Combination Chemotherapy Followed By Autologous Stem Cell Transplant, and White Blood Cell Infusions in Treating Patients With Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as carmustine, etoposide, cytarabine, and melphalan work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. A peripheral stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. Giving white blood cells, that have been treated in the laboratory with antibodies, may make the transplant work better. Giving combination chemotherapy followed by an autologous stem cell transplant, and white blood cell infusions may be an effective treatment for non-Hodgkin's lymphoma. PURPOSE: This phase I trial is studying the side effects and best dose of white blood cell infusions when given together with combination chemotherapy, and autologous stem cell transplant in treating patients with non-Hodgkin's lymphoma that has relapsed, is refractory, or is in remission.

Detailed Description
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OBJECTIVES: Determine the toxicity of high-dose combination chemotherapy comprising cyclophosphamide, thiotepa, and carboplatin followed by autologous peripheral blood stem cell transplantation and immunotherapy consolidation therapy comprising anti-CD3 x anti-CD20 bispecific antibody (CD20Bi)-activated T cells (ATC) in patients with non-Hodgkin's lymphoma. Determine the maximum tolerated dose of CD20Bi-ATC in patients treated with this regimen. Determine whether ATC traffic to tumor sites in select patients treated with this regimen. Assess the immune reconstitution of B cells and incidence of infection in patients treated with this regimen. Compare relapse rates and overall survival of patients treated with this regimen with historical controls. OUTLINE: This is a dose-escalation study of activated T cells. Peripheral blood stem cell (PBSC) mobilization and collection: Patients receive filgrastim (G-CSF) subcutaneously (SC) once daily for 5 days. They then undergo leukaphereses to collect peripheral blood stem cells (PBSC). Some of the lymphocytes are treated in the laboratory to produce anti-CD3 x anti-CD20 bispecific antibody (CD20Bi)-activated T cells (ATC). High-dose chemotherapy and PBSC transplantation: Patients receive carmustine IV on day -7, etoposide IV twice daily and cytarabine IV twice daily on days -6, -5, -4, and -3, and melphalan IV on day -2. Autologous PBSC are reinfused on day 0. Immunotherapy consolidation: Patients receive immunotherapy consolidation comprising CD20Bi-ATC IV over 15-30 minutes starting on day 4, once a week for 4 weeks for a total of four infusions. Cohorts of 3-6 patients receive escalating doses of CD20Bi-ATC 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. After completion of study treatment, patients are followed periodically for survival. PROJECTED ACCRUAL: A total of 12-24 patients will be accrued for this study.

Official Title
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Immune Consolidation With Activated T Cells Armed With OKT3 x Rituxan (Anti-CD3 x Anti-CD20) Bispecific Antibody (CD20Bi) After Peripheral Blood Stem Cell Transplant for High Risk CD20+ Non-Hodgkin's Lymphomas

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: therapeutic autologous lymphocytes
* Drug: carmustine
* Drug: cytarabine
* Drug: etoposide
* Drug: melphalan
* Procedure: peripheral blood stem cell transplantation (PBSCT)


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed CD20+ non-Hodgkin's lymphoma Disease is refractory, relapsed, or in remission Measurable or evaluable disease PATIENT CHARACTERISTICS: Performance status ECOG 0-2 Life expectancy Not specified Hematopoietic Hemoglobin > 8 g/dL Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 50,000/mm^3 Hepatic Bilirubin ≤ 2.0 mg/dL SGOT or SGPT ≤ 2.5 times normal No history of severe hepatic dysfunction Renal Creatinine ≤ 2.0 mg/dL OR Creatinine clearance ≥ 60 mL/min No uncompensated major adrenal dysfunction BUN < 1.5 times normal Cardiovascular No severe cardiac dysfunction No major heart disease LVEF ≥ 50% by MUGA No uncontrolled hypertension No congenital or acquired heart disease or cardiac arrhythmias unless cardiac consult and evaluation are done Pulmonary DLCO ≥ 50% of normal No symptomatic obstructive or restrictive disease Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No active infections HIV negative No significant skin breakdown from tumor or other diseases Dental evaluation and teeth cleaning with no potential sources of infection required No uncompensated major thyroid dysfunction PRIOR CONCURRENT THERAPY: Biologic therapy No prior stem cell transplantation Chemotherapy No prior total doxorubicin or daunorubicin dose ≥ 450 mg/m^2 unless endomyocardial biopsy shows < grade 2 drug effect AND ejection fraction ≥ 50% by gated blood pool scan Endocrine therapy No concurrent hormonal therapy except steroids for adrenal failure, septic shock, or pulmonary toxicity or hormones for non-disease-related conditions (e.g., insulin for diabetes)

