BG & TMZ Therapy of Glioblastoma Multiforme
Condition: Glioblastoma Multiforme
MeSH terms: Glioblastoma
Study type: Interventional
Phase: Phase 1

Summary: 
      RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop
      the growth of tumor cells, either by killing the cells or by stopping them from dividing.
      O6-benzylguanine may help temozolomide work better by making tumor cells more sensitive to
      the drug. Giving genetically modified peripheral blood stem cells during or after treatment
      may prevent side effects caused by chemotherapy.

      PURPOSE: This clinical trial studies O6-benzylguanine and temozolomide in combination with
      genetically modified peripheral blood stem cells in treating patients with newly diagnosed
      glioblastoma multiforme.
    

Detailed 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 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.
    

Intervention name(s): MGMTP140K-encoding retroviral vector; O6-benzylguanine; temozolomide; laboratory biomarker analysis; autologous hematopoietic stem cell transplantation; in vitro-treated peripheral blood stem cell transplantation; radiation therapy
Intervention type(s): Biological; Drug; Drug; Other; Procedure; Procedure; Radiation
Intervention MeSH terms: Temozolomide; O(6)-benzylguanine
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: adult giant cell glioblastoma; adult glioblastoma; adult gliosarcoma