Lenalidomide and Ibrutinib in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma
Lenalidomide and Ibrutinib in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma
This phase I trial studies the side effects and best dose of lenalidomide and ibrutinib in
 treating patients with B-cell non-Hodgkin lymphoma that has returned or not responded to
 treatment. Biological therapies, such as lenalidomide, may stimulate the immune system in
 different ways and stop cancer cells from growing. Ibrutinib may stop the growth of cancer
 cells by blocking some of the enzymes needed for cell growth. Giving lenalidomide with
 ibrutinib may work better in treating non-Hodgkin lymphoma than giving either drug alone.
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 cycle 1). Cycles 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; due to the known teratogenic potential of lenalidomide
 and the unknown teratogenic potential of ibrutinib, pregnant or nursing patients may
 not be enrolled; 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)