BG & TMZ Therapy of Glioblastoma Multiforme

Summary

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Description

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 Glioblastoma multiforme (GBM) patients. To assess the safety associated with infusion of autologous hematopoietic stem ...

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 Glioblastoma multiforme (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 the efficacy of various types of chemotherapy with or without radiotherapy on conditioning the patient's bone marrow to host the transduced autologous hematopoetic stem cells. 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 radiotherapy (60cGy in 30 2cGy daily doses) and TMZ 75mg/m2 /daily for 6 weeks, cell infusion at week 7 (T0) followed by BG 120 mg/m2 intravenous infusion over 1h and TMZ 50 mg/m2/day x 5 days, every 28 days (starting on T+28) for 6 cycles. Cohort 2 (LV P140K MGMT gene transfer prior to concurrent chemoradiotherapy): Patients receive BG 120mg/m2 intravenous infusion over 1h and TMZ 400 mg/m2 one dose given on day T-2 or T-3 days prior to cell infusion, followed within 72-96 hours by radiotherapy (60cGy in 30 2cGy daily doses) and concurrent BG + TMZ at 50 mg/m2/day x 5 days, every 28 days,starting on T+28 for a total of 7 cycles of BG + TMZ. Cohort 3 (intra-patient dose escalation of TMZ in patients with evidence of P140K-marked cells): Dose escalation of TMZ in patients with evidence of P140K marked cells in vivo given as described above for cohort 1 or cohort 2. After completion of radiotherapy, patients will receive BG + TMZ at 50 mg/m2/day x 5 days. Patients not experiencing any grade 3 toxicity will be increased to the next TMZ dose level of 65 mg/m2/day x 5. Subsequent dose escalation without grade 3 toxicity will be 80 mg/m2/day, 100 mg/m2/day, 120mg/m2/day and 140 mg/m2/day x 5. If at subsequent cycles a grade 3 or greater hematologic toxicity occurs, the dose level for the next cycle will be reduced one level. 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.

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