Abstract Objective: Ramucirumab is a VEGFR2 antagonist. The aim of this trial is to evaluate the efficacy and safety of ramucirumab combined with nab-paclitaxel, lobaplatin and S-1 in neoadjuvant and conversion therapy for advanced gastric cancer.

Methods and analysis: This study is a prospective single-center, randomized controlled and open label clinical study containing two cohorts with 140 patients of advanced gastric cancer (Cohort A n=70; Cohort B n=70). The main efficacy indicator is pathological complete response (pCR) of the cancer after neoadjuvant or conversion therapy. The secondary efficacy indicators are R0 resection rate after neoadjuvant or conversion therapy, the incidence of adverse events (AE), progression-free survival (PFS), overall survival (OS), objective response rate (ORR), total response rate and total response time, disease control rate (DCR) and duration of overall response (DOR).

Ethics: Ethics approval has been obtained from the Ethics Committee at the First Affiliated Hospital (Xijing Hospital) of Air force Military Medical University (KY20232220-F-1).

Inclusion Criteria:

Cohort A: Patients are diagnosed with locally advanced gastric or gastroesophageal junction adenocarcinoma by cytology or histopathology and in need of preoperative neoadjuvant therapy to reduce recurrence and metastasis rates; Cohort B: Patients with advanced gastric cancer who have undergone surgery after neoadjuvant chemotherapy with previously used nab-paclitaxel, lobaplatin and S-1.

Patients are adults aged 18-75 years with an Eastern Cooperative Oncology Group(ECOG) performance status score less than or equals to 1.

Have not received anti-tumor treatment (such as surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy) .

Functions of the major organs and bone marrow meet the following criteria within 7 days before treatment: hemoglobin ≥ 80g/L, absolute neutrophil count ≥ 1.5 × 109/L, platelet (PLT) ≥ 100× 109/L, without blood transfusion within 14 days, total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5x ULN or if complicated with liver metastasis then ALT and AST ≤ 5x ULN, serum creatinine ≤ 1.5x ULN or creatinine clearance ≥ 50mL/min or urinary protein<2+, activated partial thromboplastin time (APTT) and international standardized ratio (INR)≤1.5×ULN.

Expected lifespan ≥ 6 months. The patients are able and willing to provide written informed consent to participate in the study.

Exclusion Criteria:

Patients who have previously suffered from other malignant tumors, except for cured skin basal cell carcinoma and cervical carcinoma in situ.

HER-2 positive patients who are willing to receive Herceptin treatment. Women who are pregnant or lactating or in the reproductive period and have not taken effective contraceptive measures, or those who have fertility requirements during the research period.

Patients with serious and uncontrolled internal diseases and infections or with chronic bowel disease or short bowel syndrome.

Patients with major organ failure, such as compensatory heart, lung, liver, and kidney failure as well as severe metabolic abnormalities in liver and kidney which affects normal drug metabolism.

Patients with a clear tendency for gastrointestinal bleeding and/or abnormal coagulation function (INR>1.5)under researchers evaluation.

hepatitis B virus or hepatitis C virus in active phase Patients with peripheral neuropathy neoadjuvant chemotherapy(NCT)-CTCAE ≥ Level 2.

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Although this trial was designed as open label, other independent researchers who conducted the imaging evaluation will be in a blinded state in the imaging evaluation phase for reducing the evaluator bias.