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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 : Active, not recruiting
First Posted : September 14, 2016
Last Update Posted : September 6, 2018
Sponsor:
Collaborators:
Genentech, Inc.
Onyx Therapeutics, Inc.
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Carfilzomib Drug: Venetoclax Drug: Dexamethasone Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2, Open-Label, Multi-Center Study of Venetoclax in Combination With Carfilzomib and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma
Actual Study Start Date : January 13, 2017
Estimated Primary Completion Date : March 27, 2020
Estimated Study Completion Date : July 17, 2020


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 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.
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.




Primary Outcome Measures :
  1. Adverse events [ Time Frame: First dose of study drug through at least 30 days after end of treatment (approximately 2 years) ]

Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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 ]
  5. Clearance (CL) of carfilzomib [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
  6. 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.

  7. Terminal phase elimination rate constant (β) of carfilzomib [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
  8. AUC from 0 to infinity (AUC∞)of carfilzomib [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
  9. 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.

  10. 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 ]
  11. 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.

  12. Cmax of carfilzomib [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
  13. Terminal elimination half-life (t1/2) of carfilzomib [ Time Frame: Approximately 4 hours post-dose on Cycle 1 Days 1 and 15 ]
  14. Time to maximum plasma concentration (peak time, Tmax) of venetoclax [ Time Frame: Approximately 24 hours post-dose on Cycle 1 Days 1 and 15 ]
  15. Maximum plasma concentration (Cmax) of venetoclax [ Time Frame: Approximately 24 hours post-dose on Cycle 1 Days 1 and 15 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02899052


Locations
United States, Alabama
University of Alabama /ID# 151405
Birmingham, Alabama, United States, 35233
United States, Arkansas
University of Arkansas for Medical Sciences /ID# 151399
Little Rock, Arkansas, United States, 72205
United States, Georgia
Emory University Hospital /ID# 161710
Atlanta, Georgia, United States, 30322
United States, Illinois
University of Chicago /ID# 151395
Chicago, Illinois, United States, 60637-1443
United States, Kentucky
University of Kentucky Chandler Medical Center /ID# 151407
Lexington, Kentucky, United States, 40536
United States, North Carolina
Carolinas Medical Center /ID# 161711
Charlotte, North Carolina, United States, 28203
Duke Univ Med Ctr /ID# 162062
Durham, North Carolina, United States, 27710
United States, Pennsylvania
University of Pennsylvania /ID# 151768
Philadelphia, Pennsylvania, United States, 19104-5502
United States, Utah
University of Utah /ID# 151397
Salt Lake City, Utah, United States, 84112-5500
United States, Washington
VA Puget Sound Healthcare Syst /ID# 155369
Seattle, Washington, United States, 98108
Puerto Rico
Auxilio Mutuo Cancer Center /ID# 157853
San Juan, Puerto Rico, 00918
VA Caribbean Healthcare System /ID# 157854
San Juan, Puerto Rico, 00921-3201
Sponsors and Collaborators
AbbVie
Genentech, Inc.
Onyx Therapeutics, Inc.
Investigators
Study Director: AbbVie Inc. AbbVie

Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT02899052     History of Changes
Other Study ID Numbers: M15-538
First Posted: September 14, 2016    Key Record Dates
Last Update Posted: September 6, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
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
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
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

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

Keywords provided by AbbVie:
Multiple Myeloma
Refractory myeloma
Relapsed myeloma
Relapsed or Refractory

Additional relevant MeSH terms:
Multiple Myeloma
Venetoclax
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors