Abstract
e13033 Background: We are conducting ascending dose trials in subjects with High Grade Glioma (HGG, NCT01156584, NCT01470794, NCT01985256), using an investigational retroviral replicating vector (Toca 511, vocimagene amiretrorepvec) in combination with Toca-FC (oral extended release 5-fluorocytosine). Toca 511 encodes an optimized yeast cytosine deaminase that converts 5-fluorocytosine (5-FC) to the anticancer drug 5-fluorouracil in infected tumors. Preclinical models provide support for a dual mechanism of action of Toca 511&5-FC that includes both direct killing of tumor by locally produced 5-fluorouracil, and induction of a local and systemic immunotherapeutic response resulting in long term survival after cessation of 5-FC treatment, and resistance to tumor re-challenge. Lomustine, an alkylating agent, is currently approved for the treatment of malignant brain tumors. To assess the safety and therapeutic potential of Toca 511&5-FC with lomustine, studies were performed in syngeneic, orthotopic glioma models. Methods: Fischer rats with F98 glioma and B6C3F1 mice with Tu2449 glioma were used to evaluate the effect of addition of lomustine on the efficacy of Toca 511&5-FC treatment and its immunological impact. Results: There were no safety related findings in animals treated with Toca 511&5-FC. Animals treated with lomustine alone or in combination with Toca 511&5-FC had transient weight loss and transient hematologic effects. In both models, animals that received Toca 511&5-FC or Toca 511&5-FC with lomustine had statistically prolonged survival compared to controls (Toca 511&PBS or 5-FC&lomustine, p < 0.05). 80% of mice that received Toca 511&5-FC with lomustine were alive > 70 days after tumor implantation compared to 60% that received Toca 511&5-FC alone (median survival not defined, not statistically significant). Rats that received Toca 511&5-FC with lomustine had statistically prolonged survival compared to Toca 511&5-FC alone (median survival 70 and 48 days respectively, p = 0.02). Conclusions: These results provide support for the investigation of Toca 511 & 5-FC in combination with lomustine in patients with HGG.
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