Abstract CT186: A first-in-human phase 1 dose-escalation and expansion study of intratumoral oncolytic reovirus (RC402) as a monotherapy or in combination with pembrolizumab in advanced solid tumors

Abstract Background: RC402 is an oncolytic reovirus that selectively infects and destroys cancer cells. Preclinical studies have shown that RC402 remodels the tumor immune microenvironments and elicits potent anti-tumor immunity, thereby enhancing immune checkpoint inhibitors. Methods: This Phase I clinical trial (ACTRN12620000777998) was designed to evaluate the safety profiles and antitumor efficacy of intratumoral (IT) RC402 in patients with advanced solid tumors refractory to standard therapy and with accessible tumor lesions for IT injection of RC402. For the dose-escalation part (Phase 1a), the RC402 monotherapy dose was evaluated at 3 dose levels in Part A and the RC402 combination therapy dose with pembrolizumab was evaluated at 2 dose levels in part B using an accelerated titration method followed by a standard 3+3 dose escalation. In the dose-expansion part (Phase 1b), patients were treated with IT RC402 in combination with pembrolizumab at the recommended dose selected from the dose escalation part. RC402 was IT injected on day 1 of each treatment cycle. Fixed-dose pembrolizumab (200mg Q3W) was intravenously administered on day 8 of each treatment cycle for Phase 1a Part B and Phase 1b. Viral shedding was assessed serially in serum, urine, sputum, and stool samples, and neutralizing antibodies to Reovirus Type 3 Dearing were analyzed in serum samples. Results: Nine patients (2 gastric cancer and 1 cutaneous squamous cell carcinoma cSCC in Phase 1a Part A, 1 cSCC and 1 colorectal cancer CRC in Phase 1a Part B, and 1 cSCC and 3 CRC in Phase 1b) were enrolled and treated with at least two doses of RC402. IT administration of RC402 was generally well tolerated with no dose-limiting toxicities at all dose levels (1. 6 × 108, 1. 4 × 109, and 1. 4 ×1010 PFU) as a monotherapy or in combination with pembrolizumab. The maximum tolerated dose was not reached. There were no treatment-emergent adverse events (TEAEs) leading to treatment discontinuation and no RC402-related serious TEAEs. The most common AEs were chills, fatigue, injection site reactions (erythema and pain) and nausea. Response evaluation showed two complete responses (one patients with cSCC in Phase 1a Part A and another patient with cSCC in the dose expansion part) lasting longer than 90 weeks and 36 weeks, respectively. No viral shedding was detected in any serum, urine, sputum, and stool samples on days 1, 2, and 15 of cycle 1, on day 2 of subsequent cycles and at the end of treatment. All patients showed an initial increase in antireoviral antibody titers on day 1 of cycle 2, followed by a decrease in subsequent cycles. Conclusion: This first-in-human study demonstrated IT RC402 is well tolerated and has a manageable safety profile with preliminary clinical activity as a monotherapy and in combination with pembrolizumab. These results warrant further clinical development of RC402. Citation Format: Mark Voskoboynik, Jia Liu, Ki-Hoon Song, Dong-Guk Park, Min-Hee Ryu, Hong Jae Chon, Chan Kim. A first-in-human phase 1 dose-escalation and expansion study of intratumoral oncolytic reovirus (RC402) as a monotherapy or in combination with pembrolizumab in advanced solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT186.