Vaccine Therapy and Sargramostim Compared With Placebo and Sargramostim Following Rituximab in Treating Patients With Non-Hodgkin's Lymphoma

Phase III, Randomized, Double Blind, Placebo-Controlled Trial of Favldand GM-CSF Versus Placebo and GM-CSF Following Rituximab in Subjects With Follicular B-Cell Non-Hodgkin's Lymphoma

RATIONALE: Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Vaccines made from a person's cancer cells may make the body build an immune response to kill cancer cells. Colony-stimulating factors such as GM-CSF increase the number of immune cells found in bone marrow and peripheral blood. It is not yet known whether combining rituximab and GM-CSF with vaccine therapy may cause a stronger immune response and kill more cancer cells.

PURPOSE: This randomized phase III trial is studying giving rituximab and GM-CSF together with vaccine therapy and comparing it to giving rituximab and GM-CSF alone in treating patients with newly diagnosed, relapsed, or refractory B-cell non-Hodgkin's lymphoma.

OBJECTIVES:

Primary

• Compare time to disease progression in patients with grade 1, 2, or 3 follicular B-cell non-Hodgkin's lymphoma who respond (i.e., complete or partial response, or stable disease) to treatment with rituximab and are then treated with sargramostim (GM-CSF) with vs without autologous immunoglobulin idiotype-KLH conjugate vaccine.

Secondary

• Compare response rate improvement in patients treated with these regimens.
• Compare overall complete response rate in patients treated with these regimens.
• Compare duration of response in patients treated with these regimens.
• Determine the safety of these regimens in these patients.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to prior treatment (yes vs no) and response to rituximab during study (complete response [CR] or partial response [PR] vs stable disease [SD]).

All patients receive rituximab IV once weekly for 4 weeks. Five weeks after the last dose of rituximab, patients are assessed for response. Patients with progressive disease are removed from the study and do not undergo randomization. Patients with a CR, PR, or SD are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive autologous immunoglobulin idiotype-KLH conjugate vaccine subcutaneously (SC) on day 1. Patients also receive sargramostim (GM-CSF) SC on days 1-4.
• Arm II: Patients receive placebo SC on day 1. Patients also receive GM-CSF SC on days 1-4.

In both arms, treatment repeats monthly for 6 months in the absence of unacceptable toxicity or clinically significant progressive disease. After the first 6 months, patients with a CR, PR, or SD may continue to receive treatment (per treatment arm as above) every 2 months for 1 year (total of 6 doses) and then every 3 months thereafter in the absence of disease progression.

Patients are followed every 3 months for 2 years and then every 6 months until disease progression.

PROJECTED ACCRUAL: A total of 342 evaluable patients (171 per treatment arm) will be accrued for this study within 18 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed follicular B-cell non-Hodgkin's lymphoma (NHL)

  • Grade 1, 2, or 3

• Meets 1 of the following criteria for treatment with rituximab:

  • Treatment naïve
  • Relapsed or refractory disease after prior chemotherapy
  • Relapsed after a prior documented response (i.e., complete or partial response) to rituximab of at least 6 months duration

• Tumor accessible for biopsy OR existing biopsy material (taken within the past 6 months) suitable for vaccine preparation

• Measurable or evaluable disease after tumor tissue procurement for vaccine production

• No more than 2 prior treatment regimens for NHL

  • Single regimens include any of the following:

    • Maintenance rituximab
    • Rituximab administered once weekly for 8 courses
    • Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab* NOTE: *CHOP followed by rituximab at time of relapse is considered 2 treatment regimens

• No history of CNS lymphoma or meningeal lymphomatosis

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Absolute granulocyte count ≥ 1,500/mm^3
• Platelet count ≥ 75,000/mm^3 (unless related to bone marrow involvement by lymphoma)
• Hemoglobin ≥ 10g/dL

Hepatic

• Not specified

Renal

• Not specified

Cardiovascular

• No congestive heart failure

Pulmonary

• No compromised pulmonary function

Immunologic

• HIV negative
• No prior allergic response to GM-CSF
• No active bacterial, viral, or fungal infection

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No psychiatric disorder that would preclude study participation
• No other malignancy within the past 2 years except nonmelanoma skin cancer or carcinoma in situ of the cervix
• No other serious nonmalignant disease that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• See Chemotherapy
• At least 4 weeks since prior immunotherapy
• No prior radiolabeled anti-lymphoma antibody (e.g., iodine I 131 tositumomab or ibritumomab tiuxetan)
• No prior autologous or allogeneic stem cell transplantation
• No prior lymphoma-specific idiotype immunotherapy (e.g., Id vaccine)
• No prior investigational vaccine or immunotherapeutic containing keyhole limpet hemocyanin (KLH)

Chemotherapy

• See Disease Characteristics
• At least 4 weeks since prior chemotherapy
• More than 9 months since prior fludarabine
• More than 2 years since prior chemotherapy/rituximab combination therapy (e.g., CHOP/rituximab or cyclophosphamide, vincristine, and prednisone [CVP]/rituximab)
• No more than 6 total prior treatment courses with fludarabine

Endocrine therapy

• No concurrent steroids for allergic reaction to sargramostim (GM-CSF)

Radiotherapy

• See Biologic therapy
• At least 4 weeks since prior radiotherapy

Surgery

• Not specified

Other

• At least 4 weeks since prior experimental therapy
• No concurrent systemic immunosuppressive therapy
• No other concurrent anti-lymphoma therapy