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

Study Overview
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Brief Summary
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This phase II trial studies how well ibrutinib in combination with rituximab and lenalidomide works in treating patients with previously untreated, stage II-IV follicular lymphoma or marginal zone lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Biological therapies, such as lenalidomide, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Giving ibrutinib in combination with rituximab and lenalidomide may work better in treating follicular lymphoma or marginal zone lymphoma.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the efficacy of ibrutinib combined with rituximab and lenalidomide in patients with previously untreated follicular lymphoma (FL) and marginal zone lymphoma (determined by progression-free survival at 2 years). SECONDARY OBJECTIVES: I. To evaluate the efficacy of ibrutinib combined with rituximab and lenalidomide in subjects with FL as assessed by complete response rate (CR) at 120 weeks, overall response rate (ORR), duration of response (DOR), event free survival (EFS), time to next anti-lymphoma treatment (TTNT), and overall survival (OS). II. To evaluate the safety and tolerability of ibrutinib combined with rituximab and lenalidomide in previously untreated subjects with FL and marginal zone lymphoma. EXPLORATORY OBJECTIVES: I. To evaluate prognostic and mechanistic biomarkers relative to treatment outcomes. OUTLINE: Patients receive lenalidomide orally (PO) on days 1-21, rituximab intravenously (IV) over 4-6 hours on days 1, 8, 15, and 22 of cycle 1 and day 1 of all subsequent cycles, and ibrutinib PO once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 12 weeks for 1 year and then every 24 weeks for 2 years.

Official Title
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An Open Label, Phase 2 Study of Ibrutinib in Combination With Rituximab and Lenalidomide in Previously Untreated Subjects With Follicular Lymphoma and Marginal Zone Lymphoma

Conditions
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CD20 Positive, Ann Arbor Stage II Follicular Lymphoma, Ann Arbor Stage II Marginal Zone Lymphoma, Ann Arbor Stage III Follicular Lymphoma, Ann Arbor Stage III Marginal Zone Lymphoma, Ann Arbor Stage IV Follicular Lymphoma, Ann Arbor Stage IV Marginal Zone Lymphoma, Grade 1 Follicular Lymphoma, Grade 2 Follicular Lymphoma, Grade 3a Follicular Lymphoma

Intervention / Treatment
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* Drug: Ibrutinib
* Other: Laboratory Biomarker Analysis
* Drug: Lenalidomide
* Biological: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed CD20+ follicular lymphoma, grade 1, 2, or 3a or marginal zone lymphoma Have had no prior systemic treatment for lymphoma Bi-dimensionally measurable disease, with at least one mass lesion >= 2 cm in longest diameter by computed tomography (CT), positron emission tomography (PET)/CT, and/or magnetic resonance imaging (MRI) In the opinion of the investigator would benefit from systemic therapy Stage II, III, or IV disease Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Absolute neutrophil count (ANC) >= 1,000/mm^3, independent of growth factor support (within 28 days prior to signing informed consent). Platelet counts >= 100,000/mm^3 or >= 50,000/mm^3 if bone marrow involvement with lymphoma, independent of transfusion support in either situation (within 28 days prior to signing informed consent). Serum aspartate transaminase (AST) or alanine transaminase (ALT) < 3 x upper limit of normal (ULN) Creatinine clearance > 30 ml/min calculated by modified Cockcroft-Gault formula Bilirubin < 1.5 x ULN unless bilirubin is due to Gilbert's syndrome, documented liver involvement with lymphoma, or of non-hepatic origin, in which case bilirubin should not exceed 3 g/dL Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN and partial thromboplastin time (PTT) < 1.5 x ULN Must be able to adhere to the study visit schedule and other protocol requirements Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study; females of childbearing potential: must either completely abstain from heterosexual sexual conduct or must use 2 methods of reliable contraception, 1 highly effective (intrauterine device, birth control pills, hormonal patches, injections, vaginal rings, or implants) and at least 1 additional method (condom, diaphragm, cervical cap) of birth control; reliable contraceptive methods must be started at least 4 weeks before lenalidomide; males who are sexually active must be practicing complete abstinence or agree to a condom during sexual contact with a pregnant female or female of child bearing potential; men must agree to not donate sperm during and after the study; for females, these restrictions apply at least 4 weeks before study treatment, during the period of therapy and for 1 month after the last dose of study drug; for males, these restrictions apply during the period of therapy and for 3 months after the last dose of study drug Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [Beta-hCG]) pregnancy test at screening; women who are pregnant or breastfeeding are ineligible for this study; females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid Risk Evaluation and Mitigation Strategy (REMS) program Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study All study participants must be registered into the mandatory Revlimid REMS program, and be willing and able to comply with the requirements of the REMS program Exclusion Criteria: Known central nervous system lymphoma or leptomeningeal disease, except subjects with a history of central nervous system lymphoma treated and in remission > 6 months Evidence of diffuse large B-cell transformation Grade 3b FL Any prior history of other malignancy besides FL or marginal zone lymphoma, unless the patient has been free of disease for >= 5 years and felt to be at low risk for recurrence by the treating physician, except: Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated cervical carcinoma in situ without evidence of disease Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk, including but not limited to: Moderate to severe hepatic impairment (Child-Pugh classes B and C) Known history of human immunodeficiency virus (HIV) or active hepatitis C virus or active hepatitis B virus infection, or any uncontrolled active systemic infection Patients with inactive hepatitis B infection must adhere to hepatitis B reactivation prophylaxis unless contraindicated Prior use of ibrutinib or other BTK inhibitors, rituximab or lenalidomide Concurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc., or chronic administration glucocorticoid equivalent of > 10 mg/day of prednisone) within 28 days of the first dose of study drug Known anaphylaxis or immunoglobulin E (IgE)-mediated hypersensitivity to murine proteins or to any component of rituximab Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon); if patients have been on warfarin or equivalent vitamin K antagonists in the past, they will not be eligible if administered within 30 days of the first dose of study drug Requires chronic treatment with strong CYP3A inhibitors; if patients have been on a strong CYP3A inhibitor in the past, they will not be eligible if the CYP3A inhibitor was administered within 7 days of the first dose of study drug Requires chronic treatment with strong CYP3A inducers, for a list of strong CYP3A inducers, see the protocol. If patients have been on a strong CYP3A inducer in the past, they will not be eligible if the CYP3A inducer was administered within 7 days of the first dose of study drug Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional classification Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree atrioventricular (AV) block, type II AV block, or 3rd degree block Known bleeding diathesis (e.g., von Willebrand's disease) or hemophilia History of stroke or intracranial hemorrhage within 6 months prior to study entry Vaccinated with live, attenuated vaccines within 4 weeks of study entry Lactating or pregnant subjects Administration of any investigational agent within 28 days of first dose of study drug Patients who have undergone major surgery within 7 days or minor surgery within 3 days of first dose of study drug

