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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Carfilzomib; Drug: Venetoclax; Drug: Dexamethasone

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

• Study Contact: Name: ABBVIE CALL CENTER; Phone Number: 844-663-3742; Email: abbvieclinicaltrials@abbvie.com

Study Locations

• Australia
  • New South Wales
    • East Albury, New South Wales, Australia, 2640
      • Border Medical Oncology Research Unit Albury Wodonga Regiona /ID# 222200
    • Waratah, New South Wales, Australia, 2298
      • Calvary Mater Newcastle /ID# 218739
  • South Australia
    • Bedford, Park, South Australia, Australia, 5042
      • Flinders Medical Centre /ID# 221345
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Royal Hobart Hospital /ID# 217546
• Hungary
  • Budapest, Hungary, 1085
    • Semmelweis Egyetem /ID# 217626
  • Budapest, Hungary, 1097
    • Del-pesti Centrumkorhaz Orszagos Hematologiai es Infektologiai Intezet /ID# 217625
  • Szeged, Hungary, 6720
    • Szegedi Tudományegyetem /ID# 219172
  • Hajdu-Bihar
    • Debrecen, Hajdu-Bihar, Hungary, 4032
      • Debreceni Egyetem-Klinikai Kozpont /ID# 217624
• Puerto Rico
  • San Juan, Puerto Rico, 00918
    • Auxilio Mutuo Cancer Center /ID# 157853
  • San Juan, Puerto Rico, 00921-3201
    • VA Caribbean Healthcare System /ID# 157854
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona /ID# 218007
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon /ID# 218005
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal /ID# 220925
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Universitario Germans Trias i Pujol /ID# 218006
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham - Main /ID# 151405
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences /ID# 151399
  • Florida
    • Hollywood, Florida, United States, 33021-3513
      • Memorial Healthcare System /ID# 224862
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University, Winship Cancer Institute /ID# 161710
  • Illinois
    • Chicago, Illinois, United States, 60637-1443
      • The University of Chicago Medical Center /ID# 151395
  • Indiana
    • Indianapolis, Indiana, United States, 46237
      • Indiana Blood & Marrow Transpl /ID# 218862
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Chandler Medical Center /ID# 151407
  • Maine
    • Lewiston, Maine, United States, 04240
      • Central Maine Medical Center /ID# 218856
  • Maryland
    • Baltimore, Maryland, United States, 21201-1544
      • University of Maryland School of Medicine /ID# 159721
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University-School of Medicine /ID# 222651
    • Springfield, Missouri, United States, 65807-5287
      • Oncology Hematology Associates (OHA) - Springfield /ID# 218855
  • North Carolina
    • Durham, North Carolina, United States, 27710-3000
      • Duke Cancer Center /ID# 162062
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-5502
      • University of Pennsylvania /ID# 151768
  • Texas
    • Dallas, Texas, United States, 75390-7208
      • University of Texas Southwestern Medical Center /ID# 218336
    • Temple, Texas, United States, 76508-0001
      • Baylor Scott & White Medical Center- Temple /ID# 218252
  • Utah
    • Salt Lake City, Utah, United States, 84112-5500
      • University of Utah /ID# 151397
  • Washington
    • Seattle, Washington, United States, 98108
      • Duplicate_VA Puget Sound Healthcare Syst /ID# 155369
  • Wisconsin
    • Wauwatosa, Wisconsin, United States, 53226-3436
      • Aurora Health Care, Aurora Cancer Center /ID# 209612

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Venetoclax + Carfilzomib + 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

Drug: Carfilzomib; 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.; Other Names: Kyprolis; Drug: Venetoclax; Venetoclax tablet administered orally once daily during Cycles 1 - onward. Venetoclax dose level 1 (Ven1) 400 mg once daily, Ven2 800 mg once daily.; Other Names: Venclexta; ABT-199; Drug: Dexamethasone; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: AbbVie
• Collaborators: Genentech, Inc; Onyx Therapeutics, Inc.
• Investigators: Study Director: ABBVIE INC., AbbVie

Publications and helpful links

General Publications

• Costa LJ, Davies FE, Monohan GP, Kovacsovics T, Burwick N, Jakubowiak A, Kaufman JL, Hong WJ, Dail M, Salem AH, Yang X, Masud AA, Munasinghe W, Ross JA, Bueno OF, Kumar SK, Stadtmauer EA. Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Blood Adv. 2021 Oct 12;5(19):3748-3759. doi: 10.1182/bloodadvances.2020004146.

Study record dates

Study Major Dates

• Study Start (Actual): January 19, 2017
• Primary Completion (Estimated): June 22, 2027
• Study Completion (Estimated): June 22, 2027

Study Registration Dates

• First Submitted: September 1, 2016
• First Submitted That Met QC Criteria: September 8, 2016
• First Posted (Estimated): September 14, 2016

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Multiple Myeloma; Relapsed or Refractory; Refractory myeloma; Relapsed myeloma
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone; Venetoclax
• Other Study ID Numbers: M15-538; 2019-004340-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols, analyses plans, clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
• IPD Sharing Time Frame: For details on when studies are available for sharing visit https://vivli.org/ourmember/abbvie/
• IPD Sharing Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous independent scientific research, and will be provided following review and approval of a research proposal and statistical analysis plan and execution of a data sharing statement. Data requests can be submitted at any time after approval in the US and/or EU and a primary manuscript is accepted for publication. For more information on the process, or to submit a request, visit the following link https://www.abbvieclinicaltrials.com/hcp/data-sharing/
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No