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.
