BEAM vs. 90-Yttrium Ibritumomab Tiuxetan (Zevalin®)/BEAM With ASCT for Relapsed DLBCL

Study Overview
=================
Brief Summary
-----------------
This randomized phase III trial studies 90-yttrium ibritumomab tiuxetan and combination chemotherapy compared with combination chemotherapy alone before stem cell transplant in treating patients with diffuse large b-cell non-Hodgkin lymphoma that has returned after a period of improvement. Radioactive substances linked to monoclonal antibodies, such as 90-yttrium ibritumomab tiuxetan, can bind to cancer cells and give off radiation which may help kill cancer cells. Drugs used in chemotherapy, such as carmustine, etoposide phosphate, cytarabine, and melphalan (BEAM), work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether 90-yttrium ibritumomab tiuxetan and BEAM before a stem cell transplant are more effective than BEAM alone in treating patients with diffuse large b-cell non-Hodgkin lymphoma.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To compare overall survival (OS) between the two transplant arms, with at least a two year of follow-up. SECONDARY OBJECTIVES: I. To compare progression-free survival (PFS), complete response (CR) and partial response (PR) proportion at day 100, time to hematopoietic recovery, incidence of infection, grade III-IV toxicities, treatment-related mortality, incidence of myelodysplastic syndrome (MDS), and secondary acute myelogenous leukemia (AML). OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive rituximab intravenously (IV) on days -21 and -14, and 90-yttrium ibritumomab tiuxetan IV on day -14. Patients also receive BEAM comprising carmustine IV over 4 hours on day -6; cytarabine IV over 2 hours twice daily (BID) on days -5 to -2; etoposide IV over 1 hour BID or once daily (QD) on days -5 to -2; and melphalan IV on day -1. Patients then undergo peripheral blood stem cell (PBSC) transplant on day 0. ARM II: Patients receive BEAM as in Arm I and undergo PBSC transplant on day 0. After completion of study treatment, patients are followed up weekly for 30 days, 100 days, 6 months, 1 year, every 3 months for 1 year, and then annually for 3 years.

Official Title
-----------------
SPINOZA / שפינוזה. Study With Preparatory INduction Of Zevalin in Aggressive Lymphoma. A Randomized Phase 3 Study of BEAM Versus 90Yttrium Ibritumomab Tiuxetan (Zevalin) / BEAM in Patients Requiring ASCT for Relapsed DLBCL

Conditions
-----------------
Recurrent Diffuse Large B-Cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma

