Neoadjuvant Regorafenib in Combination With Nivolumab and Short-course Radiotherapy in Stage II-III Rectal Cancer

This is a multicenter, single-arm, phase II study of nivolumab in combination with regorafenib in subjects with locally-advanced rectal cancer who are eligible for a curative treatment including pre-operative SCRT and TME(or watch \& wait approach). The study is based on the Simon's two-stage design and a maximum of 60 subjects will be enrolled. In addition to the standard efficacy interim analysis according to the statistical design, a safety interim analysis will be performed on the first 6 subjects who have completed the study treatment to ensure safe continuation of the study investigation. Eligible subjects will be treated according to the following sequential treatment plan: * Induction treatment: This consists of treatment with nivolumab (240 mg intravenously, on day 1 and 15) and regorafenib (60 mg/day orally, from day 1 to 14) * Standard SCRT: This consists of 25 Gy delivered in 5 fractions (from day 22 to 26) * Consolidation treatment: This consists of treatment with nivolumab (240 mg intravenously, on day 29, 43 and 57) and regorafenib (60 mg/day orally, from day 29 to 49) * Surgery: Surgical resection will be performed according to the principles of TME (between day 74 and 87, i.e., between 7 to 8 weeks after completion of SCRT). As an alternative to surgery, subjects who achieve cCR can be offered a watch \& wait approach. * Adjuvant chemotherapy: Administration of adjuvant chemotherapy will be left to the discretion of the treating physician The study also includes translational procedures (i.e. collection of tumour biopsies, blood samples and stool samples at pre-specified time points) for exploratory molecular and immune contexture analyses. These are mandatory for all study subjects.

NCT Number	NCT04503694
Lead Sponsor	Jules Bordet Institute
Conditions	Rectal Cancer Stage II, Rectal Cancer Stage III
Enrollment	72 participants
Start Date	2021-03-25
Primary Completion	2026-12-31 (estimated)
Study Completion	2032-12 (estimated)
Updated on ClinicalTrials.gov	2026-05-22