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

NCT01794520 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: M13-3672012-000589-38
• Study Type: interventional
• Target: 117
• Locations: 4 countries
• Sites: 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

Keywords

Relapsed multiple myeloma; Refractory multiple myeloma; Multiple myeloma; Relapsed/refractory multiple myeloma

Outcome Measures

Primary Outcomes (6)

• Number of Participants With Adverse Events

  An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study drug. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug.

  From first dose of study drug until 30 days following last dose of study drug (up to 2482 days)

• Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax

  Cmax is the highest concentration that a drug achieves in the blood after administration in a dosing interval.

  Cycle 2, Day 1 at predose, 2, 4, 6, 8, and 24 hours postdose

• Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax

  Tmax is the the time at which the maximum plasma concentration (Cmax) is observed.

  Cycle 2, Day 1 at predose, 2, 4, 6, 8, and 24 hours postdose

• Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax

  AUC is a measure of how long and how much drug is present in the body after dosing.

  Cycle 2, Day 1 at predose, 2, 4, 6, 8, and 24 hours postdose (dose escalation cohort); (1200 mg dose): Cycle 2, Day 1 at predose (safety expansion cohort, 1200 mg dose)

• Phase 2: Overall Response Rate

  Overall response rate is defined as the percentage of participants with documented best overall response of Partial Response (PR) or better (PR, Very good partial response \[VGPR\], Complete response \[CR\], or Stringent complete response \[sCR\]) per 2016 standard International Myeloma Working Group (IMWG) criteria.

  Response was assessed at Cycle 2, Day 1, and on Day 1 of every cycle thereafter; estimated median time on follow-up was 31.7 months

• Phase 2: Very Good Partial Response Rate or Better

  The percentage of participants with documented best overall response of Very Good Partial Response (VGPR) or better (VGPR, Complete response \[CR\], or Stringent complete response \[sCR\]) per 2016 standard International Myeloma Working Group (IMWG) criteria was computed.

  Response was assessed at Cycle 2, Day 1, and on Day 1 of every cycle thereafter; estimated median time on follow-up was 31.7 months

Secondary Outcomes (10)

• Phase 1: Overall Response Rate

  Response was assessed at Cycle 2, Day 1, and on Day 1 of every cycle thereafter; estimated median time on follow-up was 8.1 months

• Time to Response (TTR)

  Response was assessed at Cycle 2, Day 1, and on Day 1 of every cycle thereafter; Estimated median time on follow-up was 8.1 months for Phase 1 and 31.7 months for Phase 2

• Time to Progression (TTP)

  Estimated median duration of follow-up was 8.1 months for Phase 1 and 31.7 months for Phase 2

• Duration of Response

  Assessed at Cycle 2, Day 1, and on Day 1 of every cycle thereafter; estimated median duration of follow-up was 8.1 months for Phase 1 and 31.7 months for Phase 2

• Phase 2: Progression-Free Survival (PFS)

  Estimated median duration of follow-up was 31.7 months

Study Arms (7)

Phase 1: Venetoclax 300 mg

EXPERIMENTAL

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.

Drug: Venetoclax

Phase 1: Venetoclax 600 mg

EXPERIMENTAL

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.

Drug: Venetoclax

Phase 1: Venetoclax 900 mg

EXPERIMENTAL

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.

Drug: Venetoclax

Phase 1: Venetoclax 1200 mg

EXPERIMENTAL

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.

Drug: Venetoclax

Phase 1 Safety Expansion: Venetoclax 1200 mg

EXPERIMENTAL

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.

Drug: Venetoclax

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

EXPERIMENTAL

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).

Drug: Venetoclax; Drug: Dexamethasone

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

EXPERIMENTAL

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).

Drug: Venetoclax; Drug: Dexamethasone

Interventions

Venetoclax 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.

Also known as: ABT-199, VENCLEXTA®

Phase 1 Combination: Venetoclax 800 mg/Dexamethasone 20 or 40 mg; Phase 1 Safety Expansion: Venetoclax 1200 mg; Phase 1: Venetoclax 1200 mg; Phase 1: Venetoclax 300 mg; Phase 1: Venetoclax 600 mg; Phase 1: Venetoclax 900 mg; Phase 2 Expansion: Venetoclax 800 mg/Dexamethasone 20 or 40 mg

Dexamethasone DRUG

Tablets were administered by mouth per the dexamethasone prescribing information.

