Background: Neoadjuvant or perioperative chemotherapy has become a standard of care for locally advanced, resectable gastric cancer and adenocarcinoma of the GEJ. However, patient’s outcome is still unsatisfactory and 5-year survival, even in prospective trials, has been below 40%. Targeting HER2 with Trastuzumab and Pertuzumab prolonged survival in patients with HER2-positive advanced breast cancer as did Trastuzumab in patients with HER2-positive advanced gastric cancer. This provides a rationale for the evaluation of anti-HER2 treatment for resectable patients. Methods: This is a prospective, multicenter, randomized, investigator initiated phase II trial. Patients with HER2-positive locally advanced adenocarcinoma of the stomach and GEJ (i.e. ≥cT2 any N or any T N-positive) with exclusion of distant metastases are enrolled. HER2 status is centrally assessed. Patients are randomized 1:1 to 4 pre-operative 2-week cycles (8 weeks) of FLOT (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m²) followed by surgery and 4 additional cycles of FLOT (arm A); or the same therapy in combination with Trastuzumab 8/6 mg/kg and Pertuzumab 840 mg every 3 weeks pre- and postop, followed by a total of 9 additional cycles of Trastuzumab/Pertuzumab monotherapy (arm B). Primary endpoint of the phase II part (n = 100) of the trial is to show numerical improvement of the rate of pathological complete remission to approx. 25% with antibodies compared to approx. 16% with FLOT alone as assessed by a centralized pathology. Main secondary endpoints are safety and tolerability. Once results from phase II become available, study transition into phase III will be evaluated based on de facto results and current medical standards. Recruitment has already started; by February 2017 a total of 19 patients have been randomized. EudraCT: 2014-002695-86 Clinical trial information: NCT02581462