This phase II trial studies how well ibrutinib works in treating patients with follicular lymphoma that has come back after a period of improvement or does not respond to treatment. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. Evaluate the overall response rate of ibrutinib in patients with relapsed or refractory follicular lymphoma.

SECONDARY OBJECTIVES:

I. Assess the safety and tolerability of ibrutinib in patients with follicular lymphoma.

II. Evaluate overall survival, time to response, duration of response, progression-free survival, time to treatment failure, and time to subsequent treatment.

TERTIARY OBJECTIVES:

I. Describe the relationship between interim positron emission tomography (PET)/computed tomography (CT) scan results, CT response, and response duration.

II. Biomarker studies including exploring associations between ibrutinib response and somatic mutations identified in follicular lymphoma, whole transcriptome shotgun sequencing (ribonucleic acid-sequencing [RNA-seq]), exploration of inhibition of Bruton's tyrosine kinase (BTK) and other kinases, expression of cytokines, chemokines, and other proteins with an aim to develop predictors of response and resistance.

III. Assess changes in various cancer-derived molecules in the blood over the course of treatment with ibrutinib.

IV. As part of ongoing research for Phase II Consortium (P2C) studies, we are banking paraffin-embedded tissue blocks/slides and blood products for future studies.

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease at the end of course 2 may continue on therapy until the end of course 5 at the discretion of the treating physician.

After completion of study treatment, patients are followed up every 3 months until progressive disease, and then every 6 months for 5 years.

Inclusion Criteria:

• Histologically confirmed diagnosis of follicular lymphoma, grade 1, 2, or 3a

  • Note: Fresh (frozen) tumor biopsy must be available or attempted; a frozen tumor biopsy equivalent to a minimum of four at least 16 gauge needle cores is an important component of this study; patients without adequate frozen material should have a biopsy performed to obtain material; if biopsy is performed and does not yield adequate material, the patient is still eligible for the study; if a biopsy cannot be done safely, the patient may still be eligible for the study if permission is granted in writing (email) by the study chair (Dr. Nancy Bartlett) or her designees; Dr. Bartlett may be consulted to discuss situations involving invasive biopsy procedures that may pose an increased risk to the patient

• Measurable disease as defined by a lymph node or tumor mass that is >= 1.5 cm in at least one dimension by CT or the CT portion of the PET/CT

• Relapsed or refractory follicular lymphoma which has progressed during or following 1 or more prior chemotherapy regimens for lymphoma

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

• Absolute neutrophil count >= 750/mm^3 (0.75 x 10^9/L)

• Hemoglobin >= 8.0 g/dL

• Platelets >= 30,000/mm^3 (30 x 10^9/L)

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) unless Gilbert's syndrome or disease infiltration of the liver is present

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.0 x institutional ULN

• Creatinine =< 2.0 x institutional ULN

• Creatinine clearance (estimated [est.] glomerular filtration rate [GFR] Cockcroft-Gault) >= 30 mL/min

• Negative serum pregnancy test done =< 7 days prior to registration for women of childbearing potential only

• Ability to understand and the willingness to sign a written informed consent document

• Willingness to provide biologic samples for correlative research purposes

Exclusion Criteria:

• Any of the following:

  • Chemotherapy/systemic therapy =< 4 weeks prior to registration
  • Radiotherapy =< 4 weeks prior to registration
  • Nitrosoureas or mitomycin C =< 6 weeks prior to registration
  • Those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Major surgery =< 10 days prior to registration or minor surgery =< 7 days prior to registration
  • Prior therapy with ibrutinib or another Bruton's tyrosine kinase inhibitor
  • Receiving any other investigational agents

• Active central nervous system (CNS) involvement

• Receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450 family 3 subfamily A member 4/5 (CYP3A4/5)

• Any of the following:

  • Pregnant women

  • Nursing women

  • Men or women of childbearing potential who are unwilling to employ adequate contraception

    • Note: Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of ibrutinib administration
    • Note: Breastfeeding should be discontinued if the mother is treated with ibrutinib

• Human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy are ineligible; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated

  • Note: HIV-positive patients who are not on anti-viral medications that are strong CYP3A4/5 inhibitors and who do not have cluster of differentiation (CD)4 counts less than the lower limit of normal by institutional criteria are eligible; no patients with CD4 counts below institutional normals are eligible

• Known active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)

• Known histological transformation from follicular lymphoma to diffuse large B-cell lymphoma

  • Note: A prior history of adequately treated transformed lymphoma does not exclude a patient if the current active disease is biopsy-proven follicular lymphoma

• History of stroke or intracranial hemorrhage =< 6 months prior to the first dose of study drug

• Requires anticoagulation with warfarin or similar vitamin K antagonist

  • Note: Warfarin or similar vitamin K antagonist must have been discontinued at least 28 days prior to study entry

• Patient has the inability to swallow tablets

• Uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection,
  • Uncontrolled diabetes mellitus
  • Cardiac disease
  • Psychiatric illness/social situations that would limit compliance with study requirements

• "Currently active" second malignancy, other than non-melanoma skin cancers

  • Note: Patients are not considered to have a "currently active" malignancy if they have completed anti-cancer therapy, and are considered by their physician to be at less than 30% risk of relapse

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib

• Concurrent treatment with therapeutic doses (> 20 mg prednisone or equivalent) of systemic steroids within 14 days of start of protocol therapy

• Prior history of allogeneic stem cell transplant