Yttrium Y 90 Ibritumomab Tiuxetan, Etoposide, Cyclophosphamide, and an AHSCT in Non-Hodgkin's Lymphoma Patients

Study Overview
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Brief Summary
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RATIONALE: Radiolabeled monoclonal antibodies, such as yttrium Y 90 ibritumomab tiuxetan, can find cancer cells and carry tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as etoposide and cyclophosphamide, work in different ways to kill cancer cells or stop them from growing. Giving radiolabeled monoclonal antibodies together with etoposide and cyclophosphamide before a peripheral blood stem cell transplant may be an effective treatment for non-Hodgkin lymphoma. PURPOSE: This phase I/II trial is studying the side effects and best dose of yttrium Y 90 ibritumomab tiuxetan when given together with etoposide and cyclophosphamide followed by an autologous stem cell transplant and to see how well it works in treating patients with non-Hodgkin lymphoma.

Detailed Description
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OBJECTIVES: To evaluate the safety and efficacy of a new preparative regimen of yttrium Y 90 ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation (ASCT) for treatment of patients with poor-risk, relapsed, or refractory non-Hodgkin lymphoma (NHL). To determine the maximum tolerated dose of yttrium Y 90 ibritumomab tiuxetan which can be given with high-dose etoposide and high-dose cyclophosphamide followed by ASCT in patients with NHL. To perform dosimetry study to estimate the radiation dose delivered to the tumor and normal organs. To evaluate the short-term and long-term complications of this new preparative regimen. OUTLINE: This is a phase I does-escalation study of yttrium Y 90 ibritumomab tiuxetan followed by an open-label phase II study. Preparation for transplantation: Peripheral blood stem cells (PBSCs) are collected via leukapheresis. Samples are analyzed by cytogenetic studies, immunophenotyping, and gene rearrangement. Patients with an adequate number of collected CD34-positive cells (≥ 3 times 10^6 /kg) proceed to radioimmunotherapy. Radioimmunotherapy: Patients receive yttrium Y 90 ibritumomab tiuxetan IV on days -21 and -14. Patients undergo bone marrow biopsy and dose estimation on day -7. Chemotherapy: Patients receive etoposide IV on day -4 and cyclophosphamide IV over 2 hours on day -2. Transplantation: Patients undergo reinfusion of PBSCs on day 1. Growth factor therapy: Patients receive filgrastim (G-CSF) IV beginning on day 1 and continuing until blood counts recover. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically.

Official Title
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A Phase I/II Trial of Escalating Dose of Yttrium-90-labeled Anti-CD20 Monoclonal Antibody in Combination With High-Dose Etoposide and Cyclophosphamide Followed by AHSCT for Patients With Relapsed B-Cell Non-Hodgkin's Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: filgrastim
* Drug: cyclophosphamide
* Drug: etoposide
* Procedure: AHSCT
* Radiation: yttrium Y 90 ibritumomab tiuxetan


