Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, Refractory myeloma, Relapsed myeloma, Relapsed or Refractory
Brief summary
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.
Interventions
DRUGCarfilzomib
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.
DRUGVenetoclax
Venetoclax tablet administered orally once daily during Cycles 1 - onward. Venetoclax dose level 1 (Ven1) 400 mg once daily, Ven2 800 mg once daily.
DRUGDexamethasone
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.
Sponsors
Genentech, Inc; Onyx Therapeutics, Inc.
AbbVie
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants with Adverse Events | First dose of study drug through at least 30 days after end of treatment (approximately 2 years) | 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. |
| 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 | First dose of study drug through at least 30 days after end of treatment (approximately 2 years) | VGPR or better response rate is defined as the percentage of participants with documented VGPR or better based on IMWG criteria. |
| 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 | First dose of study drug through at least 30 days after end of treatment (approximately 2 years) | ORR is defined as the percentage of participants with a documented PR or better based on IMWG criteria. |
| 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 | First dose of study drug through at least 30 days after end of treatment (approximately 2 years) | Complete response or better rate is defined as the percentage of participants with documented CR or better based on IMWG criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Up to approximately 17 months | 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. |
| 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 | Up to approximately 17 months | ORR is defined as the proportion of participants with documented partial response (PR) or better based on International Myeloma Working Group (IMWG) criteria. |
| 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 | Up to approximately 17 months | 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). |
| Area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) post-dose of Venetoclax | Approximately 24 hours post-dose on Cycle 1 Days 1 and 15 | AUC0-24 post-dose of venetoclax. |
| Clearance (CL) of Carfilzomib | Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 | CL of carfilzomib. |
| Terminal Phase Elimination Rate Constant (β) of Carfilzomib | Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 | β of carfilzomib. |
| 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 | Up to approximately 17 months | VGPR or better response rate is defined as the proportion of participants with documented VGPR or better based on IMWG criteria. |
| AUC from Time 0 to the Time of the Last Measurable Concentration (AUCt) of Carfilzomib | Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 | AUCt of carfilzomib. |
| Maximum Plasma Concentration (Cmax) of Venetoclax | Approximately 24 hours post-dose on Cycle 1 Days 1 and 15 | Cmax of venetoclax. |
| Cmax of Carfilzomib | Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 | Cmax of carfilzomib. |
| Terminal Elimination Half-life (t1/2) of Carfilzomib | Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 | t1/2 of carfilzomib. |
| Time to Maximum Plasma Concentration (Peak Time, Tmax) of Venetoclax | Approximately 24 hours post-dose on Cycle 1 Days 1 and 15 | (Peak time, Tmax) of venetoclax. |
| AUC from 0 to Infinity (AUC∞) of Carfilzomib | Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 | AUC∞ of carfilzomib. |
| 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 | Up to approximately 17 months | 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. |
| Minimal residual disease (MRD) | Up to 2 years (Screening, Cycle 3 Day 1, and Confirmation of Stringent Complete Response [sCR]/Complete Response [CR]) | MRD in the bone marrow by next generation sequencing. |
| 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 | Up to approximately 17 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 PD or death due to MM, whichever occurs first. |
Countries
Australia, Hungary, Puerto Rico, Spain, United States
Outcome results
None listed