Journal Article

Study protocol of a randomized controlled phase II trial comparing nivolumab, ipilimumab plus radiotherapy versus nivolumab plus ipilimumab for advanced or recurrent esophageal cancer: Japan Clinical Oncology Group study JCOG2311 (ART NOUVEAU)

Sasaki, Keita, Watanabe, Akinori, Tsushima, Takahiro, Takeuchi, Hiroya, Kawabata, Kota, Hamai, Yoichi, Kato, Ken, Sakanaka, Katsuyuki, Matsuda, Satoru, Machida, Ryunosuke, Fukuda, Haruhiko

2025

Overview

Background The immunogenic cell death induced by radiotherapy (RT) has been demonstrated to enhance the systemic antitumor effect of immune checkpoint inhibitors (ICIs). The incorporation of RT into ICIs has the potential to mitigate the occurrence of early treatment failure, particularly with dual ICI combination, in patients with advanced or recurrent esophageal cancer. Methods This randomized phase II trial, initiated in November 2024, aims to explore the superiority of the combination of RT with nivolumab plus ipilimumab over nivolumab plus ipilimumab alone in patients with advanced or recurrent esophageal squamous cell carcinoma. The primary endpoint is progression-free survival, while the secondary endpoints include overall survival, response rate, duration of response, and adverse events. We assumed a 6-month PFS of 35% in the nivolumab plus ipilimumab alone arm and expected a 15% increase in the 6-month PFS for the RT with nivolumab plus ipilimumab arm (HR, 0.66). The total required sample size was calculated to be 70 (35 per arm) to achieve a desired power of 80% with an overall one-sided alpha of 20%, an accrual period of 2.5 years, and a follow-up period of 1 year. A total of 74 patients will be enrolled from 41 institutions in Japan. An ancillary study analyzes cytokine profiles and phenotypic characteristics in peripheral blood mononuclear cells during treatment with the protocol. Discussion The objective of this trial is to assess the safety and efficacy of RT in combination with dual ICIs in reducing early treatment failure and improving outcomes with translational research. Findings from this trial will inform a future phase III trial in this patient population. Trial registration This trial has been registered on November 5th, 2024, in the Japan Registry of Clinical Trials as jRCT1031240461 ( https://jrct.mhlw.go.jp/en-latest-detail/jRCT1031240461 ).

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Antibiotics / Antibodies / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Antitumor activity / Apoptosis / Autoimmune diseases / Biomedical and Life Sciences / Biomedicine / Blood / Cancer / Cancer Research / Cancer therapies / Care and treatment / Cell death / Chemoradiotherapy - methods / Chemotherapy / Clinical trials / Clinical Trials, Phase II as Topic / Coronary vessels / Development and progression / Diseases / Dysphagia / Equivalence Trials as Topic / Esophageal cancer / Esophageal carcinoma / Esophageal Neoplasms - drug therapy / Esophageal Neoplasms - mortality / Esophageal Neoplasms - pathology / Esophageal Neoplasms - therapy / Esophageal squamous cell carcinoma / Esophageal Squamous Cell Carcinoma - mortality / Esophageal Squamous Cell Carcinoma - pathology / Esophageal Squamous Cell Carcinoma - therapy / Esophagus / Female / Health aspects / Health Promotion and Disease Prevention / Humans / Immune checkpoint inhibitors / Immune response / Immunogenicity / Ipilimumab / Ipilimumab - administration & dosage / Ipilimumab - therapeutic use / Japan / Lesions / Leukocytes (mononuclear) / Lung cancer / Lymphatic system / Medical prognosis / Medicine/Public Health / Metastasis / Neoplasm Recurrence, Local - pathology / Neoplasm Recurrence, Local - therapy / Neutrophils / Nivolumab / Nivolumab - administration & dosage / Nivolumab - therapeutic use / Oncology / Oncology, Experimental / Patient outcomes / Patients / Peripheral blood mononuclear cells / Progression-Free Survival / Radiation therapy / Radiotherapy / Registration / Relapse / Squamous cell carcinoma / Study Protocol / Surgical Oncology / Vertebrae