NCT02242942CompletedPhase 3
A Prospective, Open-Label, Multicenter Randomized Phase III Trial to Compare The Efficacy and Safety of A Combined Regimen of Obinutuzumab and Venetoclax Versus Obinutuzumab and Chlorambucil in Previously Untreated Patients With CLL and Coexisting Medical Conditions
Hoffmann-La Roche122 sites in 14 countries445 target enrollmentStarted: December 31, 2014Last updated:
Conditions
Interventions
Drugs
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 445
- Locations
- 122
- Primary Endpoint
- Progression Free Survival (PFS) Based on Investigator Assessment According to IWCLL Criteria
Study Overview
Brief 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 time on study treatment was approximately one year and the follow-up period will be up to 9 years.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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 participants 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
Arms & Interventions
Obinutuzumab + Chlorambucil
Experimental
Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days.
Intervention: Chlorambucil (Drug)
Safety Run-in Obinutuzumab + Venetoclax
Experimental
Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.
Intervention: Venetoclax (Drug)
Safety Run-in Obinutuzumab + Venetoclax
Experimental
Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.
Intervention: Obinutuzumab (Drug)
Obinutuzumab + Chlorambucil
Experimental
Participants will receive obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles will comprise 28 days.
Intervention: Obinutuzumab (Drug)
Obinutuzumab + Venetoclax
Experimental
Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.
Intervention: Venetoclax (Drug)
Obinutuzumab + Venetoclax
Experimental
Participants will receive obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles will comprise 28 days.
Intervention: Obinutuzumab (Drug)
Outcomes
Primary Outcomes
Progression Free Survival (PFS) Based on Investigator Assessment According to IWCLL Criteria
Time Frame: Baseline until disease progression or death up to approximately 3.75 years
PFS was determined according to IWCLL 2008 criteria and defined as the time from randomization to the first occurrence of PD or death from any cause. Disease progression was characterized by at least one of the following: 1) \>/= 50% increase in the absolute number of circulating lymphocytes to at least 5\*10\^9/L, 2) Appearance of new palpable lymph nodes (\> 15 mm in longest diameter) or any new extra-nodal lesion; 3) \>/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) \>/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology.
Secondary Outcomes
- Progression Free Survival (PFS) Based on Institutional Review Committee (IRC)-Assessments According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria(Baseline until disease progression or death up to approximately 3.75 years)
- Percentage of Participants With an Overall Response (OR) at Completion of Treatment, as Determined by the Investigator According to IWCLL Criteria(At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months))
- Percentage of Participants With a Complete Response Rate (CRR) at the Completion of Treatment Assessment as Determined by the Investigator According to IWCLL Criteria(At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months))
- Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood as Measured by Allele-Specific Oligonucleotide Polymerase Chain Reaction (ASO-PCR) at Completion of Treatment(At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months))
- Percentage of Participants With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Treatment(At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months))
- Overall Survival (OS)(Baseline until death, up to approximately 10.75 years)
- Percentage of Participants With MRD Negativity in Peripheral Blood as Measured by ASO-PCR at Completion of Combination Treatment Assessment(Day 1 Cycle 9 or 3 months after last IV infusion, approximately 9 months)
- Percentage of Participants With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Combination Treatment Assessment(Day 1 Cycle 9 or 3 months after last IV infusion at approximately 9 months)
- Percentage of Participants With OR at Completion of Combination Treatment Response Assessment(Day 1 Cycle 7 or 28 days after last IV infusion, approximately 6 months)
- Duration of Objective Response (DOR)(Time from the first occurrence of a documented objective response to the time of PD as determined by the investigator or death from any cause, up to approximately 10.75 years)
- Percentage of Participants By Best Response Achieved (CR, CRi, PR, Stable Disease (SD), or PD)(Baseline up to the completion of treatment assessment 3 months after treatment completion (up to approximately 15 months))
- Event-Free Survival(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 10.75 years)
- Time to Next Anti-Leukemic Treatment(Time between the date of randomization and the date of first intake of new anti-leukemic therapy, up to 10.75 years)
- Number of Participants With Adverse Events (AEs)(Up to approximately 10.75 years)
- Percentage of Participants With CD19 + /CD5+ B Cells or CD14+ Monocytes(Baseline up to approximately 10.75 years)
- Percentage of Participants With Human-Anti-Human Antibodies(Baseline up to approximately 10.75 years)
- Percentage of Participants Recorded as Premature Study Withdrawals(Up to approximately 10.75 years)
- Plasma Concentrations of Venetoclax(Pre-venetoclax dose (0 hour) and 4 hours post- venetoclax dose on Day 1 Cycle 4)
- Serum Concentrations of Obinutuzumab(Pre-obinutuzumab infusion (0 hour) and end of obinutuzumab infusion on Day 1 Cycle 4)
- Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) Score(Baseline up to approximately 10.75 years)
- Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC30)(Baseline up to approximately 10.75 years)
- Change From Baseline in EuroQol 5 Dimension Questionnaire (EQ-5D-3L)(Baseline up to approximately 10.75 years)
Investigators
Study Sites (122)
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