Anaplastic Astrocytoma (WHO Grade III) Clinical Trial
Official title:
A Pilot Study of Temozolomide and 06Benzylguanine for Treatment of Newly Diagnosed High Grade Glioma, Using Autologous Peripheral Blood Stem Cells Genetically Modified for Chemoprotection
Cure rates for patients with high grade glioma remain disappointing, in part because tumor cells are often resistant to chemotherapy, and because using higher doses of chemotherapy causes damage to normal blood cells. This trial is designed to try to overcome both of these barriers. The idea is to make tumor cells more sensitive to a chemotherapy agent, Temozolomide, by using 06Benzylguanine (06BG). In addition, patients will have a portion of their blood cells modified by the insertion of a chemotherapy resistance gene which may help protect blood cells from damage by the combination of the Temozolomide and 06BG.
The use of temozolomide (TEM) both during and after irradiation is a promising new approach
for the treatment of patients with high-grade glioma. However, this treatment is limited by
tumor cell resistance and therapy-related hematologic toxicity. To overcome TEM resistance,
in this study we will add the chemotherapy sensitizing drug O6-Benzylguanine (BG). To
overcome hematologic toxicity, patients will receive autologous hematopoietic stem cells
transduced with a chemotherapy resistance gene designed to protect these cells from
subsequent therapy with this drug combination.
The potential benefit of using transduced blood stem cells is the possibility for dose
escalation of TEM, since hematologic toxicity has heretofore limited higher doses.
Transduction will be accomplished with a retroviral vector carrying MGMTP140K, which codes
for a mutated form of the resistance protein methylguanine-DNA methyltransferase (MGMT).
Successful transduction of hematopoietic cells with MGMTP140K makes them resistant to the
toxic effects of both TEM + BG. Repeated doses of these drugs should therefore result in an
increase in the percentage of transduced (and thus protected) blood stem cells, thus
reducing the likelihood of hematologic toxicity with further therapy. Accordingly, patients
who are tolerating therapy well and who have laboratory evidence of chemoprotection will
receive intrapatient dose escalation of TEM + BG during courses 2-6.
Eligible patients must be between 5 and 55 years of age and have newly-diagnosed high-grade
glioma (anaplastic astrocytoma or glioblastoma multiforme) which cannot be completely
resected. No prior therapy other than surgery is allowed, and patients must have adequate
performance status and organ function as defined in the protocol.
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Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic