A Phase 1 Trial of the Safety, Tolerability, and Biological Effects of Intravenous Enadenotucirev (EnAd), a Novel Oncolytic Virus, in Combination with Chemoradiotherapy in Locally Advanced Rectal Cancer (CEDAR)

Novel treatment combinations are required to increase response rates in rectal cancer. EnAd is an intravenous, tumor selective, oncolytic adenovirus with high affinity for malignant colorectal epithelial cells. Pre-clinical evidence of synergy with radiation warranted further clinical evaluation and assessment of safety in combination with chemoradiation (CRT), 25 × 2Gy and concurrent capecitabine.EnAd was escalated using 2 dose levels of viral particles (1 × 1012, 3 × 1012), given Monday, Wednesday, Friday over 3 schedules (pre-CRT, pre & post CRT). Toxicity and efficacy were used as dual end points in escalation decisions. A 2-parameter and 3-parameter logistic Time to Event Continual Reassessment Method (TiTE-CRM) were used estimate the dose-toxicity and dose-efficacy relationship, respectively. Results are shown as probability and 95% credible interval (Cr.I). The dose limiting toxicity (DLT) window was 13 weeks. Patients who had not completed their DLT window at the time of a dose decision were included in the safety analysis but down-weighted according to their follow-up time and amount of IMP received. Efficacy was assessed at 13 weeks using MRI Tumor Regression Grade (mrTRG), where mrTRG 1-2 equals response. The trial (NCT03916510) was conducted in 4 UK centers.A total of 13 patients were enrolled, 12 of whom were evaluable. Median age was 57 (range 31-84), and 10/13 were male. One patient had two G3 adverse events (AE); diarrhea, acute kidney injury. All other adverse events (AEs) were G1 or 2, with no G4/5 events. The most common AE by organ system was gastrointestinal (20.8%, G1). There were two observed DLTs on Dose schedule 3; leg swelling and acute kidney injury. Responses and toxicities increased with escalating schedules of EnAd (Table 1).CEDAR is the first trial to successfully combine an intravenous oncolytic adenovirus with radiation, demonstrating the feasibility and acceptability of this approach, and a new paradigm in radiosensitization in rectal cancer. Within this small Phase I study, EnAd demonstrated an acceptable safety profile with evidence of a higher-than-expected rate of response by mrTRG. Translation analysis of tissue, blood and microbiome for biological correlates of radiation synergy is underway.PsiOxus, CRUK (A24474).University of Oxford.