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

This study has suspended participant recruitment.
(Temporarily Closed to Accrual)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
First received: April 9, 2013
Last updated: March 10, 2015
Last verified: November 2014

This phase I clinical trial studies the side effects and best dose of lenalidomide and ibrutinib when given together with rituximab in treating patients with previously untreated stage II-IV follicular lymphoma. 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. Monoclonal antibodies, such as rituximab, can find cancer cells and help kill them. Giving lenalidomide and ibrutinib together with rituximab may work well in treating follicular lymphoma.

Condition Intervention Phase
Stage II Grade 1 Contiguous Follicular Lymphoma
Stage II Grade 1 Non-Contiguous Follicular Lymphoma
Stage II Grade 2 Contiguous Follicular Lymphoma
Stage II Grade 2 Non-Contiguous Follicular Lymphoma
Stage II Grade 3 Contiguous Follicular Lymphoma
Stage II Grade 3 Non-Contiguous Follicular Lymphoma
Stage III Grade 1 Follicular Lymphoma
Stage III Grade 2 Follicular Lymphoma
Stage III Grade 3 Follicular Lymphoma
Stage IV Grade 1 Follicular Lymphoma
Stage IV Grade 2 Follicular Lymphoma
Stage IV Grade 3 Follicular Lymphoma
Drug: Lenalidomide
Drug: Ibrutinib
Biological: Rituximab
Other: Pharmacological Study
Other: Laboratory Biomarker Analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Rituximab, Lenalidomide, and Ibrutinib in Previously Untreated Follicular Lymphoma

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximally tolerated dose (MTD) of lenalidomide and ibrutinib for combination with rituximab, determined by dose-limiting toxicities (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Defined as the highest dose at which 0 or 1 of 6 patients experience DLT.

Secondary Outcome Measures:
  • Toxicities by attribute and grade, assessed using NCI CTCAE version 4.0 [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
    Summarized for each dose level.

  • Complete response rate [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Estimated for each dose level.

  • Overall response rate [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Estimated for each dose level.

  • Progression-free survival (PFS) [ Time Frame: The time between registration and disease progression or death, assessed up to 10 years ] [ Designated as safety issue: No ]
    Estimated by Kaplan-Meier method for the whole number of patients in this study and at the MTD.

  • Overall survival (OS) [ Time Frame: The time between registration and death, assessed up to 10 years ] [ Designated as safety issue: No ]
    Estimated by Kaplan-Meier method for the whole number of patients in this study and at the MTD.

Other Outcome Measures:
  • Pharmacokinetic parameters of ibrutinib and major metabolite PCI-45227 [ Time Frame: Days 1 and 15 of course 1 and week 13 (pre-dose, 1, 2, 4, 7, and 24 hours post-ibrutinib dose) ] [ Designated as safety issue: No ]
    Tabulated and summarized using descriptive statistics.

  • BTK parameters [ Time Frame: At 4 hours and 24 hours post ibrutinib dosing ] [ Designated as safety issue: No ]
    Tabulated and summarized using descriptive statistics.

Estimated Enrollment: 33
Study Start Date: June 2013
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (lenalidomide, ibrutinib, and rituximab)
Patients receive lenalidomide PO QD on days 1-21 and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients also receive rituximab IV on days 1, 8, 15, and 22 of course 1 and once weekly at weeks 13, 21, 29, and 37.
Drug: Lenalidomide
Given PO
Other Names:
  • CC-5013
  • CC5013
  • CDC 501
  • IMiD-1
Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765
Biological: Rituximab
Given PO
Other Name: MOAB IDEC-C2B8
Other: Pharmacological Study
Correlative studies
Other Name: pharmacological studies
Other: Laboratory Biomarker Analysis
Correlative studies

Detailed Description:


I. To determine the recommended phase II doses of ibrutinib and lenalidomide for combination with rituximab in previously untreated follicular lymphoma.


I. To determine pharmacokinetics of ibrutinib and its major metabolite (PCI-45227) when combined with lenalidomide and rituximab.

II. To determine the pharmacodynamics of basophil activation and Bruton tyrosine kinase (BTK) occupancy in peripheral blood mononuclear cells (PBMCs) over a 24-hour period of ibrutinib when given in combination with lenalidomide and rituximab.

OUTLINE: This is a dose-escalation study of lenalidomide and ibrutinib.

Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21 and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients also receive rituximab intravenously (IV) on days 1, 8, 15, and 22 of course 1 and once weekly at weeks 13, 21, 29, and 37.

