Study Evaluating ABT-199 in Participants With Relapsed or Refractory Multiple Myeloma

NCT ID: NCT01794520

Last Updated: 2023-04-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 117 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-10-10
• Study Completion Date: 2021-11-29

Brief Summary

The Phase 1 primary objectives of this study were to assess the safety profile, characterize pharmacokinetics (PK) and determine the dosing schedule, maximum tolerated dose (MTD), and recommended Phase 2 dose (RPTD) of ABT-199 (venetoclax) when administered in participants with relapsed or refractory multiple myeloma. This study also assessed the safety profile and PK of venetoclax in combination with dexamethasone in participants with t(11;14)-positive multiple myeloma.

The Phase 2 primary objective was to further evaluate the objective response rate (ORR) and very good partial response or better rate (VGPR+) in participants with t(11;14)-positive multiple myeloma.

Conditions

Relapsed/Refractory Multiple Myeloma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase 1: Venetoclax 300 mg

Participants in the dose-escalation cohort received 300 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly.

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: DRUG

Each dose of venetoclax was to be taken with approximately 240 mL of water. On days that pre-dose pharmacokinetic (PK) sampling was required, dosing was to occur in the morning at the clinic at approximately 0900 (± 1 hour) to facilitate PK sampling. Dose Escalation cohort participants were to take venetoclax within 30 minutes after the completion of a standard low-fat breakfast with approximately 240 mL of water on Cycle 2 Day 1. On all other dosing days, participants were instructed to take venetoclax orally QD within 30 minutes after the completion of a low-fat breakfast. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed.

Phase 1: Venetoclax 600 mg

Participants in the dose-escalation cohort received 600 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly.

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: DRUG

Each dose of venetoclax was to be taken with approximately 240 mL of water. On days that pre-dose pharmacokinetic (PK) sampling was required, dosing was to occur in the morning at the clinic at approximately 0900 (± 1 hour) to facilitate PK sampling. Dose Escalation cohort participants were to take venetoclax within 30 minutes after the completion of a standard low-fat breakfast with approximately 240 mL of water on Cycle 2 Day 1. On all other dosing days, participants were instructed to take venetoclax orally QD within 30 minutes after the completion of a low-fat breakfast. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed.

Phase 1: Venetoclax 900 mg

Participants in the dose-escalation cohort received 900 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly.

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: DRUG

Each dose of venetoclax was to be taken with approximately 240 mL of water. On days that pre-dose pharmacokinetic (PK) sampling was required, dosing was to occur in the morning at the clinic at approximately 0900 (± 1 hour) to facilitate PK sampling. Dose Escalation cohort participants were to take venetoclax within 30 minutes after the completion of a standard low-fat breakfast with approximately 240 mL of water on Cycle 2 Day 1. On all other dosing days, participants were instructed to take venetoclax orally QD within 30 minutes after the completion of a low-fat breakfast. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed.

Phase 1: Venetoclax 1200 mg

Participants in the dose-escalation cohort received 1200 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly.

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: DRUG

Each dose of venetoclax was to be taken with approximately 240 mL of water. On days that pre-dose pharmacokinetic (PK) sampling was required, dosing was to occur in the morning at the clinic at approximately 0900 (± 1 hour) to facilitate PK sampling. Dose Escalation cohort participants were to take venetoclax within 30 minutes after the completion of a standard low-fat breakfast with approximately 240 mL of water on Cycle 2 Day 1. On all other dosing days, participants were instructed to take venetoclax orally QD within 30 minutes after the completion of a low-fat breakfast. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed.

Phase 1 Safety Expansion: Venetoclax 1200 mg

Participants in the safety expansion cohort received 1200 mg of venetoclax daily on Days 1 - 21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly.

