Abstract
Investigational Toca 511, a retroviral replicating vector, and Toca FC (extended-release flucytosine) are used in combination to target recurrent high grade glioma at resection by transducing the tumor with the gene encoding cytosine deaminase, converting flucytosine to 5-FU intratumorally. Preclinically, additive efficacy with temozolomide, lomustine and radiation therapy has been observed. Patients treated on two protocols (NCT 01156584 and NCT01470794) delivering intracranial Toca 511 and Toca FC were enrolled in a continuation protocol for extended safety observations, which allows Toca FC with investigator's choice of subsequent therapy. Exploratory safety analysis of the combinability of Toca 511 and Toca FC with concurrent subsequent therapy was conducted. Five patients received Toca FC in combination with other therapies. These patients were 37-68 years old; 4 had recurrent glioblastoma and 1 recurrent anaplastic oligodendroglioma. Concurrent therapy was administered for 2 to 10 months, including Toca FC + lomustine (1), lomustine + procarbazine (1), lomustine + bevacizumab (2), sequential bevacizumab + lomustine then bevacizumab + carboplatin (1). Patients reported adverse events (AEs) ranging from Grade 1 to Grade 3. No Toca 511- or Toca FC- related serious AEs were reported. AEs related to Toca 511 occurred in 2 patients: grade 1 fatigue, generalized aching and to Toca FC in 4 patients: grade 1 fatigue, decreased appetite, nausea, constipation, diarrhea; grade 2 heartburn, nausea, vomiting, constipation. Overall survival was 11-30+ months (2 alive as of data cut-off date). Preliminary data suggest that in combination with chemotherapy and/or bevacizumab, Toca 511 and Toca FC are tolerated with a manageable safety profile. Updates with prospectively collected data on treatment with lomustine or bevacizumab will be provided. The safety of combining Toca 511 and Toca FC with multimodality treatment will be further explored in a Phase 1b in newly diagnosed glioblastoma to begin enrollment in 2016.
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