Background: Even though the recurrence rate remains high, chemoradiotherapy (CRT) alone is the standard treatment in locally advanced squamous cell anal carcinoma (SCAC), in the absence of effective neoadjuvant/adjuvant treatment.Modified docetaxel, cisplatin and 5FU (mDCF) is one of the standard regimens in metastatic SCAC, and induced a radiological complete response (cCR) in 45% of patients, with a biological CR (the conversion from positive to negative HPV ctDNA by liquid biopsy) in 61% of patients. Among chemotherapy-naïve patients, the cCR was as high as 55%, with 90% of ORR and 100% of disease control rate during the first 4 months. Moreover, mDCF was associated with a decrease in Myeloid-Derived Suppressive Cells (MDSC) and an increase in the antitumor anti-hTERT immunity, two major factors correlated with prognosis in advanced SCAC, rendering mDCF a good partner to combine with immunotherapy. Anti-PD1 immunotherapy is effective in chemorefractory SCAC. In sensitive tumors, neoadjuvant anti-PD1, with or without chemotherapy, induced a high rate (30-45%) of complete or near-complete pathological response. The combination of mDCF and immunotherapy is safe. Methods: INTERACTION is an open-label, pivotal, single arm, phase II study in neoadjuvant setting for stage 3 SCAC patients (NCT04719988). Fifty-five patients will receive up to 6 cycles of mDCF (docetaxel 40 mg/m² and cisplatin 40 mg/m² on day 1, 5-fluorouracil 2400 mg/m² over 46 h) every 2 weeks, in association with ezabenlimab (anti-PD1 mAb) at 240 mg every 3 weeks. CT-scan, MRI, tumor and liquid biopsies will be performed before treatment, and after 4 cycles. CRT will be start after cycle 6. Then, ezabenlimab will be administered in the adjuvant setting up to 10 months from cycle 1. Eligible candidates include patients with treatment-naïve histologically proven locally advanced SCAC, an ECOG PS of 0 or 1, and age ≥18 years. The primary endpoint is the clinical complete response rate at 10 months from the first cycle of mDCF plus ezabenlimab. Main secondary endpoints are the major pathological response (complete/near-complete response) and biological CR (HPV ctDNA negative) after induction treatment. Other secondary endpoints include the ORR, OS, PFS, RFS, HRQoL and safety. An extensive ancillary study will be performed to predict response or resistance to treatment. Peiffert D et al. JCO 2012;30:1941–8; James RD et al. Lancet Oncol 2013;14:516–24; Kim S et al. Lancet Oncol 2018; 19:1094–106; Kim S et al. TAMO 2020;12:1758835920975356; Spehner L et al. IJMS 2020;21:6838; Ott PA et al. Ann Oncol 2017;28:1036–41; Morris VK et al. Lancet Oncol 2017;18:446–53; Huang AC et al. Nat Med 2019;25:454–61; Necchi A et al. JCO 2018;36:3353–60; Forde PM et al. NEJM 2018;378:1976–86; Kim S et al. BMC Cancer 2020;20:352. Clinical trial information: EudraCT 2020-006046-40 and Clinicaltrials.gov NCT04719988.