Safety and efficacy of the tumor-selective adenovirus enadenotucirev, in combination with nivolumab, in patients with advanced/metastatic epithelial cancer: a phase I clinical trial (SPICE).

BACKGROUND

Novel combination therapies to overcome anti-PD-1 resistance are required. Enadenotucirev, a tumor-selective blood stable adenoviral vector, has demonstrated a manageable safety profile and ability to increase tumor immune-cell infiltration in phase I studies in solid tumors.

METHODS

We conducted a phase I multicenter study of intravenous enadenotucirev plus nivolumab in patients with advanced/metastatic epithelial cancer not responding to standard therapy. Co-primary objectives were safety/tolerability and maximum tolerated dose and/or maximum feasible dose (MTD/MFD) of enadenotucirev plus nivolumab. Additional endpoints included response rate, cytokine responses, and anti-tumor immune responses.

RESULTS

Overall, 51 heavily pre-treated patients were treated, 45/51 (88%) of whom had colorectal cancer (35/35 patients with information available were microsatellite instability-low/microsatellite stable) and 6/51 (12%) had squamous cell carcinoma of the head and neck. The MTD/MFD of enadenotucirev plus nivolumab was not reached, with the highest dose level tested (1×10

CONCLUSIONS

Intravenously dosed enadenotucirev plus nivolumab demonstrated manageable tolerability, an encouraging overall survival and induced immune cell infiltration and activation in patients with advanced/metastatic epithelial cancer. Studies of next-generation variants of enadenotucirev (T-SIGn vectors) designed to further re-program the tumor microenvironment by expressing immune-enhancer transgenes are ongoing.

TRIAL REGISTRATION NUMBER

NCT02636036.

Informations de copyright

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: MF: Honoraria (advisory, speakers bureau): Amgen, Inc. Consulting: AstraZeneca, Bayer Corporation, Bristol Myers Squibb, Incyte Corporation, Mirati Therapeutics, Inc., Akamis Bio Ltd, Taiho Oncology. Advisory: Bayer Corporation, Roche/Genentech, Xenthera. Advisory board: Mirati Therapeutics Inc., Nouscom. Editorial board: Mirati Therapeutics Inc. Grants to institutions: Bristol Myers Squibb (study-related drugs provided to Institution), Genentech, Verastem. WH: None. DM: Speakers Bureau: Caris Life Sciences and Guardant Health. Steering Committee: Janssen. HB: Consultancy: Myovant, Corea Therapeutics, Novocure, Coherus BioSciences. Speakers Bureau: Guardant360. Research funds: Blue Earth, Novocure, Spirita Oncology. Tumor board: CARIS. Steering Committee/Medical Advisory Board: Novocure, Virogin Biotech, Idera, and JS InnoPharm. JB: Advisory board member: Insmed, Bayer, Mirati, Ipsen, QED, Oxford Biotherapeutics. Data and Safety Monitoring Board: Novocure, Pancreatic Cancer Action Network, Karyopharm. Research funding to institution: I-Mab, Dragonfly, Astellas, Atreca, AbbVie, Pfizer, Karyopharm, Boston Biomedical, Akamis Bio Ltd, EMD Serono, BMS; Grants (to Institution): Novartis, Abbvie, Bayer, Lilly, Incyte, EMD Serono, Dragonfly, I-Mab, Incyte, Pfizer, BMS, Transcenta, Totus, Tyra, 23 and me, Sumitomo Dainippon Pharma; Advisory board: Bayer, Mirati, Insmed, Oxford Biotherapeutics, Biosapien, EMD Serono, Ipsen, Merck, Merus; Data safety monitoring board: AstraZeneca, Novocure; Scientific and medical advisory board: Pancreatic Cancer Action Network, Debbie’s Dream Foundation; Nominating committee: ASCO. LR: Akamis Bio Ltd: Research Funding to Institution. TL, DK, CC, JC, MPa, LP, MPo: employees and stock options, Akamis Bio Ltd.