Background: A randomized phase III trial (JCOG0501) failed to demonstrate a survival advantage of neoadjuvant chemotherapy with S-1 plus cisplatin (SP) for patients with resectable macroscopic type 4 and large type 3 gastric cancer (GC). Currently, initial resection followed by adjuvant chemotherapy is performed as the standard treatment for this population as well as general type GC in Japan. However, macroscopic type 4 and large type 3, mostly overlapping with scirrhous or linitis plastica type, have distinctive natures in age, dominant histology and metastatic site, exhibiting unfavorable prognosis after surgery with curative intent. Further therapeutic development using peri-operative chemotherapy is urgently desired for the improvement of this hard-to-treat subset of GC. Based on the successful results of the FLOT4 trial and PRODIGY trial, FLOT (5-fluorouracil/leucovorin/oxaliplatin/docetaxel) and DOS (docetaxel/oxaliplatin/S-1) will be anticipated to offer more potent efficacy compared to platinum doublet. However, it remains unclear which of these two regimens should be selected as a test arm of future phase III confirming efficacy of neoadjuvant chemotherapy in Japan. Methods: JCOG2204 is a multi-center, randomized phase II trial comparing neoadjuvant chemotherapy with FLOT (5-fluorouracil/levofolinate/oxaliplatin/docetaxel) versus DOS for resectable type 4 and large type 3 GC. This trial adopted the selection design to determine the most promising regimen for the subsequent phase III trial. Patients with histologically confirmed adenocarcinoma of the stomach, presenting with macroscopic type 4 or larger lesions (≥8 cm) of type 3, are eligible for this trial. Prior to registration, it is required to confirm the absence of non-curable factors other than positive lavage cytology (CY1) or peritoneal dissemination localized around the stomach (P1a) in a staging laparoscopy. Neoadjuvant FLOT arm consist of 4 courses of oxaliplatin (85 mg/m²) and docetaxel (50 mg/m²) with levofolinate (200 mg/m²) IV infusion for 1-2 hours, then 5-FU (2600 mg/m², civ) for 24 hours on day 1, biweekly. Neoadjuvant DOS arm consists of 3 courses of oxaliplatin (100 mg/m²) and docetaxel (40 mg/m²) IV infusion for 1-2 hours on day 1, followed by oral S-1 80–120 mg/m²/day for 2 weeks (days 1–14), in a 3-week cycle. Adjuvant chemotherapy is performed according to the pathological TNM stage. A sample size was calculated based on Simon’s selection design assuming that a proportion of patients achieving pathological response Grade 1b or higher will be 65% in the superior regimen, 10% higher than 55% in the other. A total of 76 patients, which are required to ensure at least an 80% probability of correct selection, are planned to be enrolled over 2 years. Enrollment in JCOG2204 begun on 14^th July, 2023 and clinical trial information is available in Japan Registry of Clinical Trials (jRCTs031230231). Clinical trial information: jRCTs031230231.