Phase I study of oncolytic adenovirus BioTTT001 in patients with peritoneal carcinomatosis.

Abstract

e14553 Background: The prognosis of secondary peritoneal carcinoma with malignant ascites（MA）is poor, highlighting the urgent need for new therapeutic regime. BioTTT001 is a novel oncolytic adenovirus (Ad) expressing a mutant form of interleukin-12, based on a new generation of tumor-targeted replicating oncolytic Ad backbone of human Ad5 by deleting E1A CR2 domain, E1B19K , and E3gp19K while keeping E3B genes of Ad intact. Here we report the results of the first-in-human Phase I clinical trial of BioTTT001 for the treatment of peritoneal metastasis. Methods: It's a dose-escalation, single-center clinical trial. Eligible patients (pts) had histopathologically confirmed refractory secondary peritoneal carcinomatosis from solid tumors, including gastric, colorectal and ovarian cancers. Dose escalation follows a 3+3 design at 3 dose levels. BioTTT001 is administered via intraperitoneal perfusion on days 1,3, and 5 in the first week, followed by weekly dosing for a total of 21 days per cycle. The primary endpoints include the Maximal Tolerable Dose / Recommended Phase 2 Dose (RP2D) and the incidence of adverse events. Secondary endpoints encompass preliminary clinical efficacy such as objective response rate, disease control rate (DCR), and changes in ascites volume assessed using the five-point method (5PM). The pharmacokinetics, pharmacodynamics characteristics of BioTTT001 and host immune responses to the virus were investigated as well. Results: As of Sep 30, 2024, nine pts were enrolled and received BioTTT001 intraperitoneal monotherapy (3 pts in cohort 5×10 9 vp, 3 pts in cohort 5×10 10 vp, 3 pts in cohort 1×10 10 vp). 5 pts had primary gastric cancer, 3 had ovarian cancer and 1 had rectal cancer. No DLTs were reported. Most treatment-related adverse events (TRAEs) were classified as grade 1-2; grade≥3 TRAEs including fatigue (22%), abdominal pain (11%) and lymphopenia (22%), occurred in 3/9 (33%) pts. The most common TRAEs were transient abdominal pain and fever following the virus administration. RP2D was identified as 1×10 10 vp. DCR reached 100% (5/5) among pts with measurable disease at baseline, while a reduction rate of ascites was noted at 80% (4/5) among evaluable subjects based on the 5PM. Additionally, CA125 levels decreased in 4/9 pts ( > 40% decrease observed in 2 pts). Notably, 2 pts with pelvic peritoneal metastasis exhibited significant regression of both pelvic metastases and adjacent intestinal lesions following the treatment. PCR analysis of ascites from 6 pts showed that BioTTT001 persisted in the peritoneal cavity (PC) for one week. Of note, BioTTT001 could result ineffective recruitment of CD8 + T and NK cells in PC. Conclusions: The intraperitoneal infusion of BioTTT001 for the treatment of peritoneal metastatic cancer was well tolerated with encouraging clinical benefit in pelvic peritoneal metastasis and MA controlling. This warrants further clinical investigation. Clinical trial information: ChiCTR2300069323 .