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

Sponsor

Barbara Ann Karmanos Cancer Institute (Other)

Overall Status

Completed

CT.gov ID

NCT00244946

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

108

Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Biological: therapeutic autologous lymphocytes Drug: carmustine Drug: cytarabine Drug: etoposide Drug: melphalan Procedure: peripheral blood stem cell transplantation (PBSCT)	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

15 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Mar 1, 2004

Actual Primary Completion Date :

Jan 1, 2010

Actual Study Completion Date :

Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Autologous lymphocytes,carmustine,etoposide, melphalan, PBSCT 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 Lymphocytes collected by standard apheresis technique either prior to or post stem cell mobilization and collection Drug: carmustine Drug: cytarabine Drug: etoposide Drug: melphalan Procedure: peripheral blood stem cell transplantation (PBSCT)

Arm

Intervention/Treatment

Experimental: Autologous lymphocytes,carmustine,etoposide, melphalan, PBSCT

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

Lymphocytes collected by standard apheresis technique either prior to or post stem cell mobilization and collection

Drug: carmustine

Drug: cytarabine

Drug: etoposide

Drug: melphalan

Procedure: peripheral blood stem cell transplantation (PBSCT)

Outcome Measures

Primary Outcome Measures

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. [When two patienst at any dose levet have their infusion stopped due to side effects.]
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.

Secondary Outcome Measures

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 [1, 2, 4, 8, 16 and/or 24, 48 and 72 hours post infusion]
Survival follow-up: 1 year, 3 years, 5 years and 10 years after transplant.

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)