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

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ClinicalTrials.gov Identifier: NCT02899052
Recruitment Status : Recruiting
First Posted : September 14, 2016
Last Update Posted : October 31, 2018
Sponsor:
Collaborators:
Genentech, Inc.
Onyx Therapeutics, Inc.
Information provided by (Responsible Party):
AbbVie

September 1, 2016
September 14, 2016
October 31, 2018
January 19, 2017
March 27, 2020   (Final data collection date for primary outcome measure)
  • Adverse events [ Time Frame: 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 RRMM as well as those with t(11;14)-positive RRMM. [ Time Frame: 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,
  • Very Good Partial Response (VGPR) or better response rate of VenKd in participants with relapsed or refractory MM (RRMM) as well as those with t(11;14)-positive RRMM [ Time Frame: 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.
Adverse events [ Time Frame: First dose of study drug through at least 30 days after end of treatment (approximately 2 years) ]
Complete list of historical versions of study NCT02899052 on ClinicalTrials.gov Archive Site
  • Very Good Partial Response (VGPR) or better response rate in participants with relapsed or refractory MM and in a subset of participants with high BCL-2 expression [ Time Frame: 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 MM and in a subset of participants with high BCL-2 expression [ Time Frame: 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) [ Time Frame: 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.
  • Area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) post-dose of venetoclax [ Time Frame: Approximately 24 hours post-dose on Cycle 1 Days 1 and 15 ]
  • Clearance (CL) of carfilzomib [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
  • Duration of overall response (DOR) in participants with relapsed or refractory MM and in a subset of participants with high BCL-2 expression [ Time Frame: 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 phase elimination rate constant (β) of carfilzomib [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
  • AUC from 0 to infinity (AUC∞)of carfilzomib [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
  • Time to progression (TTP) in participants with relapsed or refractory MM and in a subset of participants with high BCL-2 expression [ Time Frame: 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.
  • AUC from time 0 to the time of the last measurable concentration (AUCt) of carfilzomib [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
  • Objective response rate (ORR) in participants with relapsed or refractory MM and in a subset of participants with high B-cell lymphocyte-2 (BCL-2) expression [ Time Frame: 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.
  • Cmax of carfilzomib [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
  • Terminal elimination half-life (t1/2) of carfilzomib [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
  • Time to maximum plasma concentration (peak time, Tmax) of venetoclax [ Time Frame: Approximately 24 hours post-dose on Cycle 1 Days 1 and 15 ]
  • Maximum plasma concentration (Cmax) of venetoclax [ Time Frame: Approximately 24 hours post-dose on Cycle 1 Days 1 and 15 ]
  • Objective response rate (ORR) in participants with relapsed or refractory MM and in a subset of participants with high B-cell lymphocyte-2 (BCL-2) expression [ Time Frame: 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.
  • Very Good Partial Response (VGPR) or better response rate in participants with relapsed or refractory MM and in a subset of participants with high BCL-2 expression [ Time Frame: 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 MM and in a subset of participants with high BCL-2 expression [ Time Frame: 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.
  • Time to progression (TTP) in participants with relapsed or refractory MM and in a subset of participants with high BCL-2 expression [ Time Frame: 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.
  • Duration of overall response (DOR) in participants with relapsed or refractory MM and in a subset of participants with high BCL-2 expression [ Time Frame: 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.
  • Minimal residual disease (MRD) [ Time Frame: 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.
  • Maximum plasma concentration (Cmax) of venetoclax [ Time Frame: Approximately 24 hours post-dose on Cycle 1 Days 1 and 15 ]
  • Time to maximum plasma concentration (peak time, Tmax) of venetoclax [ Time Frame: Approximately 24 hours post-dose on Cycle 1 Days 1 and 15 ]
  • Area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) post-dose of venetoclax [ Time Frame: Approximately 24 hours post-dose on Cycle 1 Days 1 and 15 ]
  • Cmax of carfilzomib [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
  • Terminal phase elimination rate constant (β) of carfilzomib [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
  • Terminal elimination half-life (t1/2) of carfilzomib [ Time Frame: 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 [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
  • AUC from 0 to infinity (AUC∞)of carfilzomib [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
  • Clearance (CL) of carfilzomib [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
Not Provided
Not Provided
 
Study of Venetoclax in Combination With Carfilzomib and Dexamethasone in Subjects 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.
Not Provided
Interventional
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Multiple Myeloma
  • Drug: Carfilzomib

    Carfilzomib lyophilized administered intravenously as a 10 to 30 minute infusion in Cycles 1 - 18 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.

    Dose Level K2: Cycle 1: 20 mg/m2 on Day 1; 70 mg/m2 on Days 8 and 15 Cycles 2 - 18: 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 - 18: 56 mg/m2 on Days 1, 2, 8, 9, 15, and 16.

    Other Name: Kyprolis
  • Drug: Venetoclax
    Venetoclax tablet administered orally once daily during Cycles 1-18. Venetoclax dose level 1 (Ven1) 400 mg once daily, Ven2 800 mg once daily.
    Other Name: ABT-199
  • Drug: Dexamethasone
    Dexamethasone tablet administered orally during Cycles 1 - 18. Dexamethasone dose level 1 (Dex1) 40 mg once weekly, Dex2 40 mg once weekly, Dex3 20 mg twice weekly.
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 9-18 subjects. 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 - 31 additional subjects. 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 60 additional subjects.

Interventions:
  • Drug: Carfilzomib
  • Drug: Venetoclax
  • Drug: Dexamethasone
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
100
40
October 16, 2022
March 27, 2020   (Final data collection date for primary outcome measure)

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.
  • Received prior treatment with at least 1, but no more than 3, prior lines 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.
  • For Part 3, Cohort 7, participants must meet the above criteria and also be positive for translocation t(11;14) as determined by an analytically validated Fluorescent In Situ Hybridization (FISH) assay per central laboratory testing.

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
  • Significant cardiovascular disease
  • Major surgery within 4 weeks prior to first dose
  • Acute infections requiring parenteral therapy
  • 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 subject'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
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact: ABBVIE CALL CENTER 847.283.8955 abbvieclinicaltrials@abbvie.com
United States,   Puerto Rico
 
 
NCT02899052
M15-538
No
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
Plan to Share IPD: Yes
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 and 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.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered.
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 (SAP) and execution of a Data Sharing Agreement (DSA). For more information on the process, or to submit a request, visit the following link.
URL: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html
AbbVie
AbbVie
  • Genentech, Inc.
  • Onyx Therapeutics, Inc.
Study Director: AbbVie Inc. AbbVie
AbbVie
October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP