Ibrutinib, Fludarabine Phosphate, Cyclophosphamide, and Obinutuzumab in Treating Patients With Chronic Lymphocytic Leukemia

PRIMARY OBJECTIVES:

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 COURSE 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 COURSES 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 COURSES 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 courses in the absence of disease
progression or unacceptable toxicity.

REGIMEN I COURSES 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
courses in the absence of disease progression or unacceptable toxicity.

REGIMEN I COURSES 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 courses in the absence of disease progression or
unacceptable toxicity.

REGIMEN II COURSES 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 courses in the
absence of disease progression or unacceptable toxicity.

REGIMEN II AFTER 12 COURSES: 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.

Inclusion Criteria:

- Patients with a diagnosis of CLL/small lymphocytic lymphoma (SLL), with mutated (> 2%
deviation from germ line) IGHV gene, who meet criteria to initiate first-line
treatment per International Workshop on CLL Working Group (IWCLL) 2008 guidelines

- Patients must not have received prior CLL-directed therapy

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Absolute neutrophil count > 500 mL

- Platelet count > 50,000/mL

- Serum total bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN for patients
with Gilbert's disease

- Estimated creatinine clearance >= 30 mL/min (calculated or measured by 24 hour urine
collection)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN

- Women of childbearing potential must have a negative serum or urine beta human
chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the
first dose of study drugs and must agree to use an effective contraception method
during the study and for 30 days following the last dose of study drug; women of
non-childbearing potential are those who are postmenopausal greater than 1 year or who
have had a bilateral tubal ligation or hysterectomy; men who have partners of
childbearing potential must agree to use an effective contraceptive method during the
study and for 30 days following the last dose of study drug

- Free of prior malignancies for 3 years with exception of patients diagnosed with basal
cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or
breast, who are eligible even if they are currently treated or have been treated
and/or diagnosed in the past 2 years prior to study enrolment; if patients have
another malignancy that was treated within the last 2 years, such patients can be
enrolled, after consultation with the principal investigator, if the likelihood of
requiring systemic therapy for this other malignancy within 2 years is less than 10%,
as determined by an expert in that particular malignancy at MD Anderson Cancer Center

- Patients or their legally authorized representative must provide written informed
consent

- Prothrombin time (PT)/international normalization ratio (INR) < 1.5 x ULN

- Partial thromboplastin time (PTT) < 1.5 x ULN

- Activated partial thromboplastin time (aPTT) < 1.5 x ULN

Exclusion Criteria:

- Major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy,
experimental therapy within 3 weeks prior to the first dose of the study drugs and/or
monoclonal antibody =< 6 weeks prior to first administration of study treatment

- Patients with del(17p) by FISH (or known tumor protein p53 [TP53] mutation)

- Patients with unmutated (=< 2% homology with germ line) IGHV

- Uncontrolled active systemic infection (viral, bacterial, and fungal)

- Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, QT
prolongation or familial history of QT prolongation, congestive heart failure, or
myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac
disease as defined by the New York Heart Association Functional Classification

- History of stroke or cerebral hemorrhage within 6 months

- Patient is pregnant or breast-feeding

- Current or chronic hepatitis B or C infection, or known seropositivity for human
immunodeficiency virus (HIV); subjects who are positive for hepatitis B or C core
antibody or hepatitis B or C surface antigen must have a negative polymerase chain
reaction (PCR) result before enrollment; those who are PCR positive will be excluded;
Note: Patients who are receiving intravenous immunoglobulins may become seropositive
for hepatitis B antibodies; these patients are allowed on the study without additional
testing

- Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune
thrombocytopenia) requiring steroid therapy

- Concurrent use of investigational therapeutic agent

- Patients may not receive other concurrent chemotherapy, radiotherapy, or
immunotherapy; localized radiotherapy to an area not compromising bone marrow function
does not apply

- Malabsorption syndrome or other condition that precludes enteral route of
administration

- Concomitant use of warfarin or other vitamin K antagonists

- Requires treatment with a strong cytochrome P450 (CYP), family 3, subfamily A (3A)
inhibitor

- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that in the opinion of the investigator may increase the risk associated
with study participation or investigational product administration or may interfere
with the interpretation of study results and/or would make the patient inappropriate
for enrollment into this study

- Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia