Background: Trimodality therapy including chemoradiation, chemotherapy and surgical resection is standard for patients with T3-4 and/or node-positive (N+) rectal adenocarcinomas. Pathologic complete response (pCR) rates after neoadjuvant chemoradiation approach 15% in all-comers and 27% in patients with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) rectal cancer. Additionally, preclinical data suggest that hypofractionated radiation (large dose per fraction) may enhance immunogenicity. Given high response rates to immunotherapy in MSI-H/dMMR early stage and metastatic colorectal cancer (CRC), we hypothesized that neoadjuvant nivolumab plus ipilimumab and short course radiation in locally advanced MSI-H/dMMR rectal cancer (LARC) would result in increased pCR rates. Methods: EA2201 (NCT04751370) is an NCTN phase II clinical trial for patients with treatment-naïve locally advanced (T3-4Nx or TxN+) rectal adenocarcinoma that is dMMR or MSI-H. Patients receive nivolumab (480 mg) and ipilimumab (1 mg/kg) every 28 days for 2 cycles, followed by short course radiation (5 Gy x 5 fractions; total 25 Gy) and an additional 2 cycles of nivolumab and ipilimumab prior to disease reassessment and TME. The primary endpoint is pCR at TME. Secondary endpoints include 5-year disease-free survival, overall survival, treatment-related toxicities, and sphincter preservation rate for low-lying tumors. This study has a single-arm, two-stage design; a pCR rate of 50% or more will be taken as evidence of promising activity in this patient population. We plan to enroll 31 patients, with accrual currently ongoing. Clinical trial information: NCT04751370.