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

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

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.

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.

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