Trial Information

A Pilot Study of Temozolomide and O-Benzylguanine for Treatment of High-Grade Glioma, Using Autologous Peripheral Blood Stem Cells Genetically Modified for Chemoprotection

OBJECTIVES:

Primary

- Determine the safety and feasibility of a conditioning regimen comprising temozolomide,
radiotherapy, and busulfan followed by an infusion of autologous stem cells genetically
modified with the MGMT gene and temozolomide and O6-benzylguanine in younger patients
with newly diagnosed high-grade gliomas.

Secondary

- Determine the tolerability of intrapatient dose escalation of temozolomide, in terms of
transgene expression, in patients treated with this regimen.

- Determine, preliminarily, the antitumor activity of this regimen in these patients.

OUTLINE: This is a pilot study.

- Surgery: Patients undergo biopsy or surgical debulking of the tumor. Two to six weeks
later, patients proceed to stem cell mobilization and apheresis.

- Autologous stem cell mobilization and apheresis: Patients receive filgrastim (G-CSF)
subcutaneously or IV once daily for at least 4 days before apheresis and continuing
until apheresis is complete. Patients undergo apheresis for up to 4 consecutive days
until a target number of 5 X 10^6 CD34-positive peripheral blood stem cells (PBSCs) are
collected. Patients with insufficient numbers of PBSCs either undergo bone marrow
harvest to collect a sufficient number of cells or are removed from the study. The
cells are selected for CD34-positive cells which are cryopreserved for later use.
Patients then proceed to chemoradiotherapy.

- Chemoradiotherapy: Patients receive oral temozolomide once daily on days 1-42 and
undergo radiotherapy once daily, 5 days a week, for 6 weeks. Four to eight weeks later,
patients proceed to the low-intensity, nonmyeloablative conditioning regimen.

- Autologous PBSC or bone marrow transduction: Peripheral blood or bone marrow
CD34-positive stem cells are transduced with the MGMT gene on day -4.

- Low-intensity, nonmyeloablative conditioning regimen: Patients receive busulfan IV over
2 hours on days -3 and -2. Patients then proceed to autologous PBSC or bone marrow
infusion.

- Autologous PBSC or bone marrow infusion: Patients undergo autologous stem cell infusion
using transduced PBSCs or bone marrow on day 0. Three to six weeks later, patients
proceed to chemotherapy.

- Chemotherapy: Patients receive O6-benzylguanine IV over 1 hour followed by oral
temozolomide once daily on days 1-5. Treatment repeats every 4 weeks for up to 6
courses in the absence of disease progression or unacceptable toxicity. Patients
experiencing unacceptable toxicity due to O6-benzylguanine may receive temozolomide
alone. Patients not experiencing dose-limiting toxicity and who have at least 5%
transduced neutrophils by peripheral blood analysis after course 1 receive escalating
doses (intrapatient) of temozolomide during courses 2-6. Some patients undergo
second-look surgery after the first course of chemotherapy.

After completion of study therapy, patients are followed monthly for 3 months, every 3
months for 3 years, every 6 months for 4 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 10 patients will be accrued for this study within 1-2 years.