SURG-10TRANSCRANIAL TOCA 511 FOLLOWED BY TOCA FC IN SUBJECTS WITH RECURRENT HIGH GRADE GLIOMA (HGG)

Abstract

Recurrent HGG remains a deadly cancer with survival from 7.2-8.1 months. Viral infection and killing of tumor cells has been demonstrated to stimulate antitumor immune responses pre-clinically. A Phase 1 study using a retroviral replicating vector (RRV), Toca 511, with oral Toca FC (extended-release 5-FC) is nearing completion. In this ongoing study (NCT 01156584) escalating doses of Toca 511 using 2 delivery methods are evaluated for safety and efficacy. Toca FC is administered in monthly cycles starting 4 weeks after injection and doses are escalated. Forty subjects have been treated (38 efficacy evaluable -received Toca 511/Toca FC). Toca 511 to 1.5 x 10^9 TU (3 mL) and Toca FC to 220 mg/kg/day have been safe and well tolerated with no DLTs. Related grade ≥3 adverse events for Toca 511 and Toca FC are infrequent (5.0%, 5.4%) and no subjects have discontinued Toca FC for toxicity. Blood tests show most subjects have no detectable virus - in those that do, clearance of virus occurs. Observed viral RNA signals are below the limit of detection after 2 cycles of Toca FC and viral DNA signal observed 4 weeks after virus injection are below the limit of detection after 3 months in the continuation study. Median survival is 13.8 months (95%CI 7.1, 22.2) using biopsy needle (N = 21); 10.6 months (95%CI 4.3, 13.1) with CED and real-time MRI-guidance (N = 17, p = 0.0276). In multivariate analysis biopsy needle delivery, tumor grade and number of recurrences are significant. Landmark survival is 45% OS12 and 10.5% OS24. Independent radiology review reveals a 3% PR rate (1/35) with clinical benefit rate (PR + SD) of 46%. This study confirms the feasibility and safety of transcranial delivery of RRV without resection. Survival compares favorably to historical data. Additional cohorts will use biopsy needle or intravenous delivery with higher doses of Toca FC.