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
- 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
- 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
PROJECTED ACCRUAL: A total of 12-18 patients will be accrued for this study.
- 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
- 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
- 18 to 70
- ECOG 0-2
- At least 12 weeks
- Absolute neutrophil count at least 1,500/mm^3
- Platelet count at least 100,000/mm^3
- Hemoglobin at least 8.5 g/dL
- 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
- Creatinine no greater than 2.0 mg/dL
- No acute cardiac disease by EKG
- No symptomatic pulmonary disease
- HIV negative
- No other severe comorbid conditions
- Not pregnant or nursing
- Fertile patients must use effective contraception during and for 2 months after study
PRIOR CONCURRENT THERAPY:
- See Chemotherapy
- No prior hematopoietic stem cell transplantation
- No prior high-dose chemotherapy
- Prior adjuvant chemotherapy allowed
- Not specified
- No prior radiotherapy to 25% or more of bone marrow
- Not specified
- At least 4 weeks since prior myelosuppressive therapy
Stanton L. Gerson, MD
Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center