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: DRUG

Each dose of venetoclax was to be taken with approximately 240 mL of water. On days that pre-dose pharmacokinetic (PK) sampling was required, dosing was to occur in the morning at the clinic at approximately 0900 (± 1 hour) to facilitate PK sampling. Dose Escalation cohort participants were to take venetoclax within 30 minutes after the completion of a standard low-fat breakfast with approximately 240 mL of water on Cycle 2 Day 1. On all other dosing days, participants were instructed to take venetoclax orally QD within 30 minutes after the completion of a low-fat breakfast. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed.

Phase 1 Combination: Venetoclax 800 mg/Dexamethasone 20 or 40 mg

Participants with t(11;14) translocation multiple myeloma received daily venetoclax at a dose of 800 mg (no lead-in period) on Days 1- 21 of each cycle concomitant with weekly dexamethasone at a dose of 40 mg (20 mg for those aged ≥ 75 years).

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: DRUG

Each dose of venetoclax was to be taken with approximately 240 mL of water. On days that pre-dose pharmacokinetic (PK) sampling was required, dosing was to occur in the morning at the clinic at approximately 0900 (± 1 hour) to facilitate PK sampling. Dose Escalation cohort participants were to take venetoclax within 30 minutes after the completion of a standard low-fat breakfast with approximately 240 mL of water on Cycle 2 Day 1. On all other dosing days, participants were instructed to take venetoclax orally QD within 30 minutes after the completion of a low-fat breakfast. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed.

Dexamethasone

Intervention Type: DRUG

Tablets were administered by mouth per the dexamethasone prescribing information.

Phase 2 Expansion: Venetoclax 800 mg/Dexamethasone 20 or 40 mg

The Phase 2 cohort further explored the efficacy of venetoclax in combination with dexamethasone in relapsed or refractory participants with t(11;14) translocation multiple myeloma. Participants received daily venetoclax at a dose of 800 mg (no lead-in period) on Days 1- 21 of each cycle concomitant with weekly dexamethasone at a dose of 40 mg (20 mg for those aged ≥ 75 years).

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: DRUG

Each dose of venetoclax was to be taken with approximately 240 mL of water. On days that pre-dose pharmacokinetic (PK) sampling was required, dosing was to occur in the morning at the clinic at approximately 0900 (± 1 hour) to facilitate PK sampling. Dose Escalation cohort participants were to take venetoclax within 30 minutes after the completion of a standard low-fat breakfast with approximately 240 mL of water on Cycle 2 Day 1. On all other dosing days, participants were instructed to take venetoclax orally QD within 30 minutes after the completion of a low-fat breakfast. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed.

Dexamethasone

Intervention Type: DRUG

Tablets were administered by mouth per the dexamethasone prescribing information.

Interventions

Venetoclax

Each dose of venetoclax was to be taken with approximately 240 mL of water. On days that pre-dose pharmacokinetic (PK) sampling was required, dosing was to occur in the morning at the clinic at approximately 0900 (± 1 hour) to facilitate PK sampling. Dose Escalation cohort participants were to take venetoclax within 30 minutes after the completion of a standard low-fat breakfast with approximately 240 mL of water on Cycle 2 Day 1. On all other dosing days, participants were instructed to take venetoclax orally QD within 30 minutes after the completion of a low-fat breakfast. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed.

Intervention Type: DRUG

Dexamethasone

Tablets were administered by mouth per the dexamethasone prescribing information.

Intervention Type: DRUG

Other Intervention Names

ABT-199; VENCLEXTA®

Eligibility Criteria

Inclusion Criteria

• ECOG (Eastern Cooperative Oncology Group) performance score of 1 or 0. Participants in the Phase 2 portion: ECOG performance score of 2, 1, or 0.
• Diagnosis of multiple myeloma (MM) previously treated with at least one prior line of therapy.

