Annual Meeting Proceedings Part 1 - American Society of Clinical ...

114s Cancer Prevention/Epidemiology
TPS1616 General Poster Session (Board #11D), Sat, 1:15 PM-5:15 PM
O6-benzylguanine (BG) and temozolomide (TMZ) therapy of glioblastoma
multiforme (GBM) with infusion of autologous lentiviral transduced
P140KMGMT� hematopoietic progenitors to protect hematopoiesis: A
phase I study. Presenting Author: Andrew E. Sloan, University Hospital
Case Medical Center, Cleveland, OH
Background: The administration of radiation therapy (RT) and concomitant
and adjuvant temozolomide (TMZ) for the treatment of newly-diagnosed
glioblastoma (GBM) is associated with modestly prolonged survival. However,
the benefit of concurrent therapy is restricted to a subgroup of
patients whose tumor exhibits methylation of the promoter for methylguanine-DNA-methyltransferase
(MGMT). Promoter methylation silences the
expression of DNA alkyltransferase (AGT), the product of the MGMT gene
which functions to repair alkylated DNA. Unfortunately, the majority of
GBMs have non-methylated MGMT promoters and do not appear to benefit
from adding TMZ to radiotherapy. Two potential strategies for targeting
MGMT-induced chemoprotection in gliomas include depletion of tumor
MGMT, and dose escalation of TMZ accomplished by minimizing TMZinduced
bone marrow toxicity. In this study, we propose to combine the
irreversible MGMT inhibitor O6-benzylguanine (BG) with infusion of autologous
hematopoetic stem cells (HSCs) transduced with lentiviral P140K-
MGMT, an MGMT mutant which is highly resistant to inactivation by BG,
with the intent to reduce or prevent the myelosuppressive effects of TMZ.
The primary objective is to assess the safety and feasibility of combining
these two strategies in patients with newly-diagnosed GBM. Methods: This
is a three cohort, Phase I study for patients with newly resected supratentorial
GBM. There will be at least four evaluable patients per cohort. Cohort 1
will receive standard RT and concomitant TMZ prior to infusion of
autologous lentiviral P140K-MGMT transduced HSCs, followed by adjuvant
TMZ. Cohort 2 will receive an induction dose of TMZ�BG followed by
infusion of autologous LV-P140K-MGMT HSCs prior to concomitant RT
�TMZ and adjuvant TMZ. Cohort 3 will include intra-patient dose escalation
of TMZ in patients who exhibit detectable levels of P140K-MGMT
marked cells in vivo, using the design (i.e. cohort 1 or 2) proven to be safest
and most effective. The study is open and has accrued the first patient.
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