CTNI-42. A BIOMARKER-GUIDED PHASE 2 STUDY OF DB107-RRV (A RETROVIRAL REPLICATING VECTOR) COMBINED WITH DB107-FC (FLUCYTOSINE EXTENDED-RELEASE TABLETS) IN PATIENTS WITH RECURRENT GLIOBLASTOMA OR ANAPLASTIC ASTROCYTOMA: A CLINICAL PROTOCOL

Abstract INTRODUCTION Despite significant advances in understanding the basic pathogenesis of glioblastoma, the median survival of patients has minimally changed in the past 25 years with a 5-year survival rate of <7%. Because of the dismal prognosis, attention has shifted to alternative adjuvant treatment modalities including gene/viral-based therapy. The first clinically tested replicating retroviral vector DB107-RRV (vocimagene amiretrorepvec, formerly Toca511) was assessed in a randomized Phase 3 study (NCT02414165) to evaluate the intracranial administration of DB107-RRV with subsequent oral administration of DB107-FC (5-fluocytosine extended-release tablets) in patients with recurrent HGG. Although the primary endpoint of overall survival (OS) in the intent-to-treat population was not met (median OS=11.07 months, DB107-RRV+ DB107-FC arm and 12.22 months for the SOC arm (HR=1.06; 95% CI:[0.83, 1.35], p=0.6154)), post-hoc analysis identified a subgroup of patients (responders) who demonstrated a marked survival benefit from the Phase III clinical trial (Toca 5, NCT02414165). Using a non-invasive genotyping pipeline, a novel biomarker, DGM7, was identified among responders that confers an improved prognosis: (DB107-RRV+DB107-FC is 18.3 months vs. 12.0 months in the SOC group (HR=0.50; 95% CI:[0.28, 0.89], p= 0.0167)). DGM7 is present in the blood of approximately 20-30% of HGG patients. METHODS This is a Phase 2, single-site, open-label, single-arm study to assess the oral administration of DB107-FC in combination with DB107-RRV in DGM7+ patients with recurrent/progressive HGG. Key inclusion criteria include presence of the DGM7 biomarker in blood, patient age 18–75 with histologically proven, measurable (MRI) recurrent/progressive HGG, and no radiation therapy for at least 12 weeks without histopathologic/MRI progression confirmation. The primary endpoint of this study will be progression-free survival at 6 months (PFS6) and OS of DB107-RRV+DB107-FC in DGM7+ patients with recurrent/progressive HGG compared to the historical study arm SOC/DGM7+ from NCT02414165.