Trial of Low-Dose MTX and I 131 Tositumomab for Previously Untreated, Advanced-Stage, Follicular Lymphoma

• Response rates. overall, complete, and partial response rates to this therapy. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• progression-free and overall survival rates [ Time Frame: 2 years ] [ Designated as safety issue: No ]

• To determine the overall, complete, and partial response rates to this therapy. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• To estimate the progression-free and overall survival in this patient population. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• To assess the safety of combination treatment with methotrexate and I-131 tositumomab. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
• To characterize the effect of prophylactic dose methotrexate on blood lymphocyte subsets by flow cytometry. [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Patients with a type of non-Hodgkin lymphoma, called follicular lymphoma and have not yet had previous systemic treatment, such as chemotherapy or immunotherapy will be invited to participate. This research study is being conducted in order to evaluate the combination of lowdose methotrexate and 131I-tositumomab (Bexxar) with regards to whether the combination will reduce the occurrence of the HAMA (Human Anti-Mouse Antibody) response. HAMA is an immune reaction against the tositumomab protein. Symptoms arising from HAMA can range from a mild form, like a rash, to a more extreme and possibly life-threatening level. HAMA can also decrease the effectiveness of the treatment, or create a future reaction if a patient is given another treatment containing mouse antibodies. In addition to evaluating the occurrence of HAMA, this research study will also look at the short and long-term effectiveness of this combination in the treatment of lymphoma, as well as its safety.

This is a single-arm, single institution, Phase II study to test the use of low-dose methotrexate in combination with I-131 tositumomab for its ability to lower the rate of (human anti-mouse antibody) HAMA formation in patients with previously untreated low-grade follicular lymphoma. Low-dose methotrexate will be given beginning 3 weeks prior to the first infusion of I-131 tositumomab (4 weekly doses) and continued for 6 weeks (10 total doses), the period of time during which the development of HAMA is most detrimental. A total of 61 patients will be enrolled. The primary endpoint of the study is the determination of the rate of HAMA conversion within the first seven weeks following treatment. The secondary endpoints include response rates, progression-free and overall survival, safety, and evaluation of the effect of methotrexate on blood lymphocyte subsets.

Inclusion Criteria:

1. Patients must have a histologically-confirmed diagnosis of follicular non-Hodgkin's B-cell lymphoma, grade 1-2 (grade 1 or grade 2 by WHO classification prior to 2009).
2. Patients must have Ann Arbor Stage III or IV extent of disease after complete staging.
3. Patients must have a willingness and ability to follow prescribed radiation precautions
4. Patients must not have had any previous treatment for low-grade lymphoma including chemotherapy or radiation. They may be newly diagnosed or observed without treatment after diagnosis. Symptomatic and asymptomatic patients will be eligible.
5. Patients must have a performance status of 0-2 on the ECOG scale and an anticipated survival of at least 3 months.
6. Patients must have an absolute neutrophil count >1500 cells/mm3 and a platelet count >100,000 cells/mm3 within 14 days of study entry. These blood counts must be sustained without support of hematopoietic cytokines or transfusion of blood products.
7. Patients must have adequate renal function (defined as serum creatinine <2.0) and hepatic function (defined as total bilirubin <1.5 x ULN and AST <3 x ULN) within 14 days of study entry.
8. Patients must have bi-dimensionally measurable disease. MRIT-II-003 May 18, 2011 Protocol Methotrexate & BEXXAR® (Tositumomab, Iodine I 131 Tositumomab) Page 5

Exclusion Criteria:

1. Patients with follicular Grade 3a or 3b by WHO Classification.
2. Patients with evidence of active infection requiring IV antibiotics at the time of study entry.
3. Patients with New York Heart Association Class III or IV heart disease or other serious illness that would preclude evaluation.
4. Patients with active obstructive hydronephrosis.
5. 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.
6. Patients with known HIV infection.
7. Patients with known brain or leptomeningeal metastases.
8. Patients who are pregnant or nursing. Patients of childbearing potential must undergo a pregnancy test within 7 days of study entry and methotrexate 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 radioimmunotherapy.
9. Patients with previous allergic reactions to iodine. This does not include reacting to IV iodine-containing contrast materials.
10. Patients with previous allergic reactions to methotrexate.
11. Patients who were previously given any monoclonal antibody, regardless of species, for any condition.
12. Detectable serum levels of HAMA.
13. Patients who are concurrently receiving either approved or non-approved (through another protocol) anti-cancer drugs or biologics.