O6-Benzylguanine-Mediated Tumor Sensitization With Chemoprotected Autologous Stem Cell in Treating Patients With Malignant Gliomas

• Chemoprotection, assessed by the ability to increase the temozolomide dose beyond 472 mg/m^2 [ Time Frame: Up to 96 weeks ] [ Designated as safety issue: No ]
  
• Duration of response [ Time Frame: From the onset of temozolomide to the date at which unequivocal disease progression, assessed up to 15 years ] [ Designated as safety issue: No ]
  
• Gene transfer efficiency and in vivo selection, assessed by gene marking in peripheral blood and marrow [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  
• Incidence of DLT (Part Ii) [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]
  
• Incidence of dose-limiting toxicity (DLT) defined as any grade 4 nonhematopoietic toxicity that is likely related to the investigational procedures (Part I) [ Time Frame: Up to 6 weeks after infusion ] [ Designated as safety issue: Yes ]
  
• Incidence of replication competent retrovirus or leukemia [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
  
• Response rate [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  
• Survival [ Time Frame: From the first day of treatment until death, assessed up to 15 years ] [ Designated as safety issue: No ]
  
• Time to progression [ Time Frame: From the first day of treatment until unequivocal progression is documented, assessed up to 15 years ] [ Designated as safety issue: No ]
  

PRIMARY OBJECTIVES:

I. Determine the safety and feasibility of infusing autologous granulocyte colony-stimulating factor (G-CSF) (filgrastim) mobilized stem cells transduced with a Phoenix-gibbon ape leukemia virus (GALV)-pseudotype vector expressing methylguanine methyltransferase (MGMT) (P140K).

II. Define the dose of BCNU (carmustine) that results in efficient engraftment of gene modified cells when given with peripheral blood stem cell support.

SECONDARY OBJECTIVES:

I. Determine the engraftment of gene-modified cells after conditioning with BCNU.

II. Determine the ability to select gene-modified cells in vivo with this regimen.

III. Evaluate the molecular and clonal composition of gene-modified cells after chemotherapy with temozolomide.

IV. Observe patients for clinical anti-tumor response.

V. Determine the correlation of the level of MGMT (P140K) marking with toxicity, temozolomide dose achieved, and response.

VI. Characterize the toxicity associated with this regimen.

OUTLINE: This is a phase I, dose-escalation study of temozolomide followed by a phase II study.

PART I: Within 35 days of surgery, patients undergo 3 dimensional (3D) conformal intensity-modulated radiation therapy (IMRT) or proton beam radiation therapy daily 5 days per week for 6 weeks. Patients receive filgrastim subcutaneously (SC) on days -7 to -3 and begin stem cell collection on the 4th day of filgrastim administration (up to 3 apheresis). Patients may also receive plerixafor SC on days -5 to -3. The CD34+ stem cells are separated from the patient's stem cells and they are transduced with Phoenix-RD114 pseudotype vector (retrovirus). One day after apheresis is completed, patients receive carmustine intravenously (IV) over 3 hours followed 2 hours later by temozolomide orally (PO). At least twenty-four hours after completion of carmustine and temozolomide, patients undergo reinfusion of genetically-modified stem cells.

PART II: Beginning approximately 4 weeks after completion of Phase 1 of the study, patients receive O6-benzylguanine IV continuously over 48 hours followed by temozolomide PO within 1 hour. Treatment may repeat at least every 28 days for a total of 24 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 1-3 months for 2 years, every 3-6 months for 3 years, and then annually thereafter for 10 years.