Trial Information

A Phase 1 Ascending Dose Trial of the Safety and Tolerability of Toca 511 in Patients With Recurrent High Grade Glioma

There is an ongoing, intensive search for novel therapies to improve the prognosis of
patients with the most common and aggressive form of primary brain cancer, glioblastoma
multiforme (GBM). Gene transfer is one such approach. Early gene-transfer studies with
replication incompetent vectors showed this approach to be generally safe, but ineffective
due to limited transduction of the tumor. More recently gene transfer has been attempted
with oncolytic, replicating viruses. However these viruses are rapidly cleared by the
immune system. To overcome these shortcomings of previous gene transfer protocols, Toca 511
has been developed utilizing a Retroviral Replicating Vector (RRV). This platform has the
following potential advantages: 1) The vector only infects dividing cells, 2) The virus
stably integrates into the genome of the tumor cells allowing for the potential for
long-term control of the tumor, 3) The virus is not intrinsically oncolytic and is not
cleared from the tumor by the immune system, and 4) The virus has been engineered to express
the prodrug-activator, cytosine deaminase (CD), a gene that catalyzes the intracellular
conversion of the antifungal drug, 5-FC (flucytosine) to the cytotoxic drug 5-FU. In both
xenograft and syngeneic intracranial mouse tumor models the Toca 511/5-FC combination was
able to significantly increase the survival of treated animals. The goal of the current
trial is to demonstrate the safety and efficacy of Toca 511 administered intratumorally to
patients with recurrent GBM followed by cyclic treatment with the prodrug 5-FC.

This is a multicenter, open-label, ascending-dose trial of the safety and tolerability of
increasing, single doses of Toca 511 administered transcranially to subjects with rHGG who
have undergone surgery, radiation therapy and chemotherapy with temozolomide. The study
will be conducted in 2 parts. Part one will study ascending, single doses of Toca 511
delivered via stereotactic, transcranial injection into the tumor. Approximately 3-4 weeks
later subjects will undergo a baseline Gd-MRI exam and then begin treatment with oral 5-FC
administered for 6 consecutive days. If tolerated, these 6-day courses of 5-FC will be
repeated every 4 weeks for 6 cycles. Subjects will undergo Gd-MRI scanning every 8 weeks. In
part 2 of the study, 9 additional subjects will be studied at the highest dose of Toca 511
found in part one to be safe and well tolerated. Each subject will receive a single,
transcranial injection of Toca 511. Approximately 3-4 weeks later subjects will undergo a
baseline Gd-MRI exam and then begin treatment with oral 5-FC administered for 6 consecutive
days. If tolerated, these 6-day courses of 5-FC will be repeated every 4 weeks for 6
cycles. Subjects will undergo Gd-MRI scanning every 8 weeks. Tumor response will be
assessed using the Macdonald criteria.