Gene Therapy and Chemotherapy in Treating Patients With Advanced Solid Tumors or Non-Hodgkin's Lymphoma

Sponsor

Case Comprehensive Cancer Center (Other)

Overall Status

Terminated

CT.gov ID

NCT00003567

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

93.1

Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Gene therapy may improve the body's ability to fight cancer or make the cancer more sensitive to chemotherapy. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: This phase I trial is studying the side effects and best dose of gene therapy together with chemotherapy in treating patients with advanced solid tumors or non-Hodgkin's lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors Lymphoma Unspecified Adult Solid Tumor, Protocol Specific	Biological: filgrastim Biological: sargramostim Biological: therapeutic autologous lymphocytes Drug: O6-benzylguanine Drug: carmustine Drug: temozolomide Procedure: in vitro-treated peripheral blood stem cell transplantation	Phase 1

Detailed Description

OBJECTIVES:

Evaluate the feasibility of introducing and expressing mutant MGMT-G156A cDNA in hematopoietic progenitors taken from patients with advanced solid tumors (including gliomas) or non-Hodgkin's lymphoma using a safety modified retroviral vector MFG.
Determine the toxicity associated with reinfusion of ex vivo-transduced hematopoietic stem cells into these patients, including the detection of replication competent retrovirus.
Evaluate the feasibility of identifying mutant MGMT-G156A-transduced and O6-benzylguanine (BG)- and temzolomide-resistant hematopoietic and stromal progenitors from the bone marrow of these patients.
Evaluate the feasibility of in vivo enrichment of the transduced hematopoietic progenitors in patients treated with BG and temzolomide.
Evaluate the toxicity of this regimen in these patients.
Determine the antitumor effect of this regimen in these patients.

OUTLINE: This is a dose-escalation study of CD34 stem cells and carmustine.

After a negative bone marrow sampling, patients receive sargramostim (GM-CSF) and filgrastim (G-CSF) subcutaneously (SC) once daily on days 1-5 (or G-CSF twice daily alone for 4-5 days). Peripheral blood progenitor cells are collected 24 hours after the last dose of growth factor injection on day 5 and also on day 6, if necessary. The CD34 positive stem cells are then infected by the retroviral mutant MGMT-G156A ex vivo.

Patients receive O6-benzylguanine (BG) IV over 1 hour followed by carmustine IV over 1 hour every 6 weeks for 5 courses, assuming recovery of peripheral blood counts. Approximately 72 hours after the end of the first course of chemotherapy, patients receive reinfusion of retrovirally-transduced hematopoietic stem cells over 5-10 minutes. Four weeks after the completion of BG and carmustine, patients receive BG IV over 1 hour followed by temozolomide IV over 1 hour every 4 weeks for up to 5 courses, in the absence of hematologic toxicity. Patients with responding disease may continue to receive BG and temzolomide in the absence of disease progression or unacceptable toxicity provided other phase II studies indicate the safety of more than 5 courses.

Cohorts of 3-6 patients receive escalating numbers of CD34 stem cells targeted for retroviral infection and escalating doses of carmustine.

Patients are followed monthly for 2 months, every 4 months for 8 months, and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 12-18 patients will be accrued for this study.

Study Design

Study Type:

Interventional

Actual Enrollment :

8 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Mutant MGMT Gene Transfer Into Human Hematopoietic Progenitors to Protect Hematopoiesis During O6-Benzylguanine (BG, NSC 637037) and Carmustine Followed by Temozolomide Therapy of Advanced Solid Tumors

Study Start Date :

May 1, 1999

Actual Primary Completion Date :

Jan 1, 2007

Actual Study Completion Date :

Feb 1, 2007

Outcome Measures

Primary Outcome Measures

Gene transfer expression [measured at days 28, 56, 84, and 112, and then every 3 months for 1 year]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

One of the following histologically confirmed diseases for which no curative surgical, radiotherapy, or chemotherapy programs are available and standard therapy offers, at best, a modest clinical benefit
Solid tumors
Gliomas
Non-Hodgkin's lymphoma
Primary and metastatic CNS malignancies are eligible
Evaluable or measurable disease
CD34 count at least 2.0 cells/μL
No bone marrow involvement
Histologically negative bone marrow biopsy

PATIENT CHARACTERISTICS:

Age:

18 to 70

Performance status:

ECOG 0-2

Life expectancy:

At least 12 weeks

Hematopoietic:

Absolute neutrophil count at least 1,500/mm^3
Platelet count at least 100,000/mm^3
Hemoglobin at least 8.5 g/dL

Hepatic:

Bilirubin no greater than 1.5 mg/dL
AST and ALT less than 2.5 times normal
Prothrombin time less than 1.2 times normal

Renal:

Creatinine no greater than 2.0 mg/dL

Cardiovascular:

No acute cardiac disease by EKG

Pulmonary:

No symptomatic pulmonary disease

Other:

HIV negative
No other severe comorbid conditions
Not pregnant or nursing
Fertile patients must use effective contraception during and for 2 months after study completion