After completion of study treatment, patients are followed up every 4 months for 2 years and then every 6 months for 8 years.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Previously untreated, histologically confirmed follicular lymphoma, World Health Organization (WHO) classification grade I, II, or IIIa (> 15 centroblasts per high power field with centrocytes present) that is stage III, IV, or bulky (i.e., single mass >= 7 cm in any unidimensional measurement) stage II and requires therapy at the discretion of the primary physician

    • Bone marrow biopsies as the sole means of diagnosis are not acceptable, but they may be submitted in conjunction with nodal biopsies; fine needle aspirates are not acceptable for diagnosis
    • Failure to submit pathology specimens within 60 days of patient registration will be considered a major protocol violation
    • Institutional flow cytometry or immunohistochemistry must confirm cluster of differentiation 20 (CD20) antigen expression
    • All risk by follicular lymphoma international prognostic index (FLIPI): 0-5 risk factors
  • No prior systemic therapy for non-Hodgkin lymphoma (NHL) including chemotherapy or immunotherapy (e.g., monoclonal antibody-based therapy), radiation therapy, or radioimmunotherapy
  • For non-NHL conditions, no chemotherapy, radiotherapy, or major surgery within 4 weeks (6 weeks for nitrosoureas or mitomycin C) of enrollment; no patients who have ongoing adverse events from agents administered more than 4 weeks previously
  • No prior exposure to any of the study agents
  • No corticosteroids within two weeks prior to study entry, except for maintenance therapy for a non-malignant disease; dose of corticosteroid or prednisone (or its equivalent) should not exceed 20 mg per day; corticosteroid premedication for rituximab is allowed
  • Eastern Cooperative Oncology Group (ECOG) performance status must be =< 2
  • Measurable disease must be present either on physical examination or imaging studies; non-measurable disease alone is not acceptable; any tumor mass > 1 cm is acceptable; lesions that are considered non-measurable include the following:

    • Bone lesions (lesions if present should be noted)
    • Ascites
    • Pleural/pericardial effusion
    • Lymphangitis cutis/pulmonis
    • Bone marrow (involvement by NHL should be noted)
  • Patients with human immunodeficiency virus (HIV) infection are eligible, provided they meet the following:

    • No evidence of coinfection with hepatitis B or C
    • Cluster of differentiation 4 (CD4)+ cell count >= 400/mm^3
    • No evidence of resistant strains of HIV
    • If not on anti-HIV therapy, HIV viral load < 10,000 copies HIV ribonucleic acid (RNA)/mL
    • If on anti-HIV therapy, HIV viral load < 50 copies HIV RNA/mL
    • No history of acquired immunodeficiency syndrome (AIDS)-defining conditions
    • No use of strong cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5) inhibitors or inducers
  • No known central nervous system (CNS) involvement by lymphoma
  • No treatment with strong inhibitors or inducers of CYP3A4/5
  • No evidence of active hepatitis B or C infections (i.e., no positive serology for anti-hepatitis B virus [HBV] or anti-hepatitis C virus [HCV] antibodies); HBV seropositive patients (hepatitis B surface antigen [HBsAg] +) are eligible if they are closely monitored for evidence of active HBV infection by HBV deoxyribonucleic acid (DNA) testing and receive suppressive therapy with lamivudine or other HBV suppressive therapy until 6 months after the last rituximab dose
  • No history of erythema multiforme, toxic epidermal necrolysis or Stevens-Johnson syndrome
  • No history of uncontrolled seizures
  • No autoimmune disorder that requires active immunosuppression
  • No intracranial hemorrhage within the last 6 months
  • 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 50 mIU/mL within 10-14 days prior to registration; 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 preceding 24 consecutive months)
  • No known human anti-chimeric antibody (HACA) positivity
  • No anticoagulation with warfarin is allowed; patients must not have received warfarin within 28 days prior to registration; alternative anticoagulant may be used
  • Patients must not be receiving concurrent treatment with other investigational drugs
  • Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to lenalidomide, ibrutinib, or other agents used in study
  • Patients must not have presence of transfusion-dependent thrombocytopenia
  • No currently active clinically significant cardiovascular disease including the following:

    • No uncontrolled arrhythmia
    • No congestive heart failure
    • No class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
    • No history of myocardial infarction, deep venous or arterial thrombosis within 6 months prior to registration
  • No prior malignancy with the exceptions listed below:

    • Malignancy treated with curative intent and with no evidence of active disease for more than 3 years prior to screening and felt to be at low risk for recurrence by the treating physician
    • Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease
    • Adequately treated cervical carcinoma in situ without current evidence of disease
  • Absolute neutrophil count (ANC) >= 1,000/microliter
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
  • Total bilirubin =< 1.5 x ULN unless attributable to NHL; unless attributable to Gilbert's syndrome, or disease infiltration of the liver is present
  • Creatinine clearance > 60 mL/min (patients on dialysis are not eligible); to be calculated by method of Cockcroft-Gault, using actual weight
  • Creatinine =< 2 x ULN
  • Platelet count >= 75,000/microliter
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01829568

United States, District of Columbia
Lombardi Comprehensive Cancer Center at Georgetown University
Washington, District of Columbia, United States, 20057
United States, Illinois
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States, 60637
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Weill Medical College of Cornell University
New York, New York, United States, 10065
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Principal Investigator: Chaitra Ujjani Alliance for Clinical Trials in Oncology
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01829568     History of Changes
Other Study ID Numbers: NCI-2013-00792, NCI-2013-00792, CALGB-A051103, A051103, A051103, U10CA180821, U10CA031946
Study First Received: April 9, 2013
Last Updated: March 10, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Lymphoma, Follicular
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Antineoplastic Agents
Antirheumatic Agents
Growth Inhibitors
Growth Substances
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on March 26, 2015