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Biopsy proven diagnosis of low- or intermediate-grade* non-Hodgkin lymphoma (NHL) including any of the following: Follicular small cleaved Follicular mixed Follicular large cell Diffuse small cleaved Diffuse mixed Diffuse large cell Immunoblastic (working formulation B, C, D, E, F, G and H) NOTE: *A new classification scheme for adult non-Hodgkin 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. Mantle cell and transformed low-grade lymphomas allowed Demonstrated monoclonal CD20-positive B-cell population in lymph nodes and/or bone marrow Favorable biodistribution on imaging dose Patient either relapsed after achieving a complete (CR) or partial response (PR) to prior therapy, never responded to prior therapy, or has poor-risk disease Sensitivity of disease based on 1 of the following: Induction failure: patients who did not achieve a CR or PR from induction chemotherapy Resistant relapse: patients who did not achieve a CR or PR from the most recent standard salvage chemotherapy Sensitive relapse: patients who did achieve a CR or PR from the most recent standard salvage chemotherapy Poor-risk disease defined as any of the following: Age-adjusted International Prognostic Index (IPI) High- (3 risk factors) or High-Intermediate (2 risk factors) based on the following risk factors: Stage III-IV disease Elevated serum lactate dehydrogenase level ECOG performance status 2-4 Patients with aggressive NHL including mantle cell lymphoma and who required 2 different induction chemotherapy regimens to achieve a CR/PR Patients with B-cell NHL and who failed to achieve a CR after adequate induction chemotherapy regimen(s) Patients must have bone marrow aspiration and biopsy within 42 days before salvage chemotherapy or stem cell collection which show ≤ 10% lymphomatous involvement of total cellularity Normal cytogenetic study on bone marrow (prior to salvage chemotherapy or stem cell collection) Cytogenetic study on peripheral blood is acceptable if bone marrow biopsy has already been done and shows no sign of myelodysplastic syndrome (MDS) or lymphoma and a repeat bone marrow is deemed unnecessary by attending physician No active or prior history of CNS diseases No human anti-mouse antibody (HAMA) or human anti-chimeric antibody PATIENT CHARACTERISTICS: ECOG performance status (PS) 0-1 or Karnofsky PS 80-100% Platelet count normal Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 60 mL/min FEV_1 > 65% of predicted or DLCO ≥ 50% of predicted LVEF > 50% by ECHO or MUGA scan Bilirubin ≤ 1.5 times normal SGOT or SGPT ≤ 2 times normal HIV antibody-negative No prior malignancy except for adequately treated basal cell or squamous cell skin cancer, adequately treated noninvasive carcinoma, or other cancer from which the patient has been disease-free for at least five years No active evidence of hepatitis B or C infection No hepatitis B surface antigen positivity No history of alcohol abuse Body weight ≤ 250 pounds PRIOR CONCURRENT THERAPY: See Disease Characteristics Patients who have received involved field external beam therapy to area excluding lung, heart, liver and kidney are allowed, but will be evaluated on a case-by-case basis Patients must have recovered from last therapy and should be at least four weeks from prior radiation or chemotherapy No prior radioimmunotherapy No prior bone marrow transplantation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zevalin 1000 cGy + VP-16 40 mg/kg + Cytoxan 100 mg/kg<br>Preparation for AHSCT: Peripheral blood stem cells (PBSCs) are collected via leukapheresis. Samples are analyzed by cytogenetic studies, immunophenotyping, and gene rearrangement. Patients with an adequate number of collected CD34-positive cells (≥ 3 times 10^6 /kg) proceed to radioimmunotherapy. Radioimmunotherapy: Patients receive yttrium Y 90 ibritumomab tiuxetan and undergo bone marrow biopsy and dose estimation. Chemotherapy: Patients receive etoposide IV and cyclophosphamide IV AHSCT: Patients undergo reinfusion of PBSCs. Growth factor therapy: Patients receive filgrastim (G-CSF) IV. Treatment continues in the absence of disease progression or unacceptable toxicity. | Biological: filgrastim<br> <br> Drug: cyclophosphamide<br> <br> * Other names: Cytoxan;Drug: etoposide<br> <br> * Other names: VP-16;Procedure: AHSCT<br> <br> * Other names: autologous hematopoietic stem cell transplantation;Radiation: yttrium Y 90 ibritumomab tiuxetan<br> <br> * Other names: Zevalin;|
| Experimental: Zevalin 1000 cGy + VP-16 60 mg/kg + Cytoxan 100 mg/kg<br>Preparation for AHSCT: Peripheral blood stem cells (PBSCs) are collected via leukapheresis. Samples are analyzed by cytogenetic studies, immunophenotyping, and gene rearrangement. Patients with an adequate number of collected CD34-positive cells (≥ 3 times 10^6 /kg) proceed to radioimmunotherapy. Radioimmunotherapy: Patients receive yttrium Y 90 ibritumomab tiuxetan and undergo bone marrow biopsy and dose estimation. Chemotherapy: Patients receive etoposide IV and cyclophosphamide IV AHSCT: Patients undergo reinfusion of PBSCs. Growth factor therapy: Patients receive filgrastim (G-CSF) IV. Treatment continues in the absence of disease progression or unacceptable toxicity. | Biological: filgrastim<br> <br> Drug: cyclophosphamide<br> <br> * Other names: Cytoxan;Drug: etoposide<br> <br> * Other names: VP-16;Procedure: AHSCT<br> <br> * Other names: autologous hematopoietic stem cell transplantation;Radiation: yttrium Y 90 ibritumomab tiuxetan<br> <br> * Other names: Zevalin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Achieving Complete Response (CR) | Complete response is defined as complete disappearance of all measureable evidence of non-evaluable disease. No new lesions. No disease related symptoms. No evidence of non-evaluable disease, including normalization of markers and other abnormal lab values. All measureable, evaluable and non-evaluable lesions and sites must be assessed using the same techniques as baseline. | Assessed up to 5 years post-ASCT | 
| Number of Patients With Grade 3 or Greater Toxicity | The NCI Common Toxicity Criteria (CTC Version 2.0) are used. The patients, whose toxicities are grade 3 or greater and at possibly related to the study treatment, are reported. | From initial of study treatment to Day 100 post-ASCT | 
| 5-Year Overall Survival (Phase II) | Overall survival (OS) was measured from peripheral stem cell infusion to death from any cause. It was estimated using the Kaplan-Meier method; the 95% confidence interval was calculated using Greenwood's formula. [Breslow NE, Day NE. Statistical methods in cancer research: volume II, the design and analysis of cohort studies. IARC Sci Publ 1987;82:1-406.] | From peripheral stem cell infusion (Day0 ASCT) to death due to any cause, assessed up to 5 years | 
| 5-Year Disease-free Survival (Phase II) | Disease-free survival (DFS) was defined as time from peripheral stem cell infusion to relapse or death. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works. Disease-free survival was estimated using the Kaplan-Meier method; the 95% confidence interval was calculated using Greenwood's formula [Breslow NE, Day NE. Statistical methods in cancer research: volume II, the design and analysis of cohort studies. IARC Sci Publ 1987;82:1-406.] | From peripheral stem cell infusion (Day0 ASCT) to first observation of relapse or death due to any cause, whichever comes first, assessed up to 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 adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent mantle cell lymphoma, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage III adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage IV adult diffuse large cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, stage III mantle cell lymphoma, stage IV mantle cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage IV adult immunoblastic large cell lymphoma