A Study of a Retroviral Replicating Vector Administered to Subjects With Recurrent Malignant Glioma

• Determine the Maximum Tolerated Dose of Toca 511 [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
  

• Determine Response Rate at MTD [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  
• Determine the PFS-6 at MTD [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  

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.