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

Study Overview
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Brief Summary
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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 Iodine I 131 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.

Detailed Description
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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, and safety.

Official Title
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Phase II Trial of Low-Dose Methotrexate and Iodine I 131 Tositumomab for Previously Untreated, Advanced-Stage, Follicular Lymphoma

Conditions
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Follicular Lymphoma

Intervention / Treatment
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* Drug: Bexxar
* Drug: Low Dose Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). Patients must have Ann Arbor Stage III or IV extent of disease after complete staging. Patients must have a willingness and ability to follow prescribed radiation precautions 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. Patients must have a performance status of 0-2 on the Eastern Cancer Oncology Group (ECOG) scale and an anticipated survival of at least 3 months. 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. Patients must have adequate renal function (defined as serum creatinine <2.0) and hepatic function (defined as total bilirubin <1.5 x ULN and Aspartate Aminotransferase (AST) <3 x ULN) within 14 days of study entry. Patients must have bi-dimensionally measurable disease. Exclusion Criteria: Patients with follicular Grade 3a or 3b by WHO Classification. Patients with evidence of active infection requiring IV 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 active obstructive hydronephrosis. 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 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 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. Patients with previous allergic reactions to iodine. This does not include reacting to IV iodine-containing contrast materials. Patients with previous allergic reactions to methotrexate. Patients who were previously given any monoclonal antibody, regardless of species, for any condition. Detectable serum levels of HAMA. Patients who are concurrently receiving either approved or non-approved (through another protocol) anti-cancer drugs or biologics.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment arm<br>Low dose methotrexate and Bexxar | Drug: Bexxar<br>* Iodine I 131 tositumomab (Bexxar) is a radioimmunotherapy (RIT) drug. RIT is a treatment strategy designed to target radiation specifically to cancer cells by attaching a radioactive atom to a monoclonal antibody, an immune system protein that binds to a particular protein. The Iodine I 131 tositumomab (Bexxar) therapeutic regimen is delivered in two sets of intravenous infusions given about 7 days apart. Nonradioactive Tositumomab is given before both the dosimetric infusion and the therapeutic infusion to improve distribution of these doses throughout the body.<br>* Other names: Iodine I 131 tositumomab;Drug: Low Dose Methotrexate<br>* Methotrexate is an antifolate drug. It interferes with cells' ability to copy their DNA. This mainly affects cells that are dividing frequently, such as immune system cells and cancer cells. Methotrexate will be used in this study to try to prevent the occurrence of HAMA by limiting your body's ability to produce anti mouse antibodies.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Early Onset HAMA (Human Anti-mouse Antibody) Conversion Following Treatment | The percentage of patients that experience early onset HAMA conversion following treatment. Early-onset HAMA is defined as antimouse antibody levels (in blood serum) of at least 5 times the level of detection, occurring at or prior to the 7th week of I-131 tositumomab therapy. | 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants That Respond to Treatment | The overall response rate (PR [partial response] + CR [complete response]) was determined. Partial response is defined as the regression of measurable disease with no new sites of disease. Complete response is defined as the disappearance of all evidence of disease. | 2 years | 
| The Percentage of Participants Alive at 2 Years | Overall survival was examined at 2 years | 2 years | 
| Median Progression Free Survival (PFS) Time | The median time patients survived without progression. | 2 Years | 
| Number of Participants That Experienced SAEs During Treatment. |  | Up to week 13 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Previously Untreated, Advanced-Stage, Follicular Lymphoma