or carfilzomib and dexamethasone | Drug: Carfilzomib<br>* Carfilzomib lyophilized administered intravenously as a 10 to 30 minute infusion in Cycles 1 and beyond within 30 minutes to 4 hours after dexamethasone dosing. Dose level 1 (K1) Cycle 1: 20 mg/m2 on Days 1 and 2, 27 mg/m2 on Days 8, 9, 15, and 16; Cycles 2 - 12: 27 mg/m2 on Days 1, 2, 8, 9, 15, and 16; Cycles 13 - 18: 27 mg/m2 on Days 1, 2, 15, and 16; Cycles 19 and beyond, for participants that have not previously transitioned to monotherapy: 27 mg/m2 on Days 1, 2, 15, and 16. Dose Level K2: Cycle 1: 20 mg/m2 on Day 1; 70 mg/m2 on Days 8 and 15 Cycles 2 - onward: 70 mg/m2 on Days 1, 8, and 15. Dose Level K3: Cycle 1: 20 mg/m2 on Days 1 and 2; 56 mg/m2 on Days 8, 9, 15, and 16. Cycles 2 - onward: 56 mg/m2 on Days 1, 2, 8, 9, 15, and 16.<br>* Other names: Kyprolis;Drug: Venetoclax<br>* Venetoclax tablet administered orally once daily during Cycles 1 - onward. Venetoclax dose level 1 (Ven1) 400 mg once daily, Ven2 800 mg once daily.<br>* Other names: ABT-199;Drug: Dexamethasone<br>* Dexamethasone tablet administered orally during Cycles 1 - onward. Dexamethasone dose level 1 (Dex1) 40 mg once weekly, Dex2 40 mg once weekly, Dex3 20 mg twice weekly.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events | An adverse event is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. | First dose of study drug through at least 30 days after end of treatment (approximately 2 years) | 
| Very Good Partial Response (VGPR) or Better Response Rate of VenKd in Participants with Relapsed or Refractory Multiple Myeloma (RRMM) as well as Those with t(11;14)-positive RRMM | VGPR or better response rate is defined as the percentage of participants with documented VGPR or better based on IMWG criteria. | First dose of study drug through at least 30 days after end of treatment (approximately 2 years) | 
| Objective Response Rate (ORR) of VenKd in Participants with Relapsed or Refractory Multiple Myeloma (RRMM) as well as Those with t(11;14)-positive RRMM | ORR is defined as the percentage of participants with a documented PR or better based on IMWG criteria. | First dose of study drug through at least 30 days after end of treatment (approximately 2 years) | 
| Complete Response (CR) or Better Rate of VenKd in Participants with Relapsed or Refractory Multiple Myeloma (RRMM) as well as Those with t(11;14)-positive RRMM | Complete response or better rate is defined as the percentage of participants with documented CR or better based on IMWG criteria. | First dose of study drug through at least 30 days after end of treatment (approximately 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Very Good Partial Response (VGPR) or Better Response Rate in Participants with Relapsed or Refractory Multiple Myeloma and in a Subset of Participants with High B-cell lymphocyte-2 (BCL-2) Expression | VGPR or better response rate is defined as the proportion of participants with documented VGPR or better based on IMWG criteria. | Up to approximately 17 months | 
| Progression-free survival (PFS) in Participants with Relapsed or Refractory Multiple Myeloma and in a Subset of Participants with High B-cell lymphocyte-2 (BCL-2) Expression | PFS is defined as the number of days from the date of the first dose of study drug to the date of the first documented progressive disease (PD) or death due to any cause, whichever occurs first. | Up to approximately 17 months | 
| Minimal residual disease (MRD) | MRD in the bone marrow by next generation sequencing. | Up to 2 years (Screening, Cycle 3 Day 1, and Confirmation of Stringent Complete Response [sCR]/Complete Response [CR]) | 
| Duration of Overall Response (DOR) in Participants with Relapsed or Refractory Multiple Myeloma and in a Subset of Participants with High B-cell lymphocyte-2 (BCL-2) Expression | 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 PD or death due to MM, whichever occurs first. | Up to approximately 17 months | 
| Time to progression (TTP) in Participants with Relapsed or Refractory Multiple Myeloma and in a Subset of Participants with High B-cell lymphocyte-2 (BCL-2) Expression | TTP is defined as the number of days from the date of the first dose of study drug to the date of first documented PD or death due to MM, whichever occurs first. | Up to approximately 17 months | 
| Objective response rate (ORR) in Participants with Relapsed or Refractory Multiple Myeloma and in a Subset of Participants with High B-cell lymphocyte-2 (BCL-2) Expression | ORR is defined as the proportion of participants with documented partial response (PR) or better based on International Myeloma Working Group (IMWG) criteria. | Up to approximately 17 months | 
| Time to Response (TTR) in Participants with Relapsed or Refractory Multiple Myeloma and in a Subset of Participants with High B-cell lymphocyte-2 (BCL-2) Expression | TTR is defined as the number of days from the date of the first dose of study drug to the date of first documented response (Partial Response (PR) or better). | Up to approximately 17 months | 
| Area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) post-dose of Venetoclax | AUC0-24 post-dose of venetoclax. | Approximately 24 hours post-dose on Cycle 1 Days 1 and 15 | 
| Clearance (CL) of Carfilzomib | CL of carfilzomib. | Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 | 
| Terminal Phase Elimination Rate Constant (β) of Carfilzomib | β of carfilzomib. | Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 | 
| AUC from 0 to Infinity (AUC∞) of Carfilzomib | AUC∞ of carfilzomib. | Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 | 
| AUC from Time 0 to the Time of the Last Measurable Concentration (AUCt) of Carfilzomib | AUCt of carfilzomib. | Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 | 
| Maximum Plasma Concentration (Cmax) of Venetoclax | Cmax of venetoclax. | Approximately 24 hours post-dose on Cycle 1 Days 1 and 15 | 
| Cmax of Carfilzomib | Cmax of carfilzomib. | Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 | 
| Terminal Elimination Half-life (t1/2) of Carfilzomib | t1/2 of carfilzomib. | Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 | 
| Time to Maximum Plasma Concentration (Peak Time, Tmax) of Venetoclax | (Peak time, Tmax) of venetoclax. | Approximately 24 hours post-dose on Cycle 1 Days 1 and 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Refractory myeloma, Relapsed myeloma, Relapsed or Refractory