Intervention / Treatment
-----------------
* Radiation: 90-Yttrium Ibritumomab tiuxetan
* Drug: Carmustine
* Drug: Etoposide
* Drug: Cytarabine
* Drug: Melphalan
* Procedure: Autologous Hematopoietic Stem Cell Transplant
* Biological: Rituximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with CD20 positive diffuse large B-cell lymphoma as confirmed by a pathological biopsy report. Patients who are candidates for autologous stem-cell transplantation due to primary refractory or first relapse of disease. Patients must have chemo-sensitive disease achieving at least partial response (Cheson 2007 criteria) to last chemotherapy. Patients with adequate autologous stem cell collection for transplantation (target >= 2.5 x 10^6 CD34+ cells/kg). Patients must sign written informed consent. Adequate birth control in fertile patients. All prior chemotherapy completed at least three weeks before study treatment. Marrow involvement less than 25% at transplantation, no limitation on blood counts (low platelet count allowed). Negative HIV antibody. Exclusion Criteria: Chemo-refractory disease as determined by less than partial response (Cheson 2007 Criteria) to last chemotherapy. Two or more relapses after initial response to induction chemotherapy. High-grade transformation from earlier diagnosis of low-grade lymphoma. Patients with De Novo Transformed DLBCL, defined as DLBCL only on lymph node biopsy and a discordant marrow with para-trabecular small cells at first diagnosis of lymphoma, are eligible if adherent to all other selection criteria. Bilirubin > 3.0 mg/dl, transaminases > 3 times upper normal limit. Creatinine > 2.0 mg/dl. KPS < 70. Uncontrolled infection. Pregnancy or lactation. Abnormal lung diffusion capacity (DLCO < 40% predicted). Severe cardiovascular disease; New York Heart Association (NYHA) Functional Classification ≥2. Active CNS disease involvement. Presence of any other malignancy or history of prior malignancy within 5 years of study entry. Within 5 years, patients treated for Stage I or II cancers are eligible provided they have a life expectancy > 5 years in relation to this prior malignance. The 5-year exclusion rule does not apply to-non melanoma skin tumors and in situ cervical cancer. Pleural effusion or ascites > 1 liter. Known hypersensitivity to rituximab. Psychiatric conditions/disease that impair the ability to give informed consent or to adequately co-operate. Prior radioimmunotherapy. Prior autologous or allogeneic HSCT. Active evidence of Hepatitis B or C infection; Hepatitis B surface antigen positive. Patients who have had prior radiation to the lung will be excluded from the study, although mediastinal irradiation will be permitted if minimal lung is in the treatment volume. Patients who have received >500cGy radiation to the kidneys will be excluded from the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (ZBEAM)<br>Patients receive rituximab IV on days -21 and -14, and 90-yttrium ibritumomab tiuxetan IV on day -14. Patients also receive BEAM comprising carmustine IV over 4 hours on day -6; cytarabine IV over 2 hours BID on days -5 to -2; etoposide IV over 1 hour BID or QD on days -5 to -2; and melphalan IV on day -1. Patients then undergo autologous hematopoietic stem cell transplant on day 0. | Radiation: 90-Yttrium Ibritumomab tiuxetan<br>* 0.4 mCi/kg given IV<br>* Other names: Zevalin;Drug: Carmustine<br>* Given IV<br>* Other names: FDA 0345;Drug: Etoposide<br>* Given IV<br>* Other names: Lastet;Drug: Cytarabine<br>* Given IV<br>* Other names: U-19920;Drug: Melphalan<br>* Given IV<br>* Other names: Alkeran;Procedure: Autologous Hematopoietic Stem Cell Transplant<br>* Autologous Hematopoietic Stem Cell Transplantation (ASCT)<br>* Other names: Autologous Stem Cell Transplant;Biological: Rituximab<br>* Given IV<br>* Other names: MOAB IDEC-C2B8;|
| Active Comparator: Arm II (BEAM)<br>Patients receive BEAM comprising carmustine IV over 4 hours on day -6; cytarabine IV over 2 hours BID on days -5 to -2; etoposide IV over 1 hour BID or QD on days -5 to -2; and melphalan IV on day -1. Patients then undergo autologous hematopoietic stem cell transplant on day 0. | Drug: Carmustine<br>* Given IV<br>* Other names: FDA 0345;Drug: Etoposide<br>* Given IV<br>* Other names: Lastet;Drug: Cytarabine<br>* Given IV<br>* Other names: U-19920;Drug: Melphalan<br>* Given IV<br>* Other names: Alkeran;Procedure: Autologous Hematopoietic Stem Cell Transplant<br>* Autologous Hematopoietic Stem Cell Transplantation (ASCT)<br>* Other names: Autologous Stem Cell Transplant;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Survival estimates will be calculated using the Kaplan-Meier method | Measured from randomization to date of death or last follow up date, whichever occurs first, for up to 5 years post randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Survival estimates will be calculated using the Kaplan-Meier method | Measured from randomization until death, relapse/progression, receipt of anti-lymphoma therapy, or last follow up whichever comes first, for up to 5 years post randomization | 
| Time to Progression | Time-to-event will be measured from the date of ASCT. | Up to 5 years | 
| Number of Patients With Complete or Partial Response at Day 30 | Definition of disease status is based on the article of Revised Response Criteria for Malignant Lymphoma Response Definitions for Clinical Trials (Cheson et al, 2007). Tests used for evaluation of disease status would be physical examination, laboratory testing, bone marrow testing, bone marrow biopsy and aspirate, PET scan, and CT scans of neck, chest, abdomen and pelvis as indicated. | Day 0 to Day +30 post-HCT | 
| Time to Neutrophil Engraftment | Time to neutrophil engraftment will be compared between treatment arms using a log-rank test, and the cumulative incidence curves will be estimated. | Day 0 to Day 100 post-HCT | 
| Incidence of Infection | Microbiologically documented infections will be reported by site of disease, date of onset, severity, and resolution, if any. The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each patient. The proportion of patients developing infections will be compared between treatment arms. | Day 0 to Day +100 post-HCT | 
| Incidence of Non-relapse Mortality (NRM) Defined as Death Occurring in a Patient From Causes Other Than Relapse or Progression | The cumulative incidence of NRM will be estimated using the method described by Gooley et al. Differences between cumulative incidence curves in the presence of a competing risk will be tested using the Gray method. | From randomization until non-disease related death, or last follow-up, whichever comes first, assessed up to 5 years | 
| Cumulative Incidence of Secondary Malignancies | Incidence of myelodysplastic syndrome (MDS), and secondary acute Myelogenous leukemia (AML) will be compared between the treatment arms using Gray's test. | Up to 5 years | 
| Time to Platelet Engraftment | Time to platelet engraftment will be compared between treatment arms using a log-rank test, and the cumulative incidence curves will be estimated. | Day 0 to Day 100 post-HCT | 
| Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Observed toxicities will be summarized in terms of type and severity. In accordance with the secondary study objectives, descriptive analyses on these data will be performed. | Day -21 to Day +100 post-HCT | 
| Cumulative Incidence of New, Abnormal Cytogenetics | The cumulative incidence of therapy related new, abnormal cytogenetics will be estimated for both groups taking into account the competing risk of death among patients who do not develop a second malignancy. | Day 0 to Year 5 post-HCT | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Non-Hodgkin's lymphoma, autologous stem cell transplantation, radioimmunotherapy, Zevalin, Lymphoma, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Non-Hodgkin, Immune System Diseases, Immunoproliferative Disorders, Lymphatic Diseases, Lymphoma, B-Cell, Lymphoproliferative Disorders, Neoplasms, Neoplasms by Histologic Type, Antibodies, Monoclonal, Immunologic Factors, Pharmacologic Actions, Physiological Effects of Drugs