Dose-Intensive Chemotherapy in Combination With Chemoprotected Autologous Stem Cells for Patients With Malignant Gliomas
I. Determine the safety and feasibility of infusing autologous G-CSF (filgrastim) and
plerixafor (Mozobil) mobilized stem cells transduced with a Phoenix-GALV-pseudotype vector
expressing methylguanine methyltransferase (MGMT) (P140K).
II. Define the dose of BCNU (carmustine) that results in efficient engraftment of gene
modified cells when given with peripheral blood stem cell support.
I. Determine the engraftment of gene-modified cells after conditioning with BCNU.
II. Determine the ability to select gene-modified cells in vivo with this regimen.
III. Evaluate the molecular and clonal composition of gene-modified cells after chemotherapy
with temozolomide. IV. Observe patients for clinical anti-tumor response. V. Determine the
correlation of the level of MGMT (P140K) marking with toxicity, temozolomide dose achieved,
VI. Characterize the toxicity associated with this regimen.
OUTLINE: This is a phase I, dose-escalation study of temozolomide followed by a phase II
PHASE I: Patients undergo radiotherapy 5 days per week for 7 weeks. Patients receive
filgrastim subcutaneously (SC) on days -7 to -3 and begin stem cell collection on the 4th
day of filgrastim administration (up to 3 aphereses). Plerixafor will be used if the CD34+
cell collection from the first apheresis is low or if on day 3 of mobilization the
peripheral stem cell count is <5/mcL with G-CSF alone. The CD34+ stem cells are separated
from the patient's stem cells and they are transduced with Phoenix-RD114 pseudotype vector
(retrovirus). One day after apheresis is completed, patients receive carmustine
intravenously (IV) over 1 hour followed 2 hours later by temozolomide orally (PO). At least
twenty-four hours after completion of carmustine and temozolomide, patients undergo
reinfusion of genetically-modified stem cells.
PHASE II: Beginning approximately 4 weeks after completion of phase 1 of the study, patients
receive O6-benzylguanine IV continuously over 48 hours followed 2 hours later by
temozolomide PO. Treatment may repeat at least every 28 days for a total of 24 courses in
the absence of disease progression or unacceptable toxicity.
After completion of study therapy, patients are followed every 1-3 months for the first 2
years, every 3-6 months for 3 years, and annually thereafter for up to 15 years.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Dose-limiting toxicity (hematologic and non-hematologic) of temozolomide (Part I)
Toxicity will be assessed according to National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version Common Terminology Criteria for Adverse Events (CTCAE) v3.
For 6 weeks after infusion of genetically modified stem cells
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
United States: Food and Drug Administration
|Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium||Seattle, Washington 98109|