VOLTAGE-2: multicenter phase II study of nivolumab monotherapy in patients with mismatch repair-deficient resectable locally advanced rectal cancer

Specifications tableSubject areaMedicine and DentistryMore specific subject areaMismatch repair-deficient locally advanced rectal cancerName of your trial in progressThe VOLTAGE-2 study (EPOC2201)Reagents/toolsThe study treatments will include 12 cycles of nivolumab monotherapy, administered at a dose of 240 mg every 2 weeks, followed by assessments using Memorial Sloan Kettering Regression Schema. If a clinical complete response (cCR) or near-complete response (nCR) is observed, non-operative management (NOM) will be pursued, with an additional 12 cycles of nivolumab. In case of an incomplete response (IR), we will shift to standard chemoradiotherapy, followed by surgical intervention.Trial designThe VOLTAGE-2 study is a non-randomized, single-arm, phase II trial. Eligible patients must be aged ≥18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and have a histological diagnosis of rectum adenocarcinoma (≤12 cm from the anal verge). The trial will include patients with cStage II (cT3-4N0M0), or cStage III (cTanyN1-2M0). The primary endpoint is the 2-year cCR. Assuming null and alternative hypotheses of cCR rates at 23% and 45%, respectively, the required sample size for primary cohort is 35. The statistical analysis will employ a one-sided alpha of 5% and aim for statistical power of 85%. In addition, as an exploratory cohort, 20 patients with cStage I (cT1-2N0M0) will be included, and the same study treatment will be carried out.Trial registrationjRCT2031220484EthicsThe trial protocol was reviewed and approved by the institutional review board of each participating site before study initiation. The study will be conducted in accordance with the tenets of the Declaration of Helsinki and Good Clinical Practice Guidelines. Written informed consent will be obtained from all patients.Value of the trial in progress•This trial will investigate the efficacy and safety of 1-year of nivolumab monotherapy in patients with dMMR-resectable LARC.•We will investigate the surrogacy of ctDNA assay as cCR by using WGS-based MRD assay and will evaluate the biomarkers of the response of anti-PD-1 antibody using WES/WTS-based tumor genomics and immune microenvironment evaluations.•We are planning spatiotemporal, trans-omics analyses using AI- and DL-driven genomics, transcriptomics, radiomics, pathomics, colonoscopic images, quality-of-life assessments, and clinical features.