NCT01269424

BG & TMZ Therapy of Glioblastoma Multiforme

06-benzylguanine (BG) and Temozolomide (TMZ) Therapy of Glioblastoma Multiforme (GBM) in Patients With MGMT Positive Tumors With Infusion of Autologous P140KMGMT+ Hematopoietic Progenitors to Protect Hematopoiesis

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 10 (actual)
• Sponsor: Stanton Gerson MD · Academic / Other
• Sex: All
• Age: 18 Years – 70 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Glioblastoma Multiforme

Interventions

Type	Name	Description
BIOLOGICAL	MGMTP140K-encoding retroviral vector
DRUG	O6-benzylguanine
DRUG	temozolomide
OTHER	laboratory biomarker analysis
PROCEDURE	autologous hematopoietic stem cell transplantation
PROCEDURE	in vitro-treated peripheral blood stem cell transplantation
RADIATION	radiation therapy

Timeline

• Start date: 2011-11-22
• Primary completion: 2020-12-07
• Completion: 2022-09-26
• First posted: 2011-01-04
• Last updated: 2023-03-02

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study