Overview

This trial is active, not recruiting.

Condition lymphocytic leukemia, chronic
Treatments chlorambucil, venetoclax, obinutuzumab
Phase phase 3
Targets BCL-2, CD20
Sponsor Hoffmann-La Roche
Collaborator AbbVie
Start date December 2014
End date November 2018
Trial size 445 participants
Trial identifier NCT02242942, 2014-001810-24, BO25323, CLL14

Summary

This open-label, multicenter, randomized Phase III study is designed to compare the efficacy and safety of a combined regimen of obinutuzumab and venetoclax versus obinutuzumab + chlorambucil in participants with chronic lymphocytic leukemia (CLL) and coexisting medical conditions. The anticipated time on study treatment will be approximately one year and the follow-up period will be up to 5 years.

United States No locations recruiting
Other countries No locations recruiting

Study Design

Allocation randomized
Intervention model parallel assignment
Primary purpose treatment
Masking no masking
Arm
(Experimental)
Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days.
chlorambucil
Chlorambucil 0.5 milligrams per kilogram (mg/kg) orally at Day 1 and Day 15 at of each 28 day cycle for 12 cycles.
obinutuzumab GA-101; Gazyva
Obinutuzumab, IV infusion: 100 mg or 1000 mg, depending on splitting rules, at Cycle 1, Day 1 (if 100 mg was received on Day 1, 900 mg will be administered on Cycle 1, Day 2); 1000 mg at Cycle 1, Day 8 and Day 15; 1000 mg at Day 1 for all subsequent cycles until the end of Cycle 6
(Experimental)
Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.
venetoclax ABT-0199, GDC-0199
Venetoclax, oral tablet: 20 mg daily during Cycle 1, Day 22-28; 50 mg daily during Cycle 2, Day 1-7; 100 mg daily during Cycle 2, Day 8-14; 200 mg daily during Cycle 2, Day 15-21; 400 mg daily during Cycle 2, Day 22-28 and on Day 1-28 for all subsequent cycles until the end of Cycle 12.
obinutuzumab GA-101; Gazyva
Obinutuzumab, IV infusion: 100 mg or 1000 mg, depending on splitting rules, at Cycle 1, Day 1 (if 100 mg was received on Day 1, 900 mg will be administered on Cycle 1, Day 2); 1000 mg at Cycle 1, Day 8 and Day 15; 1000 mg at Day 1 for all subsequent cycles until the end of Cycle 6

Primary Outcomes

Measure
Progression-Free Survival (PFS) Based on Investigator Assessment (Using IWCLL Criteria), Defined as the Time From Randomization to the First Occurrence of Progression, Relapse or Death From Any Cause
time frame: Baseline until disease progression or death (up to approximately 7 years)

