O6-Benzylguanine and Temozolomide in Combination With Genetically Modified Peripheral Blood Stem Cells in Newly Diagnosed Glioblastoma Multiforme

• Feasibility of infusing autologous P140K MGMT-transduced hematopoietic progenitors into patients with GBM [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
  Patients will be assessed for clinical symptoms and side-effects from time of treatment until protocol is stopped due to toxicity, progression, patient choice, or patient election to enroll on new therapeutic option.
  
  
• Safety (grade IV toxicity) [ Time Frame: up to 5 years ] [ Designated as safety issue: Yes ]
  CTCAE v 4.0 will be used as the criteria for evaluating infusion-related events.
  
  

• Successful transduction rate [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
  Quantitate P140K transduced hematopoietic cells from the bone marrow and peripheral blood in patients infused with P140K transduced CD34 progenitors
  
  
• To evaluate the in vivo enrichment of P140K expressing hematopoietic cells by repeated treatments of BG and TMZ [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
  To evaluate the in vivo enrichment of P140K expressing hematopoietic cells by repeated treatments of BG and TMZ
  
  
• Progression-free [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
  Progression-free survival defined as the time interval between the date of initial histological diagnosis and the date of disease progression or death, whichever comes first
  
  
• Number of patients with radiological progression [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
  New tumor or increased tumor size on T1WI + Gd of > 25% as measured by the sum of two perpendicular diameters compared to the smallest measurements ever recorded for the same lesion by the same technique.
  
  
• Overall Survival [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
  From the date of enrollment to death, last contact or last tumor assessment before further anti-tumor therapy, assessed up to 5 years.
  
  

OBJECTIVES:

Primary

• To evaluate the feasibility of introducing and expressing P140K MGMT cDNA from a lentiviral-based provirus in autologous hematopoietic stem cells harvested from GBM patients.
• To assess the safety associated with infusion of autologous hematopoietic stem cells transduced ex vivo with a lentiviral vector expressing P140K MGMT in patients with GBM.

Secondary

• To determine whether any patients who receive P140K MGMT-transduced CD34 cells tolerate O6-benzylguanine (BG) and dose-escalated temozolomide (TMZ) without myelosuppression.
• To evaluate the ability to detect P140K-transduced BG and TMZ-resistant hematopoietic cells from the bone marrow and peripheral blood in patients infused with P140K-transduced CD34 progenitors.
• To evaluate the feasibility of in vivo enrichment of P140K-expressing hematopoietic cells by repeated treatments of BG and TMZ at doses that appear therapeutic for GBM.
• To evaluate tumor response, progression-free survival, and overall survival.

OUTLINE: Patients are assigned to 1 of 3 treatment cohorts.

• Cohort 1 (LV P140K MGMT gene transfer after concurrent chemoradiotherapy): Patients receive concurrent radiotherapy 5 days a week and oral temozolomide (TMZ) daily for 6 weeks. Patients then undergo cell reinfusion of autologous P140K MGMT-transduced hematopoietic cells over 5-10 minutes at week 7. Beginning 4 weeks later, patients receive O6-benzylguanine (BG) IV over 1 hour on days 1-28 and oral TMZ on days 1-5. Treatment with BG and TMZ repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
• Cohort 2 (LV P140K MGMT gene transfer prior to concurrent chemoradiotherapy): Patients receive BG IV over 1 hour and a single dose of oral TMZ 2-3 days prior to reinfusion of autologous P140K MGMT-transduced hematopoietic cells over 5-10 minutes on day 0. Patients then undergo radiotherapy 5 days a week and receive concurrent BG daily and TMZ 5 days a week beginning on days 28 and 56. Beginning on day 56, treatment with BG and TMZ repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
• Cohort 3 (intra-patient dose escalation of TMZ in patients with evidence of P140K-marked cells [using the preferred treatment schema determined from Cohorts 1 and 2 above]): After completion of radiotherapy, patients receive BG and TMZ and undergo cell infusion as in cohort 1 (cohort 3a) or 2 (cohort 3b). TMZ dose may be increased, as tolerated, during the 6 courses after radiotherapy.

Blood samples are collected periodically for replication-competent lentivirus detection and other laboratory biomarker studies.

After completion of study therapy, patients are followed up every 2 months.