Study of Venetoclax in Combination With Carfilzomib and Dexamethasone in Participants With Relapsed or Refractory Multiple Myeloma (MM)
- Conditions
- Multiple Myeloma
- Interventions
- Registration Number
- NCT02899052
- Lead Sponsor
- AbbVie
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 120
- 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.
-
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Venetoclax + Carfilzomib + Dexamethasone Carfilzomib 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 Venetoclax + Carfilzomib + Dexamethasone Venetoclax 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 Venetoclax + Carfilzomib + Dexamethasone Dexamethasone 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
- Primary Outcome Measures
Name Time Method 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.
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.
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 Outcome Measures
Name Time Method 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.
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.
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 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.
AUC from 0 to Infinity (AUC∞) of Carfilzomib Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 AUC∞ of carfilzomib.
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.
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.
Trial Locations
- Locations (32)
Oncology Hematology Associates (OHA) - Springfield /ID# 218855
🇺🇸Springfield, Missouri, United States
University of Pennsylvania /ID# 151768
🇺🇸Philadelphia, Pennsylvania, United States
University of Texas Southwestern Medical Center /ID# 218336
🇺🇸Dallas, Texas, United States
Memorial Healthcare System /ID# 224862
🇺🇸Hollywood, Florida, United States
Emory University, Winship Cancer Institute /ID# 161710
🇺🇸Atlanta, Georgia, United States
University of Arkansas for Medical Sciences /ID# 151399
🇺🇸Little Rock, Arkansas, United States
University of Kentucky Chandler Medical Center /ID# 151407
🇺🇸Lexington, Kentucky, United States
The University of Chicago Medical Center /ID# 151395
🇺🇸Chicago, Illinois, United States
University of Maryland School of Medicine /ID# 159721
🇺🇸Baltimore, Maryland, United States
Central Maine Medical Center /ID# 218856
🇺🇸Lewiston, Maine, United States
Border Medical Oncology Research Unit Albury Wodonga Regiona /ID# 222200
🇦🇺East Albury, New South Wales, Australia
Calvary Mater Newcastle /ID# 218739
🇦🇺Waratah, New South Wales, Australia
Royal Hobart Hospital /ID# 217546
🇦🇺Hobart, Tasmania, Australia
Flinders Medical Centre /ID# 221345
🇦🇺Bedford, Park, South Australia, Australia
Debreceni Egyetem-Klinikai Kozpont /ID# 217624
🇭🇺Debrecen, Hajdu-Bihar, Hungary
Auxilio Mutuo Cancer Center /ID# 157853
🇵🇷San Juan, Puerto Rico
Semmelweis Egyetem /ID# 217626
🇭🇺Budapest, Hungary
Del-pesti Centrumkorhaz Orszagos Hematologiai es Infektologiai Intezet /ID# 217625
🇭🇺Budapest, Hungary
Szegedi Tudományegyetem /ID# 219172
🇭🇺Szeged, Hungary
Hospital Universitario Germans Trias i Pujol /ID# 218006
🇪🇸Badalona, Barcelona, Spain
VA Caribbean Healthcare System /ID# 157854
🇵🇷San Juan, Puerto Rico
Hospital General Universitario Gregorio Maranon /ID# 218005
🇪🇸Madrid, Spain
Hospital Clinic de Barcelona /ID# 218007
🇪🇸Barcelona, Spain
Hospital Universitario Ramon y Cajal /ID# 220925
🇪🇸Madrid, Spain
Baylor Scott & White Medical Center- Temple /ID# 218252
🇺🇸Temple, Texas, United States
Washington University-School of Medicine /ID# 222651
🇺🇸Saint Louis, Missouri, United States
Aurora Health Care, Aurora Cancer Center /ID# 209612
🇺🇸Wauwatosa, Wisconsin, United States
University of Alabama at Birmingham - Main /ID# 151405
🇺🇸Birmingham, Alabama, United States
Indiana Blood & Marrow Transpl /ID# 218862
🇺🇸Indianapolis, Indiana, United States
Duke Cancer Center /ID# 162062
🇺🇸Durham, North Carolina, United States
University of Utah /ID# 151397
🇺🇸Salt Lake City, Utah, United States
Duplicate_VA Puget Sound Healthcare Syst /ID# 155369
🇺🇸Seattle, Washington, United States