Secondary Outcomes

Measure
PFS Based on Institutional Review Committee (IRC)-Assessments, Defined as the Time From Randomization to the First Occurrence of Progression or Relapse or Death From any Cause
time frame: Baseline until disease progression or death (up to approximately 7 years)
Percentage of Participants with an Overall Response of Complete Response (CR), CR with Incomplete Bone marrow Recovery (CRi), or Partial Response (PR), as Determined by the Investigator at Completion of Treatment According to IWCLL Criteria
time frame: Baseline up to within 3 months of last day of treatment, approximately 1 year
Percentage of Participants With Minimal Residual Disease (MRD) Negativity as Measured by Allele-Specific Oligonucleotide Polymerase Chain Reaction (ASO-PCR) at Completion of Treatment
time frame: Baseline up to within 3 months of last day of treatment, approximately 1 year
Percentage of Participants With OR at Completion of Combination Treatment Response Assessment
time frame: Day 1 Cycle 7 or 28 days after last IV infusion, approximately 6 months
Percentage of Participants With MRD Negativity, as Measured by ASO-PCR at Completion of Combination Treatment Response Assessment
time frame: Day 1 Cycle 9 or 3 months after last IV infusion, approximately 9 months
Overall Survival
time frame: Baseline until death (up to approximately 7 years)
Duration of Objective Response
time frame: Time from the first occurrence of a documented objective response to the time of progressive disease as determined by the investigator or death from any cause, up to approximately 7 years
Percentage of Participants By Best Response Achieved (CR, CRi, PR, Stable Disease, or Progressive Disease)
time frame: Baseline up to within 3 months of last day of treatment, approximately 1 year
Event-Free Survival
time frame: Time between date of randomization and the date of disease progression/relapse on the basis of investigator-assessment, death, or start of a new anti-leukemic therapy, up to 7 years
Time to Next Anti-Leukemic Treatment
time frame: Time between the date of randomization and the date of first intake of new anti-leukemic therapy, up to 7 years
Percentage of Participants With Adverse Events Assessed According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0
time frame: 28 days after the last dose of venetoclax or after 90 days after last dose (up to 13 months)
Percentage of Participants With Human-Anti-Human Antibodies
time frame: Baseline up to approximately 7 years
Percentage of Participants With Adverse Events of Special Interest
time frame: Baseline up to approximately 7 years
Apparent Clearance of Obinutuzumab
time frame: Pre-obinutuzumab infusion (0 hour) and end of obinutuzumab infusion (duration of infusion: 25 - 400 milligrams per hour [mg/hr]) on Day 1 Cycle 4
Apparent Clearance of Venetoclax
time frame: Pre-venetoclax dose (0 hour) and 4 hours post- venetoclax dose on Day 1 Cycle 4
Apparent Volume of Distribution of Obinutuzumab
time frame: Pre-obinutuzumab infusion (0 hour) and end of obinutuzumab infusion (duration of infusion: 25 - 400 mg/hr) on Day 1 Cycle 4
Apparent Volume of Distribution of Venetoclax
time frame: Pre-venetoclax dose (0 hour) and 4 hours post- venetoclax dose on Day 1 Cycle 4
Number of CD19 + CD5+ Cells
time frame: Baseline up to 7 years
Number of CD19 + CD5- Cells
time frame: Baseline up to 7 years
Change From Baseline in M.D. Anderson Symptom Inventory (MDASI) score
time frame: Baseline up to 28 days after last dose, approximately 1 year
Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC30)
time frame: Baseline up to 28 days after last dose, approximately 1 year
Change From Baseline in EuroQol 5 Dimension Questionnaire (EQ-5D-3L)
time frame: Baseline up to 28 days after last dose, approximately 1 year

Eligibility Criteria

All participants at least 18 years old.

Inclusion Criteria

  • Documented previously untreated CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria
  • CLL requiring treatment according to IWCLL criteria
  • Total Cumulative Illness Rating Scale (CIRS score) greater than (>) 6
  • Adequate marrow function independent of growth factor or transfusion support within 2 weeks of screening as per protocol, unless cytopenia is due to marrow involvement of CLL
  • Adequate liver function
  • Life expectancy > 6 months
  • Agreement to use highly effective contraceptive methods per protocol

Exclusion Criteria

  • Transformation of CLL to aggressive Non-Hodgkin's lymphoma (Richter's transformation or pro-lymphocytic leukemia)
  • Known central nervous system involvement
  • Participants with a history of confirmed progressive multifocal leukoencephalopathy (PML)
  • An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system
  • Participants with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
  • Inadequate renal function
  • History of prior malignancy, except for conditions as listed in the protocol if patients have recovered from the acute side effects incurred as a result of previous therapy
  • Use of investigational agents or concurrent anti-cancer treatment within the last 4 weeks of registration
  • Participants with active bacterial, viral, or fungal infection requiring systemic treatment within the last two months prior to registration
  • History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
  • Hypersensitivity to chlorambucil, obinutuzumab, or venetoclax or to any of the excipients
  • Pregnant women and nursing mothers
  • Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B surface antigen [HBsAg] serology) or positive test result for hepatitis C (hepatitis C virus [HCV] antibody serology testing)
  • Participants with known infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus-1 (HTLV-1)
  • Requires the use of warfarin, marcumar, or phenprocoumon
  • Received agents known to be strong and moderate Cytochrome P450 3A inhibitors or inducers within 7 days prior to the first dose of study drug

Additional Information

Official title A Prospective, Open-Label, Multicenter Randomized Phase III Trial to Compare The Efficacy and Safety of A Combined Regimen of Obinutuzumab and Venetoclax (GDC-0199/ABT-199) Versus Obinutuzumab and Chlorambucil in Previously Untreated Patients With CLL and Coexisting Medical Conditions
Trial information was received from ClinicalTrials.gov and was last updated in February 2017.
Information provided to ClinicalTrials.gov by Hoffmann-La Roche.