• Induction therapy followed by stem cell transplant and maintenance therapy will be considered a single line of therapy.
• For Safety Expansion, participants must have been previously treated with a proteasome inhibitor (e.g., bortezomib) and an immunomodulatory agent (e.g., thalidomide, lenalidomide).
• For Venetoclax-Dexamethasone Combination, participants must have been previously treated with a proteasome inhibitor (e.g., bortezomib) and an immunomodulatory agent (e.g., thalidomide, lenalidomide) AND have t(11;14)-positive multiple myeloma per the central lab testing.
• For Phase 2, participants must have MM positive for the t(11;14) translocation, as determined by an analytically validated fluorescence in situ hybridization (FISH) assay per the central laboratory testing (enrollment with local t(11;14)-positive FISH results only will be considered at the discretion of the Therapeutic Area MD). Participants must have evidence of disease progression on or within 60 days of last dose of most recent previous treatment based on International Myeloma Working Group (IMWG) criteria AND must have previously received at least 2 lines of therapy, including an immunomodulatory drug (lenalidomide or pomalidomide), a proteasome inhibitor (bortezomib, carfilzomib or ixazomib), daratumumab, and glucocorticoids.

• For US participants: Daratumumab combination regimen must be one of the prior lines of therapy (for this study, daratumumab plus corticosteroids will not be considered a combination regimen).
• For Non-US participants: Either daratumumab monotherapy or combination therapy is acceptable. Daratumumab monotherapy will be limited to approximately 20 percent of the total number of Phase 2 participants.
• Measurable disease at Screening:

• Serum monoclonal protein of at least 1.0 g/dL (10g/L) by protein electrophoresis.
• At least 200 mg of monoclonal protein in the urine on 24-hr electrophoresis.
• Serum immunoglobulin free light chain of at least 10 mg/dL and abnormal serum immunoglobulin kappa to lambda free light chain ratio.
• Participants with a history of autologous or allogenic stem cell transplantation must have adequate peripheral blood counts independent of any growth factor support, and have recovered from any transplant related toxicity(s) and be:

• At least 100 days post-autologous transplant prior to first dose of study drug or
• At least 6 months post-allogenic transplant prior to first dose of study drug and not have active graft-versus-host disease (GVHD), i.e., requiring treatment.
• Meet the following laboratory parameters, per the reference range, at least once during the screening period:

• Absolute Neutrophil Count (ANC) of at least 1000/μL (Participants may use growth factor support to achieve ANC eligibility criteria).
• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) not higher than 3 x Upper Limit of Normal Range (ULN).
• Calculated creatinine clearance of at least 30 mL/min using a modified Cockcroft-Gault calculation.
• Platelet count of at least 30,000 mm³ (independent of transfusion for 2 weeks).
• Hemoglobin of at least 8.0 g/dL (participants may receive blood transfusion to achieve hemoglobin eligibility criteria).
• Total bilirubin not higher than 1.5 x ULN (Participants with Gilbert's Syndrome may have bilirubin higher than 1.5 x ULN).

Exclusion Criteria

• Exhibits evidence of other clinically significant uncontrolled condition(s), including, but not limited to:

• Acute infection within 14 days prior to first dose of study drug requiring antibiotic, antifungal, or antiviral therapy.
• Diagnosis of fever and neutropenia within 1 week prior to first dose of study drug.
• Cardiovascular disability status of New York Heart Association Class ≥ 3.
• Significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular or hepatic disease, within the last 6 months that, in the opinion of the investigator, would adversely affect his/her participation in the study.
• History of other active malignancies other than multiple myeloma within the past 3 years prior to study entry, with the following exceptions:

• Adequately treated in situ carcinoma of the cervix uteri;
• Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
• Localized prostate cancer Gleason grade 6 or lower AND with stable prostate specific antigen (PSA) levels off treatment
• Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
• Known Human Immunodeficiency Viral (HIV) infection.
• Active hepatitis B or C infection.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genentech, Inc.

INDUSTRY

Sponsor Role: collaborator

AbbVie

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

ABBVIE INC.

