Clinical trial NCT01794520: Study Evaluating ABT-199 in Participants With Relapsed or Refractory Multiple Myeloma
Official title: A Phase 1/2 Study Evaluating the Safety and Pharmacokinetics of ABT-199 in Subjects With Relapsed or Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Relapsed/Refractory Multiple Myeloma
Keywords: Relapsed multiple myeloma
Refractory multiple myeloma
Multiple myeloma
Relapsed/refractory multiple myeloma
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
Collaborators: name: Genentech, Inc.
First posted: 2013-02-20
Enrollment: 117
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: From first dose of study drug until 30 days following last dose of study drug (up to 2482 days)
measure: Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax
timeFrame: Cycle 2, Day 1 at predose, 2, 4, 6, 8, and 24 hours postdose
measure: Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax
timeFrame: Cycle 2, Day 1 at predose, 2, 4, 6, 8, and 24 hours postdose
measure: Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax
timeFrame: 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)
measure: Phase 2: Overall Response Rate
timeFrame: 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
measure: Phase 2: Very Good Partial Response Rate or Better
timeFrame: 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:
measure: Phase 1: Overall Response Rate
timeFrame: 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
measure: Time to Response (TTR)
timeFrame: 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
measure: Time to Progression (TTP)
timeFrame: Estimated median duration of follow-up was 8.1 months for Phase 1 and 31.7 months for Phase 2
measure: Duration of Response
timeFrame: 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
measure: Phase 2: Progression-Free Survival (PFS)
timeFrame: Estimated median duration of follow-up was 31.7 months
measure: Phase 2: Overall Survival (OS)
timeFrame: Estimated median duration of follow-up was 31.7 months
measure: Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain
timeFrame: Baseline; Cycle 3, Day 1; Cycle 5, Day 1; Cycle 7, Day 1; Cycle 9, Day 1; Cycle 11, Day 1; Cycle 13, Day 1; Cycle 15, Day 1; Cycle 17, Day 1; Cycle 19, Day 1; Cycle 21, Day 1; Cycle 23, Day 1; Cycle 25, Day 1; Final visit
measure: Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
timeFrame: Baseline; Cycle 3, Day 1; Cycle 5, Day 1; Cycle 7, Day 1; Cycle 9, Day 1; Cycle 11, Day 1; Cycle 13, Day 1; Cycle 15, Day 1; Cycle 17, Day 1; Cycle 19, Day 1; Cycle 21, Day 1; Cycle 23, Day 1; Cycle 25, Day 1; Final visit
measure: Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
timeFrame: Baseline; Cycle 3, Day 1; Cycle 5, Day 1; Cycle 7, Day 1; Cycle 9, Day 1; Cycle 11, Day 1; Cycle 13, Day 1; Cycle 15, Day 1; Cycle 17, Day 1; Cycle 19, Day 1; Cycle 21, Day 1; Cycle 23, Day 1; Cycle 25, Day 1; Final visit
measure: Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score
timeFrame: Baseline; Cycle 3, Day 1; Cycle 5, Day 1; Cycle 7, Day 1; Cycle 9, Day 1; Cycle 11, Day 1; Cycle 13, Day 1; Cycle 15, Day 1; Cycle 17, Day 1; Cycle 19, Day 1; Cycle 21, Day 1; Cycle 23, Day 1; Cycle 25, Day 1; Final visit
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic - Scottsdale /ID# 75808
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences /ID# 170002
state: Arkansas
city: New Haven
country: United States
facility: Yale University /ID# 203704
state: Connecticut
city: Atlanta
country: United States
facility: Emory University, Winship Cancer Institute /ID# 74993
state: Georgia
city: Harvey
country: United States
facility: Ingalls Memorial Hosp /ID# 205346
state: Illinois
city: New Orleans
country: United States
facility: Tulane Cancer Center Clinic /ID# 204123
state: Louisiana
city: Boston
country: United States
facility: Tufts Medical Center /ID# 203814
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center Michigan Medicine /ID# 170007
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Rochester /ID# 74994
state: Minnesota
city: Hattiesburg
country: United States
facility: Hattiesburg Clinic /ID# 201187
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University-School of Medicine /ID# 76094
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center /ID# 169158
state: Nebraska
city: Hackensack
country: United States
facility: The John Theurer Cancer /ID# 200248
state: New Jersey
city: Durham
country: United States
facility: Duke Cancer Center /ID# 129356
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals - Seidman Cancer Center /ID# 204502
state: Ohio
city: Columbus
country: United States
facility: Ohio State Cancer Center /ID# 200249
state: Ohio
city: Sioux Falls
country: United States
facility: Avera Cancer Institute /ID# 204178
state: South Dakota
city: Dallas
country: United States
facility: Baylor University Medical Ctr. /ID# 170056
state: Texas
city: Seattle
country: United States
facility: Swedish Cancer Institute - Edmonds /ID# 170006
state: Washington
city: Madison
country: United States
facility: Univ of Wisconsin Hosp/Clinics /ID# 200246
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin /ID# 205229
state: Wisconsin
city: Jette
country: Belgium
facility: UZ Brussel /ID# 170711
state: Bruxelles-Capitale
city: Antwerp
country: Belgium
facility: ZNA Stuivenberg /ID# 170067
city: Leuven
country: Belgium
facility: Duplicate_University Hospital Leuven /ID# 170715
city: Lille
country: France
facility: CHRU Lille - Hopital Claude Huriez /ID# 74995
state: Hauts-de-France
city: Tours CEDEX 9
country: France
facility: CHRU Tours - Hopital Bretonneau /ID# 126639
state: Indre-et-Loire
city: Nantes
country: France
facility: CHU de Nantes, Hotel Dieu -HME /ID# 75033
state: Pays-de-la-Loire
city: Grenoble
country: France
facility: Duplicate_CHU Grenoble - Hopital Michallon /ID# 126658
city: Oslo
country: Norway
facility: Ulleval, OUS /ID# 170707
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References:
citation: 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.