Background: Retrospective data suggest that patients with advanced colorectal carcinoma wild-type (WT) for RAS, BRAF or Pi3K achieve increased response rates from anti-EGFR therapy as compared with mutated tumors. Neoadjuvant chemotherapy with oxaliplatin/fluoropyrimidine combination has shown to induce encouraging pathological complete response (pCR) in clinically staged T3 rectal cancer tumours (Schragg et al, JCO 2014 and Fernandez-Martos et al, The Oncologist 2014). We hypothesize this efficacy could be improved in a selected population (quadruple WT [4WT]) combining chemotherapy and anti-EGFR therapy. The objective is to assess the feasibility, efficacy and safety of neoadjuvant therapy with mFOLFOX-6 + P in rectal adenocarcinoma patients of intermediate risk and 4WT. Methods: PIER is a prospective, phase II, single-arm, multicentre, open-label clinical trial (NCT03000374). Key eligibility criteria include patients < 75 years with rectal adenocarcinoma in the middle third , clear mesorectal fascia, candidate for R0 resection with sphincter preservation surgery and absence of mutations in KRAS (exon 2 [codons 12/13], exon 3 [codons 59/61] and exon 4 [codon 117/146]), NRAS ( exon 2 [codons 12/13], exon 3 [codons 59/61] and exon 4 [codons 117/146]), BRAF (exon 15 [codon 600]) and PI3KCA in exons 9 and 20. All pre- and post-treatment MRI scans are centrally reviewed. Treatment: 6 induction cycles of mFOLFOX6 + P every 14 days. After the last cycle, a CT-scan, MRI and rectal endoscopy will be performed and patients will undergo TME surgery within 4 weeks +/- 1 week after the last dose. In case of progression patients will receive standard preoperative chemoradiation. The primary end point is pCR; key secondary end points include R0 resection rate, and clinical complete response. Statistical design: 42 evaluable patients (assuming a P0 of 16% and a P1 35%, with 0.1 alfa and 0.1 beta); 2-stage Simon’s optimal design. Enrolment in PIER is ongoing. Clinical trial information: NCT03000374