Role: STUDY_DIRECTOR

AbbVie

Locations

Mayo Clinic - Scottsdale /ID# 75808

Scottsdale, Arizona, United States

University of Arkansas for Medical Sciences /ID# 170002

Little Rock, Arkansas, United States

Yale University /ID# 203704

New Haven, Connecticut, United States

Emory University, Winship Cancer Institute /ID# 74993

Atlanta, Georgia, United States

Ingalls Memorial Hosp /ID# 205346

Harvey, Illinois, United States

Tulane Cancer Center Clinic /ID# 204123

New Orleans, Louisiana, United States

Tufts Medical Center /ID# 203814

Boston, Massachusetts, United States

University of Michigan Comprehensive Cancer Center Michigan Medicine /ID# 170007

Ann Arbor, Michigan, United States

Mayo Clinic - Rochester /ID# 74994

Rochester, Minnesota, United States

Hattiesburg Clinic /ID# 201187

Hattiesburg, Mississippi, United States

Washington University-School of Medicine /ID# 76094

St Louis, Missouri, United States

University of Nebraska Medical Center /ID# 169158

Omaha, Nebraska, United States

The John Theurer Cancer /ID# 200248

Hackensack, New Jersey, United States

Duke Cancer Center /ID# 129356

Durham, North Carolina, United States

University Hospitals - Seidman Cancer Center /ID# 204502

Cleveland, Ohio, United States

Ohio State Cancer Center /ID# 200249

Columbus, Ohio, United States

Avera Cancer Institute /ID# 204178

Sioux Falls, South Dakota, United States

Baylor University Medical Ctr. /ID# 170056

Dallas, Texas, United States

Swedish Cancer Institute - Edmonds /ID# 170006

Seattle, Washington, United States

Univ of Wisconsin Hosp/Clinics /ID# 200246

Madison, Wisconsin, United States

Medical College of Wisconsin /ID# 205229

Milwaukee, Wisconsin, United States

UZ Brussel /ID# 170711

Jette, Brussels Capital, Belgium

ZNA Stuivenberg /ID# 170067

Antwerp, , Belgium

Duplicate_University Hospital Leuven /ID# 170715

Leuven, , Belgium

CHRU Lille - Hopital Claude Huriez /ID# 74995

Lille, Hauts-de-France, France

CHRU Tours - Hopital Bretonneau /ID# 126639

Tours, Indre-et-Loire, France

CHU de Nantes, Hotel Dieu -HME /ID# 75033

Nantes, Pays de la Loire Region, France

Duplicate_CHU Grenoble - Hopital Michallon /ID# 126658

Grenoble, , France

Ulleval, OUS /ID# 170707

Oslo, , Norway

Countries

United States; Belgium; France; Norway

References

Badawi M, Coppola S, Eckert D, Gopalakrishnan S, Engelhardt B, Doelger E, Huang W, Dobkowska E, Kumar S, Menon RM, Salem AH. Venetoclax in biomarker-selected multiple myeloma patients: Impact of exposure on clinical efficacy and safety. Hematol Oncol. 2024 Jan;42(1):e3222. doi: 10.1002/hon.3222. Epub 2023 Sep 23.

Reference Type: DERIVED

PMID: 37740931 (View on PubMed)

Kumar S, Kaufman JL, Gasparetto C, Mikhael J, Vij R, Pegourie B, Benboubker L, Facon T, Amiot M, Moreau P, Punnoose EA, Alzate S, Dunbar M, Xu T, Agarwal SK, Enschede SH, Leverson JD, Ross JA, Maciag PC, Verdugo M, Touzeau C. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017 Nov 30;130(22):2401-2409. doi: 10.1182/blood-2017-06-788786. Epub 2017 Oct 10.

Reference Type: DERIVED

PMID: 29018077 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.rxabbvie.com/

This clinical study may be evaluating a usage that is not currently FDA approved. Please see US Prescribing Information for approved uses.

Other Identifiers

2012-000589-38

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

M13-367

Identifier Type: -

Identifier Source: org_study_id