Dose-Intensive Chemotherapy in Combination With Chemoprotected Autologous Stem Cells for Patients With Malignant Gliomas

• Dose-limiting toxicity (hematologic and non-hematologic) of temozolomide (Part I) [ Time Frame: For 6 weeks after infusion of genetically modified stem cells ] [ Designated as safety issue: Yes ]
  Toxicity will be assessed according to National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version Common Terminology Criteria for Adverse Events (CTCAE) v3.
  
  
• Dose-limiting toxicity (hematologic and non-hematologic) of temozolomide (Part II) [ Time Frame: For 28 days after each dose of O6-benzylguanine and temozolomide ] [ Designated as safety issue: Yes ]
  Toxicity will be assessed according to NCI CTC version CTCAE v3.
  
  
• Development of replication competent retrovirus or leukemia [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
  
• Allowable dose level for carmustine during conditioning [ Time Frame: One day after apheresis is completed (day -2 or -1) ] [ 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 (TTP) [ Time Frame: From the first day of treatment until unequivocal progression is documented, assessed up to 15 years ] [ Designated as safety issue: No ]
  
• Gene transfer efficiency and in vivo selection by gene marking in peripheral blood and marrow [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  
• Chemoprotection in terms of the ability to increase the temozolomide dose beyond 472 mg/m^2 [ Time Frame: After first 2 doses of O6-benzylguanine and temozolomide, provided that at least 1% MGMT(P140K)+ granulocytes cells are present ] [ Designated as safety issue: Yes ]
  

PRIMARY OBJECTIVES:

I. Determine the safety and feasibility of infusing autologous G-CSF (filgrastim) and plerixafor (Mozobil) mobilized stem cells transduced with a Phoenix-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.

PHASE I: Patients undergo radiotherapy 5 days per week for 7 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 aphereses). Plerixafor will be used if the CD34+ cell collection from the first apheresis is low or if on day 3 of mobilization the peripheral stem cell count is <5/mcL with G-CSF alone. 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 1 hour 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.

PHASE II: Beginning approximately 4 weeks after completion of phase 1 of the study, patients receive O6-benzylguanine IV continuously over 48 hours followed 2 hours later by temozolomide PO. 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 therapy, patients are followed every 1-3 months for the first 2 years, every 3-6 months for 3 years, and annually thereafter for up to 15 years.