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 70 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: Autologous lymphocytes,carmustine,etoposide, melphalan, PBSCT<br>minus Day 8 ADMIT for Hydration minus Day 7 Carmustine 300 mg/m2 x 1 dose minus Day 6 Etoposide 100 mg/m2 q 12 hr; Cytarabine 100 mg/m2 q 12 hr minus Day 5 Etoposide 100 mg/m2 q 12 hr; Cytarabine 100 mg/m2 q 12 hr minus Day 4 Etoposide 100 mg/m2 q 12 hr; Cytarabine 100 mg/m2 q 12 hr minus Day 3 Etoposide 100 mg/m2 q 12 hr; Cytarabine 100 mg/m2 q 12 hr minus Day 2 Melphalan 140 mg/m2 x 1 dose minus Day 1 Day of Rest Day 0 Transplant | Biological: therapeutic autologous lymphocytes<br>* Lymphocytes collected by standard apheresis technique either prior to or post stem cell mobilization and collection<br>Drug: carmustine<br> <br> Drug: cytarabine<br> <br> Drug: etoposide<br> <br> Drug: melphalan<br> <br> Procedure: peripheral blood stem cell transplantation (PBSCT)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To perform a dose escalation trial of ATC armed with CD20Bi immunotherapy after PBSCT to determine the maximum tolerated dose (MTD) of ATC armed with CD20BI. | This will be the called the maximum tolerated dose. The maximum tolerated dose (MTD) is defined as the dose level below the one at which the side effects are serious enough to prevent an increase in the dose or level of the treatment. | When two patienst at any dose levet have their infusion stopped due to side effects. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the toxicities of ATC infusions armed with CD20Bi |  | 2 weeks (+/- 7 days), 1, 2, 3, 6 months (+/- 7 days) and 12, and 24 months (+/- one month) after Peripheral Blood Stem Cell Transplants (PBSCT) | 
| Evaluate immune B-cell recovery after ATC infusion |  | 2 weeks (+/- 7 days), 1, 2, 3, 6 months (+/- 7 days) and 12, and 24 months (+/- one month) after Peripheral Blood Stem Cell Transplants (PBSCT) | 
| Evaluate response rates of infusions and compare relapse rates and overall survival to historical controls | Survival follow-up: 1 year, 3 years, 5 years and 10 years after transplant. | 1, 2, 4, 8, 16 and/or 24, 48 and 72 hours post infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nodal marginal zone B-cell lymphoma, recurrent adult Burkitt 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 adult lymphoblastic lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, splenic marginal zone lymphoma, stage III adult Burkitt lymphoma, stage III adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage III adult lymphoblastic lymphoma, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage III mantle cell lymphoma, stage III marginal zone lymphoma, stage IV adult Burkitt lymphoma, stage IV adult diffuse large cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, stage IV adult immunoblastic large cell lymphoma, stage IV adult lymphoblastic lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage IV mantle cell lymphoma, stage IV marginal zone lymphoma, recurrent small lymphocytic lymphoma, stage III small lymphocytic lymphoma, stage IV small lymphocytic lymphoma, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II mantle cell lymphoma, noncontiguous stage II marginal zone lymphoma, noncontiguous stage II small lymphocytic lymphoma