Bortezomib, Rituximab, and Yttrium Y 90 Ibritumomab Tiuxetan in Treating Patients With Relapsed or Refractory Low-Grade, Follicular, or Mantle Cell Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, and radiolabeled monoclonal antibodies, such as yttrium Y 90 ibritumomab tiuxetan, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them without harming normal cells. Giving bortezomib together with rituximab and yttrium Y 90 ibritumomab tiuxetan may kill more cancer cells. PURPOSE: This phase I trial is studying the side effects and best dose of bortezomib when given together with rituximab and yttrium Y 90 ibritumomab tiuxetan in treating patients with relapsed or refractory low-grade, follicular, or mantle cell non-Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose (MTD) of bortezomib in combination with rituximab and yttrium Y 90 ibritumomab tiuxetan in patients with relapsed or refractory low-grade, follicular B-cell, or mantle cell non-Hodgkin's lymphoma. Determine the dose-limiting toxicity of this regimen in these patients. Secondary Determine the response rate in patients treated with this regimen. OUTLINE: This is a multicenter, open-label, nonrandomized, dose-escalation study of bortezomib. Patients receive rituximab IV over 4 hours followed by indium In 111 ibritumomab tiuxetan IV over 10 minutes on day 1 to assess biodistribution. Patients without altered biodistribution receive rituximab IV over 4 hours followed by yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes on day 8. Patients also receive bortezomib IV over 3-5 seconds on days 4, 8, 11, and 15. Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Additional patients may be treated at the MTD. After completion of study treatment, patients are followed every 3 months for 18 months and then every 6 months thereafter.

Official Title
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A Phase I Study Evaluating Combined Zevalin (Ibritumomab Tiuxetan) and Valcade (Bortezomib) in Relapsed/Refractory Low-Grade or Follicular B-Cell and Mantle Cell Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: rituximab
* Drug: bortezomib
* Radiation: yttrium Y 90 ibritumomab tiuxetan
* Radiation: Indium 111 ibritumomab tiuxetan


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed low-grade, follicular B-cell, or mantle cell non-Hodgkin's lymphoma Bone marrow biopsy required for pretreatment evaluation Unilateral bone marrow biopsy allowed Core biopsies allowed if they contain adequate tissue for primary diagnosis and immunophenotyping Relapsed or refractory disease as defined by disease progression after initial complete response (CR) or failure to achieve CR No bone marrow involvement ≥ 25% within the past 30 days No pleural effusion or significant ascites No active CNS involvement PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy ≥ 3 months Platelet count ≥ 100,000/mm^3 Absolute neutrophil count ≥ 1,500/mm^3 AST ≤ 2.5 times upper limit of normal (ULN) Total bilirubin ≤ 2.5 times ULN Creatinine clearance ≥ 50 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Hepatitis B surface antigen negative No current infection with hepatitis B virus No HIV positivity No neuropathy or neuropathic pain ≥ grade 2 No history of allergic reaction to boron or mannitol No active serious infection or medical or psychiatric illness that would preclude study therapy No other malignancy within the past 5 years except for the following: Basal cell or squamous cell carcinoma of the skin that has been completely resected In situ malignancy that has been completely resected T1-T2a, N0, M0 prostate cancer treated with a prostatectomy or radiotherapy within the past 2 years with an undetectable PSA level No other condition, including any of the following: Myocardial infarction within the past 6 months New York Heart Association class III-IV heart failure Uncontrolled angina Severe uncontrolled ventricular arrhythmias Electrocardiographic evidence of acute ischemia or active conduction system abnormalities PRIOR CONCURRENT THERAPY: Recovered from all prior therapy More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C), radiotherapy, or surgical resection of malignancy No limitations on the number of prior therapies More than 4 weeks since prior major surgery More than 14 days since prior filgrastim (G-CSF) or sargramostim (GM-CSF) More than 14 days since prior and no other concurrent investigational agents Concurrent participation in a nontreatment study allowed No prior radioimmunotherapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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 |
| --- | --- |
| Other: Zevalin + Velcade Single Arm Study<br>Zevalin (Ibritumomab Tiuxetan) and Velcade (Bortezomib) | Biological: rituximab<br>* 250mg/m2, IV, Days 1 and 8<br>* Other names: Rituxan;Drug: bortezomib<br>* dose escalation 1.0, 1.3, or 1.5, IVP; Days 4, 8, 11, 15<br>* Other names: Velcade;Radiation: yttrium Y 90 ibritumomab tiuxetan<br>* Dose dependant upon platelet count (0.4mCi/kg) not to exceed 32mCi; Day 8<br>Radiation: Indium 111 ibritumomab tiuxetan<br>* 5cmCi; IV day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of bortezomib |  | 2 years | 
| Dose-limiting toxicity |  | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate |  | 5 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 mantle cell lymphoma, recurrent small lymphocytic lymphoma