Monoclonal Antibody Therapy, Combination Chemotherapy, and Peripheral Stem Cell Transplant in Non-Hodgkin's Lymphoma

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Monoclonal antibodies can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplant may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. PURPOSE: This phase II trial is studying how well monoclonal antibody therapy, chemotherapy, and peripheral stem cell transplant work in treating patients with relapsed or refractory non-Hodgkin's lymphoma.

Detailed Description
-----------------
OBJECTIVES: Compare the response rates and time to treatment failure in patients with relapsed or refractory non-Hodgkin's lymphoma treated with iodine I 131 monoclonal antibody anti-B1, followed by high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM), and autologous peripheral blood stem cell transplantation (APBSCT) vs historical control patients treated with high-dose BEAM or carmustine, etoposide, cytarabine, and cyclophosphamide and APBSCT. Determine the safety of this regimen in these patients. OUTLINE: Autologous peripheral blood stem cells (PBSC) are harvested and selected for CD34+ cells or granulocyte macrophage colony-forming units. On day -19, patients receive unlabeled monoclonal antibody anti-B1 (MOAB anti-B1) IV followed by a dosimetric dose of iodine I 131 MOAB anti-B1 IV over 20 minutes. On day -12, patients receive unlabeled MOAB anti-B1 IV followed by a therapeutic dose of iodine I 131 MOAB anti-B1 IV over 20 minutes. Patients then receive high-dose chemotherapy comprising carmustine IV on day -6, etoposide IV and cytarabine IV twice daily on days -5 to -2, and melphalan IV on day -1. Patients undergo autologous PBSC transplantation on day 0. Patients are followed at days 30 and 100, at 6 months, and then annually thereafter. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study over 5 years.

Official Title
-----------------
BEAM Plus Iodine-131 Anti-B1 Antibody and Autologous Hematopoietic Stem Cell Transplantation for Treatment of Recurrent Diffuse Large B-Cell Non-Hodgkin's Lymphoma

Conditions
-----------------
Lymphoma

Intervention / Treatment
-----------------
* Drug: carmustine
* Drug: cytarabine
* Drug: etoposide
* Drug: melphalan
* Procedure: peripheral blood stem cell transplantation
* Radiation: tositumomab and iodine I 131 tositumomab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of non-Hodgkin's lymphoma (NHL) of one of the following types: Diffuse large B-cell Composite (at least 50% of tumor showing diffuse histology) Diffuse mixed cell Immunoblastic Relapsed or refractory disease sensitive to initial or subsequent conventional therapy (at least a partial response) Eligible for high-dose carmustine, etoposide, cytarabine, and melphalan protocol and autologous bone marrow transplantation or peripheral blood stem cell transplantation Evidence of CD20 antigen expression in tumor tissue Bidimensionally measurable disease Adequate peripheral blood stem cells At least 15,000,000 CD34+ cells/kg or At least 25,000 granulocyte macrophage colony-forming units/kg Age: 19 to 70 Performance status: Karnofsky 70-100% Life expectancy: at least 4 months post-transplantation Bilirubin less than 2.0 mg/dL Creatinine less than 2.0 mg/dL Cardiac ejection fraction at least 40% for any of the following criteria: Age 60 and over Significant cardiac history (myocardial infarction or congestive heart failure) Received greater than 350 mg/m^2 of prior doxorubicin DLCO at least 50% of predicted HIV negative Fertile patients must use effective contraception during and for at least 6 months after study participation At least 4 weeks since prior biologic therapy and recovered Human antimouse antibody negative At least 4 weeks since prior cytotoxic chemotherapy and recovered At least 4 weeks since prior radiotherapy and recovered At least 4 weeks since prior immunosuppressants and recovered Exclusion Criteria: No progressive disease in a field that has been previously irradiated with more than 3,500 cGy within the past year No known brain or leptomeningeal metastases No active obstructive hydronephrosis No New York Heart Association class III or IV heart disease No evidence of severe organ dysfunction No other major medical illnesses No active infection requiring IV antibiotics No other malignancy within the past 5 years except adequately treated skin cancer or carcinoma in situ of the cervix Not pregnant/negative pregnancy test No prior peripheral blood stem cell transplantation following high-dose chemotherapy or chemoradiotherapy No other concurrent biologic therapy for NHL No concurrent steroids except maintenance-dose steroids for noncancerous disease No concurrent external beam radiotherapy for NHL No other concurrent participation on protocol involving non-FDA-approved drugs or biologics

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Iodine-131 Anti-B1 Antibody/BEAM/autologous hematopoietic stem cell transplantation (AHSCT) | Drug: carmustine<br>* 300 mg/m2 IV on Day -6<br>* Other names: BCNU;Drug: cytarabine<br>* 100 mg/m2 BID on Days -5 through -2<br>* Other names: cytosine arabinoside;Drug: etoposide<br>* 100 mg/m2 BID on Days -5 through -2<br>* Other names: Etopophos, Toposar;Drug: melphalan<br>* 140 mg/m2 IV on Day -1<br>* Other names: Evomela;Procedure: peripheral blood stem cell transplantation<br>* Following the chemotherapy, on Day 0 of treatment, the previously stored hematopoietic stem cells will be administered to the patient intravenously through a central line to the patient.<br>* Other names: Autologous Hematopoietic Stem Cell Transplantation;Radiation: tositumomab and iodine I 131 tositumomab<br>* Patients will receive two administrations of Iodine-131 Anti-B1 Antibody; the dosimetric dose and the therapeutic dose. The dosimetric dose will consist of an infusion of unlabeled Anti-B1 Antibody (450 mg) immediately followed by an infusion of Anti-B1 Antibody (35 mg) which has been trace labeled with 5 mCi of Iodine-131 Anti-B1 Antibody. Using whole body anterior and posterior gamma camera scans and serial imaging studies over approximately one week, the clearance of the whole body dosimetric dose will be used to calculate the subsequent therapeutic dose of Iodine-131 Anti-B1 Antibody which delivers a total body dose of 75 cGy to the subject<br>* Other names: Iodine-131 Anti-B1 Antibody;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival rate | Participant survival without adverse events or progression | 100 days post transplant and at yearly intervals | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to treatment failure | Time from registration to time of treatment discontinuation or withdrawal for progression | time of registration to time of treatment discontinuation or withdrawal for progression | 
| Overall survival | Time from first participant enrollment to last participant death or end of study | Time from registration to last participant death | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult immunoblastic large cell lymphoma