Lenalidomide and Rituximab in Treating Patients With Previously Untreated Stage II, Stage III, or Stage IV Follicular Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This phase II trial studies how well lenalidomide and rituximab work in treating patients with previously untreated stage II, stage III, or stage IV follicular non-Hodgkin lymphoma. Biological therapies, such as lenalidomide, may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Giving lenalidomide together with rituximab may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the response rate (overall and complete) to lenalidomide + rituximab in follicular non-Hodgkin lymphoma (NHL) patients who have received no prior systemic therapy. II. To determine the time to progression after lenalidomide + rituximab in previously untreated patients with cluster of differentiation (CD)20+ follicular NHL. SECONDARY OBJECTIVES: I. To determine the toxicity profile of lenalidomide + rituximab therapy in previously untreated patients with CD20+ follicular NHL. II. To establish whether the therapeutic effects of lenalidomide + rituximab combination are sufficiently promising to warrant evaluation in a subsequent randomized trial (in comparison to rituximab alone). III. To correlate fragment crystallizable gamma (Fcg) receptor polymorphism profiling with response to lenalidomide + rituximab in previously untreated patients with follicular NHL. IV. To determine the impact of lenalidomide on immune parameters in patients with previously untreated follicular lymphoma. V. To determine the impact of lenalidomide on angiogenic parameters in patients with previously untreated follicular lymphoma. VI. To correlate lymphoma-associated macrophages (LAM) and forkhead box P3 (FOXP3), granzyme B (GzB), CD10, multiple myeloma oncogene 1 (MUM1), and B-cell lymphoma 2 (BCL2) expression with response to rituximab + lenalidomide in previously untreated patients with follicular lymphoma. VII. Determine whether immune gene signatures previously identified as prognostic factors in follicular lymphoma (FL) can be applied to paraffin-embedded tissues in rituximab treated patients; evaluate micro ribonucleic acid (RNA) signatures associated with these gene signatures and outcome; to validate immunohistochemical markers associated with outcome in FL (CD68 LAMs, FOXP3, CD10, BCL6, FOXP1, MUM1); and investigate whether markers of angiogenesis may be of value in prognosis of FL. OUTLINE: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21. Treatment with lenalidomide repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients also receive rituximab intravenously (IV) on days 1, 8, 15, and 22 and on weeks 13, 21, 29, and 37 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 4 months for 2 years and then every 6 months for up to 8 years.

Official Title
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A Phase II Trial of Lenalidomide (Revlimid (TM), CC-5013) (NSC #703813) Plus Rituximab in Previously Untreated Follicular Non-Hodgkin Lymphoma (NHL)

Conditions
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Ann Arbor Stage II Grade 1 Contiguous Follicular Lymphoma, Ann Arbor Stage II Grade 1 Non-Contiguous Follicular Lymphoma, Ann Arbor Stage II Grade 2 Contiguous Follicular Lymphoma, Ann Arbor Stage II Grade 2 Non-Contiguous Follicular Lymphoma, Ann Arbor Stage II Grade 3 Contiguous Follicular Lymphoma, Ann Arbor Stage II Grade 3 Non-Contiguous Follicular Lymphoma, Ann Arbor Stage III Grade 1 Follicular Lymphoma, Ann Arbor Stage III Grade 2 Follicular Lymphoma, Ann Arbor Stage III Grade 3 Follicular Lymphoma, Ann Arbor Stage IV Grade 1 Follicular Lymphoma, Ann Arbor Stage IV Grade 2 Follicular Lymphoma, Ann Arbor Stage IV Grade 3 Follicular Lymphoma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously untreated, histologically confirmed follicular lymphoma, World Health Organization (WHO) classification grade 1, 2, or 3a (> 15 centroblasts per high power field with centrocytes present) that is stage III, IV, or bulky (i.e., single mass >= 7 cm in any uni-dimensional measurement) stage II 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 CD20 antigen expression Low or intermediate risk by Follicular Lymphoma International Prognostic Index (FLIPI): 0-2 risk factors No prior systemic therapy for NHL, including chemotherapy or immunotherapy (e.g., monoclonal antibody-based therapy); patients may have received involved-field radiation therapy No corticosteroids within two weeks prior to study entry, except for maintenance therapy for a non-malignant disease Eastern Cooperative Oncology Group (ECOG) performance status =< 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) No known central nervous system (CNS) involvement by lymphoma Patients with human immunodeficiency virus (HIV) infection are eligible, provided they meet the following No evidence of coinfection with hepatitis B or C 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 RNA/mL If on anti-HIV therapy, HIV viral load < 50 copies HIV RNA/mL No history of acquired immune deficiency syndrome (AIDS)-defining conditions No evidence of active hepatitis B or C infection (i.e., no positive serology for anti-hepatitis B core [HBc] or anti-hepatitis C virus [HCV] antibodies); hepatitis B virus (HBV) seropositive patients (hepatitis B surface antigen positive [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 Patients with a history of erythema multiforme, toxic epidermal necrolysis or Stevens-Johnson syndrome are not eligible Patients with uncontrolled seizures are not eligible Patients with an autoimmune disorder requires active immunosuppression are not eligible 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 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); all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure No known human anti-chimeric antibody (HACA) positivity Absolute neutrophil count (ANC) >= 1,000/microliter Platelet count >= 75,000/microliter Creatinine clearance >= 30 mL/min unless attributable to NHL; to be calculated by method of Cockcroft-Gault, using actual weight; maximum creatinine clearance (CrCl) 125 mL/min Total bilirubin =< 2 times upper limit of normal (ULN) unless attributable to NHL or Gilbert disease

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)<br>Patients receive lenalidomide PO QD on days 1-21. Treatment with lenalidomide repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients also receive rituximab IV on days 1, 8, 15, and 22 and in weeks 13, 21, 29, and 37 in the absence of disease progression or unacceptable toxicity. | 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 |
| --- | --- | --- |
| Number of Participants Who Achieved a Complete Response | Response is assessed by investigator according to International Working Group (IWG) criteria. Complete response requires disappearance of all evidence of disease. | At 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity of Study Treatment, Assessed by the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Data will be summarized using frequency tables. | Up to 5 years | 
| Disease Progression | Kaplan-Meier method will be used. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Up to 5 years | 
| Best Response | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Up to 5 years |