Phase 1 Combination: Venetoclax 800 mg/Dexamethasone 20 or 40 mg; Phase 2 Expansion: Venetoclax 800 mg/Dexamethasone 20 or 40 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• AbbVie: lead
• Genentech, Inc.: collaborator

Study Sites (29)

Mayo Clinic - Scottsdale /ID# 75808

Scottsdale, Arizona, 85259-5452, United States

Location

University of Arkansas for Medical Sciences /ID# 170002

Little Rock, Arkansas, 72205, United States

Location

Yale University /ID# 203704

New Haven, Connecticut, 06510, United States

Location

Emory University, Winship Cancer Institute /ID# 74993

Atlanta, Georgia, 30322, United States

Location

Ingalls Memorial Hosp /ID# 205346

Harvey, Illinois, 60426, United States

Location

Tulane Cancer Center Clinic /ID# 204123

New Orleans, Louisiana, 70112, United States

Location

Tufts Medical Center /ID# 203814

Boston, Massachusetts, 02111-1552, United States

Location

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

Ann Arbor, Michigan, 48109, United States

Location

Mayo Clinic - Rochester /ID# 74994

Rochester, Minnesota, 55905-0001, United States

Location

Hattiesburg Clinic /ID# 201187

Hattiesburg, Mississippi, 39401, United States

Location

Washington University-School of Medicine /ID# 76094

St Louis, Missouri, 63110, United States

Location

University of Nebraska Medical Center /ID# 169158

Omaha, Nebraska, 68198-6840, United States

Location

The John Theurer Cancer /ID# 200248

Hackensack, New Jersey, 07601, United States

Location

Duke Cancer Center /ID# 129356

Durham, North Carolina, 27710-3000, United States

Location

University Hospitals - Seidman Cancer Center /ID# 204502

Cleveland, Ohio, 44106-1716, United States

Location

Ohio State Cancer Center /ID# 200249

Columbus, Ohio, 43210, United States

Location

Avera Cancer Institute /ID# 204178

Sioux Falls, South Dakota, 57105, United States

Location

Baylor University Medical Ctr. /ID# 170056

Dallas, Texas, 75246, United States

Location

Swedish Cancer Institute - Edmonds /ID# 170006

Seattle, Washington, 98104, United States

Location

Univ of Wisconsin Hosp/Clinics /ID# 200246

Madison, Wisconsin, 53792-0001, United States

Location

Medical College of Wisconsin /ID# 205229

Milwaukee, Wisconsin, 53226-3522, United States

Location

UZ Brussel /ID# 170711

Jette, Brussels Capital, 1090, Belgium

Location

ZNA Stuivenberg /ID# 170067

Antwerp, 2060, Belgium

Location

Duplicate_University Hospital Leuven /ID# 170715

Leuven, 3000, Belgium

Location

CHRU Lille - Hopital Claude Huriez /ID# 74995

Lille, Hauts-de-France, 59037, France

Location

CHRU Tours - Hopital Bretonneau /ID# 126639

Tours, Indre-et-Loire, 37044, France

Location

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

Nantes, Pays de la Loire Region, 44000, France

Location

Duplicate_CHU Grenoble - Hopital Michallon /ID# 126658

Grenoble, 38043, France

Location

Ulleval, OUS /ID# 170707

Oslo, 0450, Norway

Location

Related Publications (2)

• 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.

  PMID: 37740931 DERIVED

• 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.

  PMID: 29018077 DERIVED

Related Links

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

MeSH Terms

Conditions

Multiple Myeloma

Interventions

venetoclax; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Results Point of Contact

• Title: Global Medical Services
• Organization: AbbVie

abbvieclinicaltrials@abbvie.com

800-633-9110

Study Officials

• ABBVIE INC.

  AbbVie

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: October 12, 2012
• First Posted: February 20, 2013
• Study Start: October 10, 2012
• Primary Completion: November 29, 2021
• Study Completion: November 29, 2021
• Last Updated: April 10, 2023
• Results First Posted: April 10, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: For details on when studies are available for sharing visit https://vivli.org/ourmember/abbvie/
• 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/

Locations

BE (3); FR (4); US (21); NO (1)