A phase I/IIa study to assess the safety, tolerability, PK, and PD of T3011, a genetically modified oncolytic virus (OVs) administered intravenously (IV) in patients with advanced solid tumors.

Abstract

2640 Background: T3011 is a genetically modified, next-generation oncolytic HSV-1 with 2 exogenous genes encoding the active heterodimer human IL-12 and the Fab fragment of an anti-human PD-1 antibody. T3011 intratumoral injection (IT) was reported to be well tolerated in patients (pts). IV therapy of OVs is rare and provides an attractive option to many pts with advanced cancers that are not candidates for IT therapy. Methods: It is a phase I/IIa multi-center, open label, single ascending dose (SAD) /multiple ascending dose (MAD) study to evaluate T3011 IV therapy. The primary objective is to evaluate the safety and tolerability. Dose cohort and regimen are shown in Table. PK and PD profiles are tested in samples of blood, saliva, urine, and tumor tissue. Results: As of 16 Dec 2022, 15 pts with stage IV disease were enrolled, 9 pts had received at least 3 lines of prior therapy. The median follow-up time is 1.58 months. Treatment-emergent adverse event (TEAE) occurred in 15 (100%) pts and treatment-related adverse event (TRAE) occurred in 10 (66.7%) pts. G3 TEAE in 3 (20%) pts (hypertriglyceridemia, dyspnea, lymphopenia) and G3 TRAE in 1 (6.7%) pt (lymphopenia), no≥ G4 AE reported. Dyspnea, the only reported SAE (1, 6.7%), is drug-unrelated. TRAEs were lymphopenia (5, 33.3%), anemia (1, 6.7%), diarrhea (1, 6.7%), malaise (1, 6.7%), urticaria (1,6.7%), rash (1, 6.7%), constipation (1, 6.7%), flu like symptoms (1, 6.7%), headache (1, 6.7%) and abnormal laboratory test results (incidence were all 6.7%), most of them are mild and manageable. No AEs led to drug withdrawal. No DLT occurred; MTD was not reached. 11/15 pts achieved stable disease (SD) by RECIST v 1.1. DCR was 73.3%. 1 pt with colorectal cancer who experienced irinotecan-based chemotherapy, anti-VEGF and radiotherapy in Cohort 1 had a long-term SD for over 4 months. In SAD part, T3011 DNA in blood at 2 hours post-dose was detected in 0% (0/3), 0% (0/4), 66.7% (2/3) and 100% (2/2) pts in Cohort 1, 2, 3 and 4 respectively. The DNA copies in pts of Cohort 4 are significantly higher than those of Cohort 3 (Mean viral DNA copies/ul 49.6 vs. 5.7). In cohort 2 of MAD part, T3011 DNA in blood at 2 hours post-dose was detected in 0% (0/3), 66.7% (2/3) and 100% (3/3) pts at C1D1, C1D4 and C1D8 respectively. T3011 DNA was not detected in saliva or urine samples. Pre-existing HSV-1 IgG was shown to hardly affect T3011 activity. Conclusions: T3011 IV is safe and well tolerated, and unlikely to spread to close contacts. Preliminary efficacy is encouraging. T3011 DNA in blood is in a dose-dependent manner with additive effect from repeated doses supporting continued recruitment of pts to higher dose cohorts. Clinical trial information: NCT05598268 . [Table: see text]