A Study of a Retroviral Replicating Vector Administered to Subjects With Recurrent Malignant GliomaTocagen 511-08-01

Investigator: David Baskin, MD

Study Coordinator: Pamela Weaver

Status: Open Not Enrolling

ClinicalTrials.gov Number: NCT01156584

Phone: 713.441.3834

IRB Number: Pro00009206


Purpose This is a multicenter, open-label, ascending-dose trial of the safety and tolerability of increasing doses of Toca 511, a Retroviral Replicating Vector (RRV), administered to subjects with recurrent high grade glioma (rHGG) who have undergone surgery followed by adjuvant radiation therapy and chemotherapy. Subjects will recieve Toca 511 via stereotactic, transcranial injection into their tumor. Cohort 7 & 9 will receive Toca 511 as an intravenous injection given daily for 3 & 5 days respectively. Approximately 3-4 weeks following injection of the RRV, treatment with Toca FC will commence and will be repeated approximately every 6 weeks until study completion or enrollment in the continuation study. Condition Intervention Phase Glioblastoma Anaplastic Astrocytoma Anaplastic Oligodendroglioma Anaplastic Oligoastrocytoma Biological: Toca 511 Drug: 5-FC Phase 1 Study Type: Interventional Study Design: Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment Official Title: A Phase 1 Ascending Dose Trial of the Safety and Tolerability of Toca 511 in Patients With Recurrent High Grade Glioma Resource links provided by NLM: MedlinePlus related topics: Genes and Gene Therapy Drug Information available for: Flucytosine Genetic and Rare Diseases Information Center resources: Anaplastic Astrocytoma Anaplastic Oligoastrocytoma Anaplastic Oligodendroglioma Diffuse Astrocytoma Glioblastoma Glioma Neuroepithelioma Oligoastrocytoma Oligodendroglioma Subependymal Giant Cell Astrocytoma U.S. FDA Resources Further study details as provided by Tocagen Inc.: Primary Outcome Measures: Determine the Maximum Feasible, Safe and Well Tolerated Dose of Toca 511 [ Time Frame: 8-10 weeks ] [ Designated as safety issue: Yes ] Secondary Outcome Measures: Evaluate the safety and tolerability of repeated treatment with Toca FC following administration of Toca 511 [ Time Frame: 6 months ] [ Designated as safety issue: Yes ] Review of adverse events including laboratory safety data (specifically any Grade 3 or higher non-hematologic toxicity or any Grade 4 or higher hematologic toxicity, felt to be related to Toca 511 or the Toca 511/Toca FC combination) Evaluate overall survival at 6, 9 and 12 months [ Time Frame: 12 months ] [ Designated as safety issue: No ] Evaluate progression free survival (PFS) at 6 months [ Time Frame: 6 months ] [ Designated as safety issue: No ] Estimated Enrollment: 70 Study Start Date: June 2010 Estimated Study Completion Date: July 2016 Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure) Arms Assigned Interventions Experimental: Single arm Toca 511 vector 5-FC prodrug Biological: Toca 511 Single, stereotactic, transcranial, intratumoral injection or intravenous injection Other Names: Retroviral Replicating Vector (RRV) Gene Therapy Gene Transfer Drug: 5-FC 4-6 week cycles of Toca FC. Doses evaluated from 120 mg/kg/day or 300 mg/kg/day. Duration of dosing evaluated: 6 days, 7 days or 14 days. Other Name: flucytosine, 5-FC, 5-FC XR, Toca FC (extended release flucytosine) Detailed Description: 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.
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