Clinical trial NCT01685892: A Study of Venetoclax in Combination With Obinutuzumab in Participants With Chronic Lymphocytic Leukemia
Official title: A Phase Ib Multicenter Dose-Finding and Safety Study of Venetoclax and Obinutuzumab in Patients With Relapsed or Refractory or Previously Untreated Chronic Lymphocytic Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lymphocytic Leukemia, Chronic
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
Collaborators: name: AbbVie (prior sponsor, Abbott)
First posted: 2012-09-14
Enrollment: 82
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: This multi-center, open-label, dose-finding study will evaluate the safety and pharmacokinetics as well as the preliminary efficacy of venetoclax (GDC-0199; ABT-199) administered in combination with obinutuzumab to participants with relapsed/refractory or previously untreated chronic lymphocytic leukemia (CLL). The study is comprised of two stages for each participant population: a dose-finding stage and a safety-expansion stage. The dose-finding stage will explore multiple doses of venetoclax to be used in combination with a fixed dose of obinutuzumab. The dose-finding stage will also explore two schedules for drug administration, Schedule A (venetoclax introduced before obinutuzumab) and Schedule B (venetoclax introduced after obinutuzumab).


Eligibility criteria: Inclusion Criteria:

* Diagnosis of relapsing/refractory or previously untreated chronic lymphocytic leukemia
* Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to (\</=) 1
* Adequate bone marrow function
* Adequate coagulation, renal and hepatic function
* For all participants, agreement to remain abstinent or use contraceptive methods that result in a failure rate of less than (\<) 1% per year during the treatment period and for at least 90 days (30 days for women) after the last dose of venetoclax or 18 months after the last dose of obinutuzumab, whichever is longer

Exclusion Criteria:

* Participants who have undergone allogenic stem cell transplant are ineligible unless they meet the following criteria, a) participants who are off all immunosuppressive therapy, b) participants who have no signs and/or symptoms of acute or chronic graft versus host disease, or c) participants must have appropriate hematology counts
* Infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
* Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
* Investigational or anti-cancer therapy within 5 half-lives prior to the first dose of study drug
* History of significant renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease

Primary outcomes:
measure: Percentage of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Schedule (Sch) A (Cycle 1 Day 1 to Day 21), Sch B (Cycle 1 Day 22 to Cycle 2 Day 28) (1 Cycle=28 days)
measure: Maximum Tolerated Dose (MTD) of Venetoclax in Combination with Obinutuzumab
timeFrame: Sch A (Cycle 1 Day 1 to Day 21), Sch B (Cycle 1 Day 22 to Cycle 2 Day 28) (1 Cycle=28 days)
Secondary outcomes:
measure: Percentage of Participants with Adverse Events
timeFrame: Baseline up to end of study (up to approximately 5 years and 5 months)
measure: Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) to Obinutuzumab
timeFrame: Baseline up to Cycle 6 (1 Cycle=28 days)
measure: Area Under the Concentration-Time Curve (AUC) of Venetoclax
timeFrame: Baseline up to Cycle 6 (1 Cycle=28 days)
measure: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax
timeFrame: Baseline up to Cycle 6 (1 Cycle=28 days)
measure: Maximal Plasma Concentration (Cmax) of Venetoclax
timeFrame: Baseline up to Cycle 6 (1 Cycle=28 days)
measure: Minimum Plasma Concentration (Cmin) of Venetoclax
timeFrame: Baseline up to Cycle 6 (1 Cycle=28 days)
measure: Cmax of Obinutuzumab
timeFrame: Baseline up to Cycle 6 (1 Cycle=28 days)
measure: Cmin of Obinutuzumab
timeFrame: Baseline up to Cycle 6 (1 Cycle=28 days)
measure: Percentage of Participants with Confirmed Complete Response (CR) as Determined by Standard CLL Response Criteria
timeFrame: Baseline up to end of study (up to approximately 5 years and 5 months)
measure: Percentage of Participants with Objective Response (Partial Response [PR] or CR [Including Cytopenic CR] as Determined by Standard CLL Response Criteria
timeFrame: Baseline up to end of study (up to approximately 5 years and 5 months)
measure: Duration of Objective Response as Determined by Standard CLL Response Criteria
timeFrame: Baseline up to end of study (up to approximately 5 years and 5 months)
measure: Overall Survival
timeFrame: Baseline up to death or end of study (up to approximately 5 years and 5 months)
measure: Progression-Free Survival as Determined by Standard CLL Response Criteria
timeFrame: Baseline up to end of study (up to approximately 5 years and 5 months)
measure: Change from Baseline in Number of B-Cells
timeFrame: Baseline up to end of study (up to approximately 5 years and 5 months)
measure: Change from Baseline in Number of T-Cells
timeFrame: Baseline up to end of study (up to approximately 5 years and 5 months)
measure: Change from Baseline in Number of Natural Killer (NK) Cells
timeFrame: Baseline up to end of study (up to approximately 5 years and 5 months)
measure: Change from Baseline in Serum Immunoglobulin Level
timeFrame: Baseline up to end of study (up to approximately 5 years and 5 months)
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: UCSD Moores Cancer Center
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute (CBCI) at Presbyterian/ St. Luke's Medical Center
state: Colorado
city: New York
country: United States
facility: Weill Cornell Medical College-New York Presbyterian Hospital
state: New York
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Springfield
country: United States
facility: Oncology Associates of Oregon
state: Oregon
city: Nashville
country: United States
facility: SCRI-Tennessee Oncology
state: Tennessee
city: Houston
country: United States
facility: The Methodist Hospital Research Institute; Academic Office of Clinical Trials
state: Texas
city: Leeds
country: United Kingdom
facility: St James University Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary NHS Trust
city: London
country: United Kingdom
facility: Barts and The London School of Medicine and Dentistry; Queen Mary, University of London
Study officials:
affiliation: Genentech, Inc.
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Flinn IW, Gribben JG, Dyer MJS, Wierda W, Maris MB, Furman RR, Hillmen P, Rogers KA, Iyer SP, Quillet-Mary A, Ysebaert L, Walter HS, Verdugo M, Klein C, Huang H, Jiang Y, Lozanski G, Pignataro DS, Humphrey K, Mobasher M, Kipps TJ. Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Blood. 2019 Jun 27;133(26):2765-2775. doi: 10.1182/blood-2019-01-896290. Epub 2019 Mar 12.
citation: Samineni D, Gibiansky L, Wang B, Vadhavkar S, Rajwanshi R, Tandon M, Sinha A, Al-Sawaf O, Fischer K, Hallek M, Salem AH, Li C, Miles D. Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial. Adv Ther. 2022 Aug;39(8):3635-3653. doi: 10.1007/s12325-022-02170-w. Epub 2022 Jun 16.