Written informed consent according to ICH/GCP, and national/local regulations

Written informed consent according to ICH/GCP, and national/local regulations. Primary endpoint: major pathological response rate ( ?10% vital residual tumor cells) according to Becker et al. in 14 countries will be centrally randomized (1:2:2 ratio) to one of the following treatment arms: CT alone. CT regimens will be FLOT (5-FU, leucovorin, oxaliplatin, taxotere) CapOx (capecitabine, oxaliplatin) or FOLFOX (5-FU, leucovorin, oxaliplatin) according to investigators choice in Europe, and cisplatin/capecitabine in Asia. CT as in control group, plus T (8?mg/kg loading dose, followed by 6?mg/kg every 3?weeks) at day 1, independent of CT chosen for 3?cycles of 3?weeks before and after surgery. CT plus T as in experimental arm 1, plus P (840?mg every 3?weeks) on day 1. Adjuvant treatment with T or T?+?P will continue for 17?cycles in total. Stratification factors are: histology (intestinal/non-intestinal); region (Asia vs Europe); location (GEJ vs non-GEJ); HER2 immunohistochemistry score (IHC 3+ vs IHC 2+/FISH+) and chemotherapy regimen. Primary objective is to detect an increase in the major pathological response rate from 25 to 45% either with CT plus T alone, or with CT plus the combination of T and P. Discussion Depending on the results of the INNOVATION trial, the addition of HER2 targeted treatment with either T or T and P to CT may inform future study designs or become a standard in the perioperative management HER2+ GC. Trial registration This article reports a health care intervention on human participants and was registered on July 10, 2014 under ClinicalTrials.gov identifier: “type”:”clinical-trial”,”attrs”:”text”:”NCT02205047″,”term_id”:”NCT02205047″NCT02205047; EudraCT: 2014C000722-38. (in Europe: FLOT is administered in cycles of 2?weeks for 4?cycles (= 8?weeks) on day 1, 15, 29 and 43 pre- and postoperatively, with Docetaxel 50?mg/m2, followed by Oxaliplatin 85?mg/m2 diluted with 250 to 500?ml of 5% glucose solution as a 2?h infusion, leucovorin 200?mg/m2 over 2?h and 5-FU 2600?mg/m2 as a 24?h-infusion. Alternatively, either CapOx is given for 3?cycles of 3?weeks (=9?weeks) on day 1, 22 and 43 pre- and postoperatively, with Oxaliplatin 130?mg/m2 on day 1, and followed by capecitabine given orally at a dose of 1000? mg/m2 twice daily from the evening of day 1 to the morning of day 15 every 3? weeks or mFOLFOX6 is given for 4?cycles of 2?weeks (=8?weeks) on day 1, 15, 29 and 43 pre- and postoperatively, with oxaliplatin at a dose of 85?mg/m2, followed by leucovorin 400?mg/m2 iv over 2?h on day 1, and 5-FU 400?mg/m2 iv bolus on day 1, then 1200?mg/m2/d ?2?days over 46C48?h continuous infusion every 2?weeks. Chemotherapy should be restarted 4 to 6 6?weeks after surgery, if the patient has sufficiently recovered, in all trial arms Experimental arm 1Chemotherapy as in standard arm, plus trastuzumab (8?mg/kg loading dose, followed by 6?mg/kg every 3?weeks) on day 1, 22 and 43, independent of the chemotherapy regimen chosen, for 3?cycles of 3?weeks before and after surgery. Experimental arm 2Chemotherapy plus Epimedin A1 trastuzumab as p35 in experimental arm 1, plus pertuzumab (840?mg every 3?weeks) at day 1, 22 and 43, independent of the Epimedin A1 chemotherapy regimen chosen. Surgery is scheduled within 2C4?weeks after the completion of cycle 3 in a 3-week-cycle, and after completion of cycle 4 in a 2-week-cycle if the white blood count has normalized again and the patient is clinically deemed fit to undergo major surgery. Surgery is performed according to the Japanese Gastric Cancer Treatment Guidelines 2014 (version 3) [18]. The extent of the surgical resection depends primarily on the location of the tumor and is either an extended total, partial or subtotal gastrectomy, or C for tumors of the GEJ C esophagogastrectomy and reconstruction via gastric tube or extended total gastrectomy according to the decision of the surgeon. Surgical CRFs, mandatory intra-operative photo documentation, the Epimedin A1 operative report, the pathology report, central pathology review and assessment of surgical complications according to Dindo [19] will be used for surgical quality assessment. Maintenance treatment is performed with trastuzumab.