Rituximab With or Without Lenalidomide in Treating Patients With Previously Untreated Follicular Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer cell growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Lenalidomide may stop the growth of non-Hodgkin lymphoma by blocking blood flow to the cancer. It is not yet known whether rituximab is more effective when given alone or together with lenalidomide in treating patients with follicular lymphoma. PURPOSE: This randomized phase II trial is studying rituximab to see how well it works compared with giving rituximab together with lenalidomide in treating patients with previously untreated follicular lymphoma.

Detailed Description
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OBJECTIVES: Primary To determine the activity of rituximab in combination with lenalidomide versus rituximab alone in patients with previously untreated follicular lymphoma in need of therapy. Secondary To determine the safety of these regimens in these patients. OUTLINE: This is a multicenter study. Patients are stratified according to grade of disease (grades 1 or 2 vs 3a), presence of bulky disease (defined as masses ≥ 6 cm) (yes vs no), Follicular Lymphoma International Prognostic Index score (1 or 2 vs ≥ 3), and participating centers. Patients are randomized to 1 of 2 treatment arms. Arm A: Patients receive rituximab IV on day 1 in weeks 1, 2, 3, 4 and weeks 12, 13, 14, 15 in the absence of disease progression or unacceptable toxicity. Arm B: Patients receive rituximab IV as in arm A. Patients also receive oral lenalidomide once daily, starting 14 days before first rituximab administration and last until 14 days after the last rituximab administration, in the absence of disease progression or unacceptable toxicity. All patients undergo restaging at week 10. Patients who show less than a minimal response (i.e., reduction of more than 25% in sum of product of diameters [SPD]) are off study treatment and transferred to the follow-up phase. Patients undergo a second restaging in week 23. Some patients may undergo biopsies and blood and bone marrow sample collection periodically for biomarker studies. After completion of study treatment, patients are followed up periodically for 20 years.

Official Title
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Rituximab Plus Lenalidomide or Rituximab Monotherapy for Untreated Patients With Follicular Lymphoma in Need of Therapy. A Randomized, Open-Label, Multicenter Phase II Trial.

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: Rituximab
* Drug: lenalidomide


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed follicular lymphoma Stage III or IV disease OR stage II disease not suitable for radiotherapy Grades 1, 2, or 3a disease Previously untreated disease CD20-positive disease Patients in need of systemic therapy, meeting at least 1 of the following criteria: Symptomatic enlarged lymph nodes, spleen, or other lymphoma manifestations Bulky disease ≥ 6 cm in long diameter Clinically significant progression over at least 6 months of any tumor lesion Anemia (hemoglobin < 100 g/L) or thrombocytopenia (platelet count < 100 x 10^9/L) due to lymphoma Clinically significant progressive decrease in hemoglobin or platelet count due to lymphoma B-symptoms, weight loss > 10% within the past 6 months, drenching night sweats, or fever > 38°C not due to infection At least one two-dimensionally measurable lesion with longest transverse diameter > 10 mm Paraffin-embedded tumor tissue available No known CNS involvement PATIENT CHARACTERISTICS: WHO performance status 0-2 EF ≥ 50% for patients with a history of cardiac disease or older than 70 years Neutrophil count ≥ 1.5 x 10^9/L Platelet count ≥ 100 x 10^9/L Bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless due to Gilbert syndrome) ALT ≤ 2.5 x ULN Alkaline phosphatase ≤ 2.5 x ULN Creatinine clearance ≥ 30 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception 4 weeks prior to, during, and for 12 months after completion of study therapy Must be compliant and geographically proximal to allow for proper staging and follow-up No serious underlying medical condition, at the judgment of the investigator, which could impair the ability of the patient to participate in the trial (e.g., active autoimmune disease or uncontrolled diabetes) No malignancy within the past 3 years except for adequately treated carcinoma in situ of the cervix or localized nonmelanoma skin cancer No psychiatric disorder precluding understanding information of trial-related topics, giving informed consent, or interfering with compliance for oral drug intake No known hypersensitivity to trial drugs or hypersensitivity to any other components of the trial drugs No known HIV positivity or hepatitis C infection No serological evidence of current or past hepatitis B infection, unless the serological findings are clearly due to vaccination PRIOR CONCURRENT THERAPY: No prior systemic therapy for this disease At least 3 months since prior radiotherapy At least 30 days since prior treatment in another clinical trial At least 4 weeks since prior and no concurrent corticosteroids unless administered as prophylaxis in at-risk patients for ≤ 3 days or at a dose equivalent to prednisone ≤ 15 mg/day, for indications other than lymphoma or lymphoma-related symptoms No concomitant drugs contraindicated for use with the trial drugs No other concurrent experimental drugs or anticancer therapy No other concurrent investigational treatments

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rituximab<br>Rituximab (MabThera®) will be administered for a maximum of 8 infusions at weeks 1, 2, 3, 4 and again at weeks 12, 13, 14, 15 if the first restaging at week 10 (+/- 1 week) shows a partial response with at least more than 25% reduction in sum of product of diameters | Biological: Rituximab<br>* Rituximab (MabThera®) will be administered for a maximum of 8 infusions at weeks 1, 2, 3, 4 and again at weeks 12, 13, 14, 15 if the first restaging at week 10 (+/- 1 week) shows a partial response with at least more than 25% reduction in sum of product of diameters<br>* Other names: Rituximab (MabThera);|
| Active Comparator: Rituximab plus Lenalidomide<br>Lenalidomide will be administered as 15 mg flat dose daily, starting 14 days before first and stopping 14 days after last rituximab administration. | Drug: lenalidomide<br>* Lenalidomide will be administered as 15 mg flat dose daily, starting 14 days before first and stopping 14 days after last rituximab administration.<br>* Other names: Lenalidomide (Revlimid);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response (CR) | The evaluation of CR is outlined in Appendix 1 Criteria for Evaluation of Response in Non-Hodgkin's Lymphoma. | at week 23 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best overall response (OR) | OR is defined as either: the disappearance of all evidence of disease (CR or CRu) the regression of measurable disease with no new sites (PR) | within 24 weeks | 
| Best Overall response (OR) | OR is defined as either: the disappearance of all evidence of disease (CR or CRu) the regression of measurable disease with no new sites (PR) | within 12 weeks | 
| Progression-free survival | PFS will be calculated from randomization until the first event of interest: disease progression or relapse according to criteria of Cheson et a.l 1999 death from any cause | until disease progression, for up to 10 years after randomization | 
| Time to first off-trial anti-lymphoma therapy | This will be calculated from randomization until the start of the first off-trial anti-lymphoma treatment. Patients not receiving any off-trial anti-lymphoma treatment will be censored at the last follow-up visit. | until off-trial therapy administration, for up to 10 years after randomization | 
| Overall survival | OS will be calculated from randomization until death. Patients not experiencing an event will be censored at the last date they were known to be alive. | every 6 months for up to 10 years after randomization | 
| Adverse events, including laboratory abnormality assessments and vital signs | This will be evaluated using the NCI CTCAE v4.0 | from inclusion until 30 days after treatment discontinuation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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contiguous stage II grade 1 follicular lymphoma, contiguous stage II grade 2 follicular lymphoma, contiguous stage II grade 3 follicular lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 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