SPICE, a phase I study of enadenotucirev in combination with nivolumab in tumours of epithelial origin: Analysis of the metastatic colorectal cancer patients in the dose escalation phase

Abstract Background Enadenotucirev (EnAd) is a tumor-selective chimeric Ad11/Ad3 group B oncolytic adenovirus. Following IV dosing of EnAd, viral delivery has been shown in various carcinomas together with CD8+ T-cells. These data provide a rationale for combination of EnAd with nivolumab (anti-PD-1). Methods EnAd was escalated in patients with metastatic epithelial tumors in a 3 + 3 design. Subjects received increasing dose levels and/or cycles of EnAd followed by up to 8 cycles of nivolumab. The primary objective of the dose escalation phase was to evaluate safety and recommend a dose for expansion. Secondary endpoints include ORR and OS. Results 31 patients with metastatic colorectal cancer (mCRC), with median 4 prior lines of therapy, were treated. Of these, 22 are confirmed MSS. EnAd dosing ranged between 1x1012 and 3x1012 virus particles infused IV 3 times weekly for one or two weeks, followed by nivolumab. Flu-like symptoms were reported in the majority of patients following EnAd administration. Adverse events of infusion reaction and hypoxia meeting DLT criteria were reported on C2D1 administration of EnAd requiring increased prophylaxis. Grade 4 acute renal injury was reported in one subject, with renal biopsy showing membranoproliferative glomerulonephritis (GN) indicative of immune complex deposition. Additional monitoring revealed changes suggestive of post-infectious GN in ∼25% of patients after 3-4 weeks of EnAd dosing. These were asymptomatic and resolved without treatment. Kinetics, cytokines and anti-drug antibody responses were consistent with known profiles for both agents. As of 03May2019, median OS is reported as 12.6 mo and median PFS is 2.8 mo. There were no objective responses, but PD markers in 6/8 matched biopsy samples show evidence of increased CD8 T cell infiltration and upregulation of markers of T cell activation. Stable disease exceeding 4 mo was seen in 6/31 (4/22 MSS). Conclusions The combination of EnAd and nivolumab has a manageable toxicity profile supporting further investigation in study expansion. Favourable OS outcome in a highly refractory CRC population was noted and may suggest delayed immune antitumor activity in this population. Clinical trial identification 2017-001231-39. Legal entity responsible for the study PsiOxus Therapeutics Ltd. Funding PsiOxus Therapeutics Ltd; Bristol-Myers Squibb. Disclosure P. Basciano: Full / Part-time employment: Bristol-Myers Squibb. R. Brown: Shareholder / Stockholder / Stock options, Full / Part-time employment: PsiOxus Therapeutics Ltds. O. Arogundade: Full / Part-time employment: PsiOxus Therapeutics Ltds. C. Cox: Full / Part-time employment: PsiOxus Therapeutics Ltds. G. Di Genova: Full / Part-time employment: PsiOxus Therapeutics Ltds. D. Krige: Full / Part-time employment: PsiOxus Therapeutics Ltds. H. McElwaine-Johnn: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: PsiOxus Therapeutics Ltds. All other authors have declared no conflicts of interest.