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (lenalidomide, rituximab, ibrutinib)<br>Patients receive lenalidomide PO on days 1-21, rituximab IV over 4-6 hours on days 1, 8, 15, and 22 of cycle 1 and day 1 of all subsequent cycles, and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Ibrutinib<br>* Given PO<br>* Other names: PCI-32765;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | Response will be assessed by the investigator based on the 2014 Cheson Lugano criteria. The 2-year PFS rate will be calculated and corresponding 95% confidence interval (CI) will be derived. Kaplan-Meier method will be used to estimate the PFS. Corresponding 95% CI will be summarized. Cox proportional hazards models will be used to assess the effects of patient prognostic factors on time-to-event endpoints. | Time from the treatment start date (course 1, day 1) until thefirst date of objectively documented progressive disease or date of death from any cause, assessed for up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response (CR) rate | Will be defined as the percentage of subjects with a CR at 120 weeks as determined by the principal investigator (Cheson, Lugano classification 2014). | At 120 weeks | 
| Overall response rate (ORR) (CR rate + partial response [PR]) | Will be defined as the percentage of subjects with an ORR and assessed by the investigator based on Cheson, Lugano 2014. The best ORR will be recorded. | Up to 3 years | 
| Duration of response (DOR) | Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% CI. | Time by which measurement criteria for CR rate or PR, whichever is recorded first, is met until death or the first date by which progressive disease is documented; assessed up to 3 years | 
| Event free survival (EFS) | Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% CI. | From the date of course 1, day 1 to the date of first documented progression, transformation to diffuse large B-cell lymphoma, initiation of new anti-lymphoma treatment, or death; assessed up to 3 years | 
| Time to next anti-lymphoma treatment (TTNT) | Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% CI. | From the date of course 1, day 1 to the date of first documented administration of any anti-lymphoma treatment (chemotherapy, radiotherapy, immune therapy, radioimmunotherapy, or other experimental therapy); assessed up to 3 years | 
| Overall survival (OS) | Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% CI. | From the date of course 1, day 1 to the date of death regardless of cause; assessed up to 3 years | 
| Frequency (number and percentage) of treatment-emergent adverse events (AEs) | Additional AE summaries will include AE frequency by AE severity and by relationship to study drug. | Up to 3 years |