This phase II trial studies how well ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab work in treating patients with chronic lymphocytic leukemia. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab together may work better in treating chronic lymphocytic leukemia.
PRIMARY OBJECTIVE: I. Estimate therapeutic activity (achievement of complete remission \[CR\] or CR with incomplete marrow recovery \[CRi\] and bone marrow minimal residual disease \[MRD\] negativity after 3 courses) of first-line treatment with ibrutinib, fludarabine (fludarabine phosphate), cyclophosphamide, obinutuzumab (GA101) (iFCG) in patients with chronic lymphocytic leukemia (CLL) who have mutated immunoglobulin heavy chain variable region (IGHV) and non-del(chromosome 7, p arm \[17p\]) fluorescence in-situ hybridization (FISH). SECONDARY OBJECTIVES: I. Estimate the rate of conversion of bone marrow MRD-positive after 3 courses of iFCG to bone marrow MRD-negative with 9 additional courses of ibrutinib and obinutuzumab (iG). II. Determine the safety of this combination in the proposed patient population. III. Determine the progression-free survival (PFS). IV. Determine the overall survival (OS). V. Determine the long-term incidence of secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), and Richter's transformation. VI. Perform ribonucleic acid (RNA) profiling to identify molecules responsible for response and/or relapse. VII. Investigate impact on breakpoint cluster region (BCR) pathway and deoxyribonucleic acid (DNA) damage response pathway proteins during therapy. OUTLINE: INDUCTION CYCLE 1: Patients receive obinutuzumab intravenously (IV) over 4-6 hours on days 1, 2, 8 and 15, fludarabine phosphate IV over 15 minutes and cyclophosphamide IV over 30 minutes on days 2-4. Patients also receive ibrutinib orally (PO) once daily (QD) on days 1-28. INDUCTION CYCLES 2 and 3: Patients receive obinutuzumab IV over 4-6 hours on day 1, fludarabine phosphate IV over 15 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Patients also receive ibrutinib PO QD on days 1-28. MAINTENANCE: Patients receive 1 of 5 maintenance regimens as determined by disease status. REGIMEN I CYCLES 4 and 6: Patients achieving CR/CRi and bone marrow MRD-negative receive maintenance therapy comprising obinutuzumab IV over 4-6 hours on day 1, and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. REGIMEN I CYCLES 7 and 12: Patients remaining bone marrow MRD-negative receive maintenance therapy comprising ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. REGIMEN I CYCLES 7 and 12: Patients converting bone marrow MRD-positive receive maintenance therapy comprising obinutuzumab IV over 4-6 hours on day 1, and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. REGIMEN II CYCLES 4 and 12: Patients achieving less than CR/CRi and/or bone marrow MRD-positive receive maintenance therapy comprising obinutuzumab IV over 4-6 hours on day 1, and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. REGIMEN II AFTER 12 CYCLES: Patients still bone marrow MRD-positive receive maintenance therapy comprising ibrutinib PO QD on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
81
M D Anderson Cancer Center
Houston, Texas, United States
Efficacy of the combination of ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab defined as achievement of complete remission/complete remission with incomplete marrow recovery and bone marrow minimal residual disease-negative status
Simon's optimal two-stage design will be employed. The proportion of patients achieving complete remission/complete remission with incomplete marrow recovery and bone marrow minimal residual disease-negative will be estimated along with the 95% confidence interval.
Time frame: After 84 days (3 cycles) of ibrutinib, fludarabine phosphate, cyclophosphamide, obinutuzumab
Bone marrow minimal residual disease-negative status
Will estimate the proportion of patients achieving bone marrow minimal residual disease negative, along with the 95% confidence interval. For the patients who did not achieve primary endpoint after 3 courses of ibrutinib, fludarabine phosphate, cyclophosphamide, obinutuzumab, will estimate the rate of conversion to bone marrow minimal residual disease-negative with an additional 9 courses of ibrutinib and obinutuzumab treatment, along with the 95% confidence interval.
Time frame: After 3 cycles of ibrutinib, fludarabine phosphate, cyclophosphamide, obinutuzumab
Incidence of treatment emergent toxicities using a Bayesian design by Thall, Simon and Estey assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03
Toxicities are defined as (prolonged grade \>= 3 neutropenia or thrombocytopenia) at least possibly related to the study drugs lasting \> 42 days from the prior chemotherapy course; febrile neutropenia; hospitalization due to infection; early death (within first 30 days of starting treatment). Safety data will be summarized using frequency and percentage, by organ type, grade and attribution.
Time frame: From the prior chemotherapy cycle to up to 84 days
Progression-free survival
The Kaplan-Meier method will be used to estimate the probabilities of progression-free survival and log-rank tests will be used to compare subgroups of patients in terms of progression-free survival.
Time frame: Up to 6 years
Overall survival
The Kaplan-Meier method will be used to estimate the probabilities of overall survival and log-rank tests will be used to compare subgroups of patients in terms of overall survival.
Time frame: Up to 6 years
Long-term incidence rate of secondary myelodysplastic syndrome/acute myeloid leukemia
Long-term incidence rate of secondary myelodysplastic syndrome/acute myeloid leukemia will be estimated along with 95% confidence interval.
Time frame: Up to 6 years
Long-term incidence rate of Richter's transformation
Long-term incidence rate of Richter's transformation will be estimated along with 95% confidence interval.
Time frame: Up to 6 years
Rate of complete remission (CR)/CR with incomplete marrow recovery (CRi) in subgroups of patients defined by fluorescence in situ hybridization (FISH) subtypes
Will also assess if the combination therapy results in improvement in the rate of CR/CRi in subgroups of patients defined by FISH subtypes.
Time frame: Up to 6 years
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