Radiolabeled Monoclonal Antibody in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. PURPOSE: Phase I trial to study the effectiveness of radiolabeled monoclonal antibody in treating patients who have relapsed or refractory non-Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose of yttrium Y 90 ibritumomab tiuxetan when administered in combination with rituximab in patients with relapsed or refractory low-grade, follicular, or transformed CD20-positive B-cell non-Hodgkin's lymphoma (NHL). Determine the toxicity of different doses of yttrium Y 90 ibritumomab tiuxetan in patients treated with this regimen. Determine the frequency of reversal of bone marrow involvement with NHL in patients treated with this regimen. Determine the antitumor response in patients treated with this regimen. OUTLINE: This is a multicenter, dose-escalation study of yttrium Y 90 ibritumomab tiuxetan. Patients receive rituximab IV once weekly on weeks 1-4. After 4 doses of rituximab, patients without bone marrow involvement and cellularity greater than 50% expected receive rituximab IV once weekly on weeks 6 and 7 and yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes with the final dose of rituximab (day 43). Cohorts of 5-6 patients receive escalating dose of yttrium Y 90 ibritumomab tiuxetan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 4 of 5 or 3 of 6 patients experience dose-limiting toxicity. Patients are followed at 6 and 12 weeks, every 2-3 months for 2 years, and then every 6 months for 2 years. PROJECTED ACCRUAL: Approximately 6-30 patients will be accrued for this study.

Official Title
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Phase I, Multicenter, Open Label, Dose Escalation Of 90Y-Zevalin Radioimmunotherapy Using A Modified Treatment Regimen For Relapsed Or Refractory CD20+ B-Cell (Follicular/Transformed) Non-Hodgkin's Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: rituximab
* Radiation: yttrium Y 90 ibritumomab tiuxetan


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed low-grade, follicular, or transformed CD20-positive B-cell non-Hodgkin's lymphoma (NHL) Relapsed after prior chemotherapy OR chemotherapy-resistant disease Failed at least 1 prior chemotherapy regimen CD20-positive B-cell population in lymph nodes or bone marrow for International Working Formulation A (small lymphocytic lymphoma) and transformed NHL Bone marrow involvement with lymphoma less than 25% bilaterally No impaired bone marrow reserve defined as at least 1 of the following criteria: Prior myeloablative therapies with bone marrow transplantation or peripheral blood stem cell rescue Platelet count less than 100,000/mm3 Bone marrow cellularity no greater than 15% Marked reduction in bone marrow precursors of one or more cell lines (e.g., granulocytic, megakaryocytic, or erythroid) Failed prior stem cell collection No CNS lymphoma, chronic lymphocytic lymphoma, or HIV or AIDS-related lymphoma No diffuse small lymphocytic/marginal zone lymphoma with lymphocyte count greater than 5,000/mm^3 No pleural effusion NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of indolent or aggressive lymphoma will replace the former terminology of low, intermediate, or high grade lymphoma. However, this protocol uses the former terminology. PATIENT CHARACTERISTICS: Age: 19 and over Performance status: WHO 0-2 Life expectancy: At least 6 months Hematopoietic: See Disease Characteristics Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Hematocrit greater than 30% Hemoglobin greater than 9.0 g/dL Hepatic: Bilirubin no greater than 1.5 mg/dL Renal: Creatinine no greater than 1.5 mg/dL Other: Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 6 months after study participation No anti-murine antibody reactivity if prior exposure to murine antibodies or proteins No other primary malignancy No other serious nonmalignant disease or infection that would preclude study participation PRIOR CONCURRENT THERAPY: Biologic therapy: See Disease Characteristics No prior radioimmunotherapy Prior rituximab allowed if more than 6 months to progression after an objective response At least 6 weeks since prior rituximab At least 3 weeks since prior filgrastim (G-CSF) or sargramostim (GM-CSF) Recovered from prior immunotherapy Chemotherapy: See Disease Characteristics No prior fludarabine At least 3 weeks since prior anticancer chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered No concurrent chemotherapy Endocrine therapy: At least 3 weeks since prior anticancer endocrine therapy No concurrent high-dose systemic corticosteroids (e.g., 50 mg or more of prednisone as a single dose or 50 mg or less of prednisone for more than 6 doses) Radiotherapy: No prior radiotherapy to more than 25% of active bone marrow (involved field or regional) At least 3 weeks since prior anticancer radiotherapy and recovered Surgery: At least 4 weeks since prior surgery (except diagnostic surgery) and recovered Other: No other concurrent anticancer therapy Concurrent oral anticoagulant therapy allowed if platelet count is at least 30,000/mm3

Ages Eligible for Study
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Minimum Age: 19 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>First radiation dose regimen of yttrium Y 90 ibritumomab tiuxetan | Biological: rituximab<br> <br> Radiation: yttrium Y 90 ibritumomab tiuxetan<br> <br> |
| Experimental: Cohort II<br>Second radiation dose regimen of yttrium Y 90 ibritumomab tiuxetan | Biological: rituximab<br> <br> Radiation: yttrium Y 90 ibritumomab tiuxetan<br> <br> |
| Experimental: Cohort III<br>Third radiation dose regimen of yttrium Y 90 ibritumomab tiuxetan | Biological: rituximab<br> <br> Radiation: yttrium Y 90 ibritumomab tiuxetan<br> <br> |
| Experimental: Cohort IV<br>Fourth radiation dose regimen of yttrium Y 90 ibritumomab tiuxetan | Biological: rituximab<br> <br> Radiation: yttrium Y 90 ibritumomab tiuxetan<br> <br> |
| Experimental: Cohort V<br>MTD radiation dose regimen of yttrium Y 90 ibritumomab tiuxetan | Biological: rituximab<br> <br> Radiation: yttrium Y 90 ibritumomab tiuxetan<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the maximum tolerated dose of yttrium Y 90 ibritumomab tiuxetan when administered in combination with rituximab in patients with relapsed or refractory low-grade, follicular, or transformed CD20-positive B-cell non-Hodgkin's lymphoma (NHL). |  | baseline through 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the toxicity of different doses of yttrium Y 90 ibritumomab tiuxetan in patients treated with this regimen |  | baseline through 4 years | 
| Determine the frequency of reversal of bone marrow involvement with NHL in patients treated with this regimen. |  | baseline through 4 years | 
| Determine the antitumor response in patients treated with this regimen. |  | baseline through 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma