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
filgrastim
+ sargramostim
+ therapeutic autologous lymphocytes
Brain Diseases+49
+ Central Nervous System Diseases
+ Chronic Disease
Treatment Study
Summary
Study start date: May 1, 1999
Actual date on which the first participant was enrolled.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.
Protocol
This section provides details of the study plan, including how the study is designed and what the study is measuring.8 patients to be enrolled
Total number of participants that the clinical trial aims to recruit.Treatment Study
Eligibility
Researchers look for people who fit a certain description, called eligibility criteria: person's general health condition or prior treatments.Any sex
Biological sex of participants that are eligible to enroll.From 18 to 70 Years
Range of ages for which participants are eligible to join.Healthy volunteers not allowed
If individuals who are healthy and do not have the condition being studied can participate.Conditions
Pathology
Criteria
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 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
Study Plan
Find out more about all the medication administered in this study, their detailed description and what they involve.Study Objectives
Primary Objectives
Study Centers
These are the hospitals, clinics, or research facilities where the trial is being conducted. You can find the location closest to you and its status.This study has 1 location
Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center
Cleveland, United StatesOpen Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center in Google Maps