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

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.