Rituximab, Lenalidomide, and Ibrutinib in Treating Patients With Previously Untreated Stage II-IV Follicular Lymphoma

PRIMARY OBJECTIVES:

I. To determine the recommended phase II doses of ibrutinib and lenalidomide for combination
with rituximab in previously untreated follicular lymphoma.

SECONDARY OBJECTIVES:

I. To determine pharmacokinetics of ibrutinib and its major metabolite (PCI-45227) when
combined with lenalidomide and rituximab.

II. To determine the pharmacodynamics of basophil activation and Bruton tyrosine kinase (BTK)
occupancy in peripheral blood mononuclear cells (PBMCs) over a 24-hour period of ibrutinib
when given in combination with lenalidomide and rituximab.

OUTLINE: This is a dose-escalation study of lenalidomide and ibrutinib.

Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21 and ibrutinib PO QD on
days 1-28. Treatment repeats every 28 days for up to 18 courses in the absence of disease
progression or unacceptable toxicity. Patients also receive rituximab intravenously (IV) on
days 1, 8, 15, and 22 of course 1 and once weekly at weeks 13, 21, 29, and 37.

After completion of study treatment, patients are followed up every 4 months for 2 years and
then every 6 months for 8 years or every 6 months or annually for 10 years.

Inclusion Criteria:

- Previously untreated, histologically confirmed follicular lymphoma, World Health
Organization (WHO) classification grade I, II, or IIIa (> 15 centroblasts per high
power field with centrocytes present) that is stage III, IV, or bulky (i.e., single
mass >= 7 cm in any unidimensional measurement) stage II and requires therapy at the
discretion of the primary physician

- Bone marrow biopsies as the sole means of diagnosis are not acceptable, but they
may be submitted in conjunction with nodal biopsies; fine needle aspirates are
not acceptable for diagnosis

- Failure to submit pathology specimens within 60 days of patient registration will
be considered a major protocol violation

- Institutional flow cytometry or immunohistochemistry must confirm cluster of
differentiation 20 (CD20) antigen expression

- All risk by follicular lymphoma international prognostic index (FLIPI): 0-5 risk
factors

- No prior systemic therapy for non-Hodgkin lymphoma (NHL) including chemotherapy or
immunotherapy (e.g., monoclonal antibody-based therapy), radiation therapy, or
radioimmunotherapy

- For non-NHL conditions, no chemotherapy, radiotherapy, or major surgery within 4 weeks
(6 weeks for nitrosoureas or mitomycin C) of enrollment; no patients who have ongoing
adverse events from agents administered more than 4 weeks previously

- No prior exposure to any of the study agents

- No corticosteroids within two weeks prior to study entry, except for maintenance
therapy for a non-malignant disease; dose of corticosteroid or prednisone (or its
equivalent) should not exceed 20 mg per day; corticosteroid premedication for
rituximab is allowed

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

- Measurable disease must be present either on physical examination or imaging studies;
non-measurable disease alone is not acceptable; any tumor mass > 1 cm is acceptable;
lesions that are considered non-measurable include the following:

- Bone lesions (lesions if present should be noted)

- Ascites

- Pleural/pericardial effusion

- Lymphangitis cutis/pulmonis

- Bone marrow (involvement by NHL should be noted)

- Patients with human immunodeficiency virus (HIV) infection are eligible, provided they
meet the following:

- No evidence of coinfection with hepatitis B or C

- CD4+ cell count >= 400/mm^3

- No evidence of resistant strains of HIV

- If not on anti-HIV therapy, HIV viral load < 10,000 copies HIV ribonucleic acid
(RNA)/mL

- If on anti-HIV therapy, HIV viral load < 50 copies HIV RNA/mL

- No history of acquired immunodeficiency syndrome (AIDS)-defining conditions

- No use of strong cytochrome P450, family 3, subfamily A, polypeptide 4/5
(CYP3A4/5) inhibitors or inducers

- No known central nervous system (CNS) involvement by lymphoma

- No treatment with strong inhibitors or inducers of CYP3A4/5

- No evidence of active hepatitis B or C infections (i.e., no positive serology for
anti-hepatitis B virus [HBV] or anti-hepatitis C virus [HCV] antibodies); HBV
seropositive patients (hepatitis B surface antigen [HBsAg] +) are eligible if they are
closely monitored for evidence of active HBV infection by HBV deoxyribonucleic acid
(DNA) testing and receive suppressive therapy with lamivudine or other HBV suppressive
therapy until 6 months after the last rituximab dose

- No history of erythema multiforme, toxic epidermal necrolysis or Stevens-Johnson
syndrome

- No history of uncontrolled seizures

- No autoimmune disorder that requires active immunosuppression

- No intracranial hemorrhage within the last 6 months

- Non-pregnant and non-nursing; females of childbearing potential (FCBP) must have a
negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within
10-14 days and again within 24 hours prior to starting cycle 1 of lenalidomide;
further, they must either commit to continued abstinence from heterosexual intercourse
or begin TWO acceptable methods of birth control: one highly effective method and one
additional effective method AT THE SAME TIME, at least 28 days before starting
lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use
a latex condom during sexual contact with a FCBP, even if they have had a successful
vasectomy; a FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy
or bilateral oophorectomy, or 2) has not been naturally postmenopausal for at least 24
consecutive months (i.e., has had menses at any time preceding 24 consecutive months)

- No known human anti-chimeric antibody (HACA) positivity

- No anticoagulation with warfarin is allowed; patients must not have received warfarin
within 28 days prior to registration; alternative anticoagulant may be used

- Patients must not be receiving concurrent treatment with other investigational drugs

- Patients must not have a history of allergic reactions attributed to compounds of
similar chemical or biologic composition to lenalidomide, ibrutinib, or other agents
used in study

- Patients must not have presence of transfusion-dependent thrombocytopenia

- No currently active clinically significant cardiovascular disease including the
following:

- No uncontrolled arrhythmia

- No congestive heart failure

- No class 3 or 4 cardiac disease as defined by the New York Heart Association
Functional Classification

- No history of myocardial infarction, deep venous or arterial thrombosis within 6
months prior to registration

- No prior malignancy with the exceptions listed below:

- Malignancy treated with curative intent and with no evidence of active disease
for more than 3 years prior to screening and felt to be at low risk for
recurrence by the treating physician

- Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma
without current evidence of disease

- Adequately treated cervical carcinoma in situ without current evidence of disease

- Absolute neutrophil count (ANC) >= 1,000/microliter

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
limit of normal (ULN)

- Total bilirubin =< 1.5 x ULN unless attributable to NHL; unless attributable to
Gilbert's syndrome

- Creatinine clearance > 60 mL/min (patients on dialysis are not eligible); to be
calculated by method of Cockcroft-Gault, using actual weight

- Creatinine =< 2 x ULN

- Platelet count >= 75,000/microliter