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

NCT ID: NCT00003567

Last Updated: 2010-06-11

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 1999-05-31
• Study Completion Date: 2007-02-28

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.

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.

Conditions

Brain and Central Nervous System Tumors; Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Interventions

filgrastim

Patients receive filgrastim (G-CSF) subcutaneously (SC) once daily on days 1-5 (or G-CSF twice daily alone for 4-5 days).

Intervention Type: BIOLOGICAL

sargramostim

Patients receive sargramostim (GM-CSF) subcutaneously (SC) once daily on days 1-5 (or G-CSF twice daily alone for 4-5 days).

Intervention Type: BIOLOGICAL

therapeutic autologous lymphocytes

Intervention Type: BIOLOGICAL

O6-benzylguanine

Patients receive O6-benzylguanine (BG) IV over 1 hour every 6 weeks for 5 courses. Four weeks after the completion of BG and carmustine, patients receive BG 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.

Intervention Type: DRUG

carmustine

Patients receive carmustine IV over 1 hour every 6 weeks for 5 courses.Cohorts of 3-6 patients receive escalating numbers of CD34 stem cells targeted for retroviral infection and escalating doses of carmustine.

Intervention Type: DRUG

temozolomide

Four weeks after the completion of BG and carmustine, patients receive 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.

Intervention Type: DRUG

in vitro-treated peripheral blood stem cell transplantation

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

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• 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

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• See Chemotherapy
• No prior hematopoietic stem cell transplantation

Chemotherapy:

• No prior high-dose chemotherapy
• Prior adjuvant chemotherapy allowed

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy to 25% or more of bone marrow

Surgery:

• Not specified

Other:

• At least 4 weeks since prior myelosuppressive therapy

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Case Comprehensive Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center

Principal Investigators

Stanton L. Gerson, MD

Role: STUDY_CHAIR

Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center

Locations

Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center

Cleveland, Ohio, United States

Countries

United States

Other Identifiers

R21CA076192

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P30CA043703

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CASE-CWRU-2Y97

Identifier Type: OTHER

Identifier Source: secondary_id

NCI-T97-0060

Identifier Type: -

Identifier Source: secondary_id

CASE-2Y97

Identifier Type: OTHER

Identifier Source: secondary_id

CWRU2Y97

Identifier Type: -

Identifier Source: org_study_id