Nivolumab, S-1 Combined With Oxaliplatin Versus Nivolumab as Neoadjuvant Therapy in Advanced Gastric Cancer

Study Overview
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Brief Summary
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The trial is a prospective, randomized, controlled phase Ⅱ study which will be conducted in Chinese PLA General Hospital, Beijing, China. Patients with eligibility will enrolled and assigned into either group A for 9 weeks of nivolumab, S-1 combined with oxaliplatin (Nivo+SOX) followed by D2 surgery and group B for 9 weeks of nivolumab followed by D2 surgery. The primary endpoint is the safety assessed by recording adverse events and the secondary endpoints are response rate, disease control rate, pathological complete response rate, D2 rate and R0 rate.

Official Title
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A Prospective, Randomized, Controlled Phase II Evaluation of Nivolumab, S-1 Combined With Oxaliplatin (Nivo+SOX) Versus Nivolumab (Nivo) as Neoadjuvant Therapy in Patients With Locally Advanced Gastric Adenocarcinoma (RESONANCE-Ⅲ Study)

Conditions
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Gastric Cancer, Chemotherapy Effect

Intervention / Treatment
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* Drug: Nivolumab plus SOX
* Drug: Nivolumab
* Procedure: Gastrectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-bedridden, aged 18 to 70 years old; Eastern Cooperative Oncology Group (ECOG) score is 0 to 1; Histologically confirmed gastric adenocarcinoma; Have evaluable lesions based on RECIST 1.1; Stage III (cT3-4aN1-3 M0, American Joint Committee on Cancer (AJCC) TNM staging system 8th edition) gastric cancer confirmed by enhanced computer tomography (enhanced CT) and laparoscopic exploration (endoscopic ultrasonography (EUS) and magnetic resonance imaging (MRI) if necessary); The surgeon have the ability to complete standard D2 radical gastrectomy and the gastrectomy can be tolerated by the patient; Laboratory test criteria: peripheral blood hemoglobin (Hb) ≥ 90 g/L, neutrophil absolute count ≥ 3× 109 /L, platelet count (PLT) ≥ 100× 109 /L, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal (ULN), total bilirubin ≤ 1.5×ULN, serum creatinine (SCr) ≤ 1.5×ULN, and serum albumin (ALB) ≥ 30 g/L; Patients with heart disease, echocardiogram showing that the left ventricular ejection fraction ≥ 50%, electrocardiogram (ECG) is basically normal within 4 weeks before operation and with no obvious symptoms are acceptable; There is no serious underlying disease that could lead to an expected life expectancy < 5 years; Willing to sign the informed consent for participation and publication of results. Exclusion Criteria: Human epidermal growth factor receptor 2 (HER2)-positive or indeterminate G/GEJ cancer; Pregnant or lactating women; Positive pregnancy test for women in childbearing age. Menopausal women without menstruation for at least 12 months can be regarded as women with no possibility of getting pregnant; Refusal of birth control during the study; Prior chemotherapy, radiotherapy or immunotherapy; History of other malignant diseases in the last 5 years (except for cervical carcinoma in situ); History of uncontrolled central nervous system diseases, which could influence the compliance; History of severe liver diseases (Child-Pugh class C), renal diseases (endogenous creatinine clearance rate (Ccr) ≤ 50 ml/min or SCr > 1.5 ULN) or respiratory diseases; Uncontrolled diabetes and hypertension; Clinically severe heart disease, such as symptomatic coronary heart disease, New York Heart Association (NYHA) class II or more severe congestive heart failure, uncontrolled arrhythmia requiring drug intervention, or a history of myocardial infarction in the last 6 months; History of dysphagia, complete or partial gastrointestinal obstruction, active gastrointestinal bleeding and gastrointestinal perforation; On steroid treatment after organ transplant; With uncontrolled severe infections; Known dihydropyrimidine dehydrogenase deficiency (DPD); Anaphylaxis to any research drug ingredient; Known peripheral neuropathy (> NCI-CTC AE 1). Patients with only disappearance of deep tendon reflex need not to be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivo + SOX<br>Nivolumab plus SOX | Drug: Nivolumab plus SOX<br>* The preoperative therapy consists of three-week cycles of intravenously administered nivolumab 360mg and oxaliplatin 130mg/m2 on day 1, and orally administered S-1 40-60 mg twice a day (BID) on day 1 to 14. The dose of S-1 depends on body surface area (BSA): BSA<1.25 m2, 40mg; 1.25<BSA<1.50 m2, 50mg; BSA>1.50 m2, 60mg. Day 15 to day 21 is the rest period.<br>* Other names: Nivo + SOX;Procedure: Gastrectomy<br>* A standard D2 radical laparoscopic gastrectomy according to the CSCO clinical guidelines for the diagnosis and treatment of gastric cancer is planned 3-4 weeks after the last cycle of preoperative therapy.<br>|
| Active Comparator: Nivo<br>Nivolumab | Drug: Nivolumab<br>* The preoperative therapy consists of three-week cycles of intravenously administered nivolumab 360mg on day 1.<br>* Other names: Nivo;Procedure: Gastrectomy<br>* A standard D2 radical laparoscopic gastrectomy according to the CSCO clinical guidelines for the diagnosis and treatment of gastric cancer is planned 3-4 weeks after the last cycle of preoperative therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | The safety is assessed by recording adverse events. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RR | Response rate, defined as the rate of patients who achieve CR or PR according to the RESIST 1.1. | 2 years | 
| DCR | Disease control rate, defined as the rate of patients who achieve CR, PR or PD according to the RESIST 1.1. | 2 years | 
| pCR rate | Pathological complete response rate, defined as the rate of patients achieving pathological complete response. | 2 years | 
| D2 rate | The rate of patients who received D2 radical gastrectomy. | 2 years | 
| R0 rate | The rate of patients who received R0 resection. | 2 years |