Lenalidomide and Ibrutinib in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. To determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of the
combination of lenalidomide and ibrutinib in patients with relapsed and refractory B-cell
non-Hodgkin's lymphoma (NHL).

II. To define the qualitative and quantitative toxicities of the combination of lenalidomide
and ibrutinib.

SECONDARY OBJECTIVES:

I. To describe the overall objective response rate to the combination of lenalidomide and
ibrutinib in patients with relapsed or refractory B-cell NHL.

II. To describe the response duration and two-year progression free survival (PFS) in
patients with B-cell NHL receiving lenalidomide and ibrutinib.

III. To characterize the pharmacokinetics of the combination of lenalidomide and ibrutinib in
patients with relapsed or refractory B-cell NHL.

IV. To identify associations of genetic polymorphisms in drug metabolizing enzymes,
transporters or target genes with pharmacokinetics, pharmacodynamics, and clinical outcomes.

V. To monitor the effects of combined therapy with ibrutinib and lenalidomide on B- T-, and
natural killer (NK)-cell subsets by flow cytometry and quantitative immunoglobulin levels.

VI. To explore the effects of the combination of ibrutinib and lenalidomide on
pharmacodynamic markers including T helper cell, type 1 (TH1) and T helper cell, type 2 (TH2)
cytokines, ex vivo NK cell cytotoxicity, serum micro ribonucleic acids (RNAs), plasma
metabolites, and levels of Bruton's tyrosine kinase occupancy and other selected kinases.

VII. To explore the relationship between pretreatment pathologic prognostic features and
overall objective response.

OUTLINE: This is a dose-escalation study.

Patients receive lenalidomide orally (PO) on days 1-21 and ibrutinib PO on days 1-28 (days
2-28 of course 1). Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks and then every 6
months thereafter.

Inclusion Criteria:

- Histologically confirmed B-cell non-Hodgkin's lymphoma (NHL) of any of the following
subtypes recognized by the World Health Organization (WHO) classification: diffuse
large B-cell lymphoma, mantle cell lymphoma, marginal zone lymphoma, lymphoplasmacytic
lymphoma, or follicular lymphoma; patients with evidence of histological
transformation to diffuse large B-cell lymphoma from indolent NHL are eligible

- Patients must have received at least one prior therapy; prior autologous stem cell
transplant is permitted; patients with diffuse large B-cell lymphoma who have not
received high-dose therapy (HDT)/autologous stem cell transplant (ASCT) must be
ineligible for HDT/ASCT; prior allogeneic stem cell transplant is not permitted; prior
ibrutinib is not permitted

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 12 weeks

- Patients must have normal organ and marrow function, independent of growth factor or
transfusion support; patients should not receive growth factors or transfusions for at
least 7 days prior to first dose of study drug, with the exception of pegylated G-CSF
(pegfilgrastim) and darbepoeitin which require at least 14 days prior to screening and
randomization

- Absolute neutrophil count >= 1,000/mcL in the absence of growth factor administration

- Platelets >= 50,000/mcL in the absence of transfusion support within 7 days prior to
determination of eligibility

- Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilberts disease

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal unless due to disease

- Creatinine =< 2.0 mg/dL OR creatinine clearance >= 50 mL/min as determined by the
Cockcroft-Gault equation or a 24 hour urine collection

- 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 prior to and again within 24 hours of 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 and for 28 days after the last dose of study drug; 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 female
who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or
bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea
following cancer therapy does not rule out childbearing potential) for at least 24
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive
months); all patients must be counseled by a trained counselor every 28 days about
pregnancy precautions and risks of fetal exposure

- Patients with human immunodeficiency virus (HIV) infection are eligible provided they
meet the following criteria: no evidence of co-infection with hepatitis B or C,
cluster of differentiation (CD)4 count >= 400 cells/mm^3, no resistant viral strains,
on highly active antiretroviral treatment (HAART) therapy with a viral load < 50 RNA
copies/ml, and no history of acquired immunodeficiency syndrome (AIDS)-defining
conditions

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

- Curative therapy must have been exhausted or not feasible to administer; patients with
diffuse large B-cell lymphoma, germinal center subtype should only enroll on the study
if there are no other potentially effective therapeutic options

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier;
steroids used for disease related symptoms should be stopped within 48 hours of
protocol therapy; patients who have had prior exposure to a Bruton's tyrosine kinase
(BTK) inhibitor; patients who received monoclonal antibody =< 6 weeks prior to first
administration of study treatment

- Patients who are receiving any other investigational agents

- Patients with active central nervous system (CNS) involvement with lymphoma should be
excluded from this clinical trial

- History of allergic reactions attributed to lenalidomide or compounds of similar
chemical or biologic composition to lenalidomide including thalidomide

- Patients receiving any medications or substances that are strong inhibitors or strong
inducers of cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5) are
ineligible

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, or psychiatric illness/social situations that would limit compliance with
study requirements; currently active clinically significant cardiovascular disease
such as uncontrolled arrhythmia, congestive heart failure or class 3 or 4 congestive
heart failure as defined by the New York Heart Association Functional Classification,
or history of myocardial infarction, unstable angina or acute coronary syndrome within
6 months prior to randomization

- Recent infections requiring systemic treatment need to have completed therapy > 14
days before the first dose of study drug

- Medications with a risk of causing Torsades de Pointes are not permitted; although
concomitant treatment with corrected QT (QTc) prolonging agents is not strictly
prohibited, these agents should be avoided whenever possible and an alternative
non-QTc prolonging drug should be substituted if possible

- Patients requiring any therapeutic anticoagulation are excluded; patients who have
received warfarin or other vitamin K antagonists within 28 days or are taking warfarin
or other vitamin K antagonists are not eligible

- Patients who are within 4 weeks of major surgery or within 2 weeks of minor surgery

- Concurrent systemic immunosuppressant therapy other than corticosteroids (e.g.
cyclosporine A, tacrolimus, etc) within 28 days of the first dose of study drug

- Vaccinated with live attenuated vaccines within 4 weeks of first dose of study drug

- Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved
to Common Terminology Criteria for Adverse Event (CTCAE, version 5), grade =< 1, or to
the levels dictated in the inclusion/exclusion criteria with the exception of alopecia

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

- Unwilling or unable to participate in all required study evaluations and procedures

- Currently active, clinically significant hepatic impairment (>= moderate hepatic
impairment according to the National Cancer Institute (NCI)/Child Pugh classification

- Patients requiring daily corticosteroids at a prednisone equivalent of >= 20 mg daily
should not be enrolled; if corticosteroids can be discontinued (or reduced to < 20 mg
per day of prednisone or equivalent), the discontinuation or dose reduction should be
done at least 7 days prior to first dose

- Unable to swallow capsules, or disease significantly affecting gastrointestinal
function, or resection of the stomach or small bowel, or symptomatic inflammatory
bowel disease or ulcerative colitis, or partial or complete bowel obstruction

- Serologic status reflecting active hepatitis B or C infection; patients that are
positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAG), or
hepatitis C antibody, must have a negative polymerase chain reaction (PCR) prior to
enrollment; (PCR positive patients will be excluded)