Study of Safety and Efficacy of a Sequential Regimen Consisting of Three Cycles of Fludarabine Followed by Tositumomab and Iodine I 131 Tositumomab

Fludarabine Monophosphate Followed by Iodine I 131 Tositumomab for Untreated Low-grade and Follicular Non-Hodgkin's Lymphoma

This is a single-arm, single institution, phase II study of fludarabine monophosphate followed by Iodine I 131 Tositumomab for patients with previously untreated, advanced-stage (stage III or IV) low-grade, transformed low-grade and follicular non-Hodgkin's lymphoma. The primary objective of the study will be to evaluate the safety of this treatment combination and the secondary endpoint will be to evaluate efficacy.

Inclusion Criteria:

• Patients must be age 18 years or older.
• Patients must have a histologically-confirmed diagnosis of low-grade or follicular non-Hodgkin's B-cell lymphoma.
• Patients must have Ann Arbor stage III or IV extent of disease after completing staging.
• Patients must have bi-dimensionally measurable disease. At least one lesion must have both perpendicular diameters > 2 cm.
• Patients must have evidence that their tumor expresses the CD20 antigen by immunohistochemistry or flow cytometry.
• Patients must have no previous treatment for NHL.
• Patients must have a Karnofsky performance status of at least 60% and an anticipated survival of at least 3 months.
• Patients must have absolute granulocyte count greater than or equal to 1500 cells/mm3 and a platelet count > 100,000 cells/mm3 within 14 days of study entry and not require sustained support with hematopoietic cytokines or transfusion of blood products.
• Patients must have adequate renal and hepatic function.
• Patients must sign IRB approved informed consent form(s) prior to study entry.

Exclusion Criteria:

• Patients who received systemic steroids within 1 week of study entry, except patients on maintenance steroid therapy for a non-cancerous disease.
• Patients with evidence of active infection requiring intravenous antibiotics at the time of study entry.
• Patients with New York Heart Association class III or IV heart disease or other serious illness that would preclude evaluation.
• Patients with known HIV Infection.
• Patients with known brain or leptomeningeal metastases.
• Patients who are pregnant or nursing. Patients of childbearing potential must undergo a pregnancy test at screening and on the day fludarabine treatment is started. Treatment is not to be administered until a negative result is obtained. Males and females must agree to use effective contraception for 6 months following the iodine I 131 tositumomab therapy.
• Patients with prior malignancy other than lymphoma, except for adequately-treated skin cancer in situ cervical cancer, or other cancer for which the patient has been disease-free for 5 years.
• Patients with hypersensitivity to fludarabine.
• Patients who are receiving either approved or non-approved (through another protocol) anti-cancer drugs or biologics.
• Patients who are HAMA positive.
• Patients with previous allergic reaction to iodine. This does not include reacting to intravenous iodine containing contrast materials.

Inclusion Criteria for Iodine I 131 Tositumomab Therapy

• Patients who completed 3 cycles of fludarabine.
• Patients must have absolute granulocyte count ≥ to 1500/mm3, platelet count of ≥ 100,000/mm3 (≥ 150,000/mm3 if > 25% bone marrow involvement at restaging), and not require sustained support with hematopoietic cytokines or transfusions with blood products.
• Patients must have adequate renal and hepatic function.

Exclusion criteria for Antibody Therapy

• Patients with active obstructive hydronephrosis.
• Patients with evidence of active infection requiring intravenous antibiotics.
• Patients who are pregnant.