Safety of Ibritumomab Tiuxetan (Zevalin®) in Combination With a Fludarabine-based Reduced Intensity Conditioning (RIC) Regimen (ZEVALLO 2007)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of Zevalin® in a Reduced Intensity Conditioning regimen followed by allogenic stem cell support in patients with aggressive lymphomas who are responsive to a salvage chemotherapy regimen.

Detailed Description
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The benefit of Zevalin® in the setting of autologous stem cell transplantation has been largely reported. The addition of Zevalin® to a fludarabine-based Reduced Intensity Conditioning regimen has been already evaluated in the setting of allo-SCT and the results reported so far seem to be promising without an overwhelming toxicity neither a delayed hematologic recovery. The assumption that the addition of Zevalin® to the conditioning regimen might improve lymphoma control and the demonstration that nucleoside analogs such as fludarabine synergize optimally with RIT led us to conduct this trial using the following preparative regimen: rituximab 250 mg/m² on days -21 and -14, Zevalin® 0,4 mCi/Kg body weight on day -14, fludarabine 30 mg/m² intravenously from days -6 to -2, Busulfan orally (4 mg/Kg body weight) or intravenously (0,8 mg/Kg body weight) on days -5 and -4 and ATG (Thymoglobulin®) 2,5 mg/Kg body weight intravenously on day -1. Cyclosporine A is administered at 2 or 3 mg/Kg body weight from day -1 to day 28 than followed by a dose reduction. The purpose of this study is to evaluate the safety and efficacy of Zevalin® in a Reduced Intensity Conditioning regimen followed by allogenic stem cell support in patients with aggressive lymphomas who are responsive to a salvage chemotherapy regimen Patients are followed from the beginning of the RIC regimen until day 365 for primary and secondary objectives of the study than on a regular basis depending on the practice of each centre. The evaluation includes physical examination (performance status, hematologic assessment, acute and chronic GVH disease), biologic tests (blood screening for blood count, renal and hepatic function, B and T-cell recovery, chimerism analysis, response assessment) and complementary examinations (marrow biopsies, tomography scan, positron emission tomography, …).

Official Title
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Safety and Efficacy of Ibritumomab Tiuxetan (Zevalin®) in Association With a Fludarabine Based Reduced Conditioning Regimen and Allogenic Stem Cell Support in Chemo-sensitive Relapsed CD20 Positive Aggressive Non-Hodgkin's Lymphoma Patients.

Conditions
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Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: Ibritumomab Tiuxetan (Zevalin)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 and ≤ 65 Patients with this lymphoma: CD20 positive diffuse large B-cell lymphoma in relapse or refractory after two prior regimens or after one regimen including autologous stem cell transplantation, or CD20 positive mantle-cell lymphoma in relapse or refractory after two prior regimens or after one regimen including autologous stem cell transplantation or Other CD20 positive aggressive lymphoma for which an indication of allograft is selected (Burkitt lymphoma, lymphoblastic lymphoma, intra-vascular lymphoma…..) or Low grade lymphoma CD20 positive (follicular lymphoma, marginal zone lymphoma) in histological processing or Low grade lymphoma CD20 positive for which an indication of allograft is selected And sensitive to relapse's treatment HLA-matched related or unrelated donor 10/10 or 9/10 with C or DQ mismatch without contra-indication for stem cell mobilization ECOG (Eastern Cooperative Oncology Group) < 2 Having or not received previously rituximab With a chemosensitive relapse NHL (at least partial response > 50% as defined with cheson criteria (See appendix 5) Eligible for an allogenic transplant With a signed informed consent (obtained on the screening day at the latest and before any investigation) Patient affiliated to or beneficiary of the National Health Service Exclusion Criteria: Patient allografted previously History of cancer Patient with HIV or HCV positive serology and requiring treatment Childbearing or child breastfeeding women Women who are pregnant or nursing, or man, in the absence of effective contraception during treatment and up to 12 months after stopping treatment Any contraindication to allogenic stem cell transplantation: Cardiac insufficiency (ejection fraction < 50% by echocardiography) Respiratory insufficiency defined as DLCO below 50% of the theoretical value Renal failure defined as creatinin clearance < 30 ml/mn Hepatic failure defined as a 2-fold increase of bilirubin or transaminases except if due to the lymphoma Known hypersensitivity to murine antibodies and other proteins, the active ingredients or any of the ingredients of the products under review Patient under the protection of justice

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Zevalin<br>Zevalin associated with a Fludarabine-based reduced-intensity conditioning regimen,all patients will receive Zevalin in the conditioning regimen | Drug: Ibritumomab Tiuxetan (Zevalin)<br>* Conditioning regimen followed by allogeneic hematopoietic stem cell transplantation. Ibritumomab Tiuxetan(Zevalin): 0.4 mCi/kg IV at day -14 (Day 0 is the transplantation)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the treatment-related mortality rate (except if the death is related to the lymphoma exclusively). |  | day 100 post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The event-free-survival (EFS)(an event is defined as: death from any cause, relapse or progression, need to another treatment except for donor-lymphocytes injection (DLI), patient lost for follow-up) |  | 1 year post transplant | 
| The rate of hematologic recovery (defined as ANC above 500/mm3 and platelets count above 20.000/mm3 for three consecutive days without stimulating growth support neither platelet transfusion) |  | day 30 | 
| Biological post allogenic effects of Zevalin® on the incidence of GVHD and B-cell and T-cell reconstitution |  | days d0, d28, d90, d180 and 1 year | 
| Chimérism |  | day d28, d56, d 80, 1 year than at least once a year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Zevalin, Reduced intensity conditioning, Allogenic stem cell transplantation