A Randomized, Multi-center, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib in Combination With Obinutuzumab Versus Chlorambucil in Combination With Obinutuzumab in Subjects With Treatment-naïve Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Overview
- Phase
- Phase 3
- Intervention
- Ibrutinib
- Conditions
- Chronic Lymphocytic Leukemia
- Sponsor
- Pharmacyclics LLC.
- Enrollment
- 229
- Locations
- 71
- Primary Endpoint
- Primary Analysis: Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 30
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
The primary objective of this study is to evaluate the efficacy of ibrutinib in combination with obinutuzumab compared to chlorambucil in combination with obinutuzumab based on the Independent Review Committee (IRC) assessment of progression free survival (PFS). Efficacy will be evaluated according to 2008 International Workshop for Chronic Lymphocytic Leukemia (IWCLL) criteria with the modification for treatment-related lymphocytosis, in subjects with treatment-naive CLL or SLL.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Disease Related:
- •Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria.
- •Age 65 yrs and older OR if less than 65 years, must have at least one of the following criteria:
- •Cumulative Illness Rating Score (CIRS) \>6
- •Creatinine clearance estimated \<70 mL/min using Cockcroft-Gault equation.
- •Del 17p by fluorescence in situ hybridization (FISH) or TP53 mutation by polymerase chain reaction (PCR) or Next Generation Sequencing
- •Active disease meeting at least 1 of the following IWCLL criteria for requiring treatment:
- •Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and thrombocytopenia
- •Massive, progressive, or symptomatic splenomegaly
- •Massive nodes (at least 10 cm longest diameter), or progressive or symptomatic lymphadenopathy.
Exclusion Criteria
- •Any prior treatment of CLL or SLL
- •Evidence of central nervous system (CNS) involvement with primary disease of CLL/SLL
- •History of other malignancies, except:
- •Malignancy treated with curative intent and with no known active disease present for ≥3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician.
- •Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura
- •Known or suspected history of Richter's transformation.
- •Concurrent administration of \>20mg/day of prednisone within 7 days of randomization unless indicated for prophylaxis or management of allergic reactions (eg, contrast)
- •Known hypersensitivity to one or more study drugs
- •Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
- •Any uncontrolled active systemic infection or an infection requiring systemic treatment that was completed ≤ 7 days before randomization.
Arms & Interventions
IBR + OB
Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.
Intervention: Ibrutinib
IBR + OB
Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.
Intervention: Obinutuzumab
CLB + OB
Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Intervention: Obinutuzumab
CLB + OB
Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
Intervention: Chlorambucil
Outcomes
Primary Outcomes
Primary Analysis: Progression Free Survival (PFS) Based on Independent Review Committee (IRC) Assessment - Kaplan Meier Landmark Estimates at Month 30
Time Frame: Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).
PFS was defined as time from the date randomization to the date of first IRC-confirmed disease progression (PD) or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. The primary analysis was performed after observing 94 PFS events as pre-specified in the study protocol. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 30 months (that is, the estimated percentage of participants with progression-free survival at Month 30) are presented.
Final Analysis: PFS Based on Investigator Assessment - Kaplan Meier Landmark Estimates at Month 48
Time Frame: Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).
PFS was defined as time from the date randomization to the date of first investigator-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 48 months (that is, the estimated percentage of participants with progression-free survival at Month 48) are presented.
Secondary Outcomes
- Primary Analysis: PFS in High-Risk Sub-Population (del17p/TP53 Mutation/Del 11q) Based on IRC Assessment - Kaplan Meier Landmark Estimates at Month 30(Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).)
- Primary Analysis: Rate of Sustained Hemoglobin Improvement(Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).)
- Primary Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response(Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).)
- Primary Analysis: Overall Response Rate (ORR) Based on IRC Assessment(Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).)
- Primary Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 30(Month 30 (Median follow-up time was 31.3 months at the time of the primary analysis [data cutoff date: 26 March 2018]).)
- Primary Analysis: Rate of Grade ≥ 3 or Serious Infusion-Related Reaction (IRR) Adverse Events(Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).)
- Primary Analysis: Rate of Sustained Platelet Improvement(Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).)
- Primary Analysis: Rate of Clinically Meaningful Improvement in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EuroQol Five-Dimension (EQ-5D-5L)(Median follow-up time was 31.3 months at the time of the primary analysis (data cutoff date: 26 March 2018).)
- Final Analysis: PFS in High-Risk Population (del17p/TP53 Mutation/Del 11q/Unmutated Immunoglobulin Heavy Chain Variable Region [IGHV]) Based on Investigator Assessment - Kaplan Meier Landmark Estimates at Month 48(Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).)
- Final Analysis: Rate of Sustained Hemoglobin Improvement(Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).)
- Final Analysis: Rate of Minimal Residual Disease (MRD)-Negative Response(Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).)
- Final Analysis: ORR Based on Investigator Assessment(Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).)
- Final Analysis: Overall Survival (OS) - Kaplan Meier Landmark Estimates at Month 48(Month 48 (Median follow-up time was 44.6 months at the time of the final analysis [data cutoff date: 17 October 2019]).)
- Final Analysis: Rate of Sustained Platelet Improvement(Median follow-up time was 44.6 months at the time of the final analysis (data cutoff date: 17 October 2019).)