This trial is active, not recruiting.

Conditions recurrent adult diffuse large cell lymphoma, recurrent follicular lymphoma, recurrent lymphoplasmacytic lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, refractory follicular lymphoma, refractory lymphoplasmacytic lymphoma, refractory mantle cell lymphoma
Treatments ibrutinib, laboratory biomarker analysis, lenalidomide, pharmacological study
Phase phase 1
Target BTK
Sponsor National Cancer Institute (NCI)
Start date September 2013
End date December 2019
Trial size 34 participants
Trial identifier NCT01955499, 9426, NCI-2013-01810, OSU 13022, P30CA016058, U01CA076576, U01CA132123, UM1CA186644, UM1CA186705, UM1CA186712


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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Endpoint classification safety study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Patients receive lenalidomide 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.
ibrutinib BTK Inhibitor PCI-32765
Given PO
laboratory biomarker analysis
Correlative studies
lenalidomide CC-5013
Given PO
pharmacological study
Correlative studies

Primary Outcomes

Incidence of toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4 criteria
time frame: Up to 2 years
MTD, defined as the highest safely tolerated dose where at most one patient experiences DLT with the next higher dose having at least 2 patients who experience DLT
time frame: 28 days

Secondary Outcomes

Degree of response
time frame: Up to 2 years
Duration of overall response
time frame: From the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 2 years
Duration of stable disease
time frame: From the start of the treatment until the criteria for progression are met, assessed up to 2 years
Number of patients responding to treatment
time frame: Up to 2 years
time frame: Duration of time from the start of treatment to the time of measured progression or death, assessed up to 2 years

Eligibility Criteria

Male or female participants at least 18 years old.

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 - 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; 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 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 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 within 28 days or are taking warfarin 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 4), grade 1 =< 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 - 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)

Additional Information

Official title A Phase I Study of Ibrutinib (PCI-32765) in Combination With Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma
Principal investigator Beth Christian
Description 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.
Trial information was received from ClinicalTrials.gov and was last updated in September 2016.
Information provided to ClinicalTrials.gov by National Cancer Institute (NCI).
Location data was received from the National Cancer Institute and was last updated in August 2016.