Study of Adjuvant Chemotherapy With or Without PD-1 Inhibitors and Chemoradiotherapy in Resected pN3 Gastric (G) or GEJ Adenocarcinoma

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to evaluate the efficacy and safety of postoperative adjuvant chemotherapy with PD-1 inhibitors and chemoradiotherapy, in comparison with adjuvant chemotherapy only, in D2/R0 resected pN3 gastric or gastroesophageal junction adenocarcinoma. PD-1+CRT cohort: A total of 216 patients will receive 6 weeks of PD-1 inhibitors and chemotherapy, then receive concurrent chemoradiotherapy, followed by 6 weeks of PD-1 inhibitors and chemotherapy, finally receive maintenance treatment of PD-1 inhibitors until (maximum 1year after radiotherapy). CT cohort: A total of 217 patients will receive 6 months of chemotherapy. The disease-free survival(DFS), overall survival(OS) and adverse effects will be analyzed.

Official Title
-----------------
A Multicenter, Randomized, Controlled Phase III Study of Chemotherapy With or Without PD-1 Inhibitors and Chemoradiotherapy as Adjuvant Regimen for D2/R0 Resected pN3 Gastric (G) or Gastroesophageal Junction (GEJ) Adenocarcinoma

Conditions
-----------------
Gastric Cancer

Intervention / Treatment
-----------------
* Drug: PD-1 inhibitor
* Drug: Oxaliplatin
* Drug: Capecitabine
* Drug: Tegafur-gimeracil-oteracil potassium
* Drug: 5-FU
* Radiation: Radiotherapy
* Drug: Chemotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1 Patients with expected survival time more than 6 months Patients after standard D2/R0 resection Postoperative histologically confirmed adenocarcinoma of the stomach or GEJ Positive lymph nodes more than 7, stage pN3 Patients without distant metastasis (M0) or M1 with abdominal exfoliated cell detection positive (CY1P0) Patients' physical condition and visceral function allows following adjuvant therapy, including chemotherapy, chemoradiotherapy and PD-1 inhibitor therapy. Patients' blood routine and biochemical indicators should meet the following standard: Hb≥90g/L, ANC≥1.5*10^9/L, PLT≥100*10^9/L, ALT & AST≤2.5 U/L, TB ≤ 1.5 UNL, serum creatinine<1 UNL. Patients who are willing to obey regimens during the study. Written informed consent is acquired before random entry, and patients should know that he/she has the right to quit, and following treatment won't be affected. Patients are willing to provide samples of blood and tissue. Exclusion Criteria: Patients with gross peritoneal metastasis (CY1P0 excluded) or distant metastasis. Patients who has received any anti-tumor therapy before surgery. Patients who had received radiotherapy for abdominal organs including stomach, liver, kidney, etc. Patients who had active systematic autoimmune diseases which need systematic treatment within 2 years before first medication in the study, substitutive therapy (such as thyroxine, insulin, etc) excluded. Patients diagnosed with immunodeficiency, or was receiving systematic glucocorticoid treatment or other immunosuppressive therapy within 7 days before medication, physiological dose of glucocorticoid is allowed (≤10 mg/d prednison or equivalent medication) Patients who have known severe allergic reaction (≥level 3) to anti-PD-1 monoclonal antibody, 5-FU, Oxaliplatin or any auxiliary material. Patient diagnosed with other malignant tumor in the past 5 years, excluding radical basal cell carcinoma of the skin and/or radical resected carcinoma in situ. Patient with severe vital organ failure. Pregnant or lactation period Patient with known mental illness or drug abuse that may influence compliance. Patient with known HIV infection, or active tuberculosis. Untreated active hepatitis B Patient with active HCV infection Uncontrolled complications Other situations that might disturb study results and compliance.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PD-1 inhibitor and chemoradiotherapy<br>PD-1 inhibitor+CapeOX/SOX/FOLFOX for 6 weeks, followed by chemoradiotherapy; 6 weeks of PD-1 inhibitor and CapeOX/SOX/FOLFOX for 6 weeks after chemoradiotherapy, followed by PD-1 inhibitor, till 12 months after chemoradiotherapy. PD-1 inhibitor Nivolumab/Toripalimab 240mg solution intravenously once daily, Q2W. OR Nivolumab/Toripalimab 360mg solution intravenously once daily, Q3W; OR Pembrolizumab/Tilelizumab/Sintilimab/Carrelizumab, 200mg solution intravenously once daily, Q3W. Chemotherapy: CapeOx or SOX or FOLFOX therapy determined by investigator. Chemoradiotherapy Radiotherapy: 1.8 Gy/fx, 45-50.5Gy Chemotherapy: Capecitabine 625mg/m2 bid orally with radiotherapy; OR Tegafur-gimeracil-oteracil potassium combination drug 40-60mg bid orally with radiotherapy. | Drug: PD-1 inhibitor<br>* Nivolumab/Toripalimab 240mg solution intravenously once daily, Q2W. OR Nivolumab/Toripalimab 360mg solution intravenously once daily, Q3W; OR Pembrolizumab/Tilelizumab/Sintilimab/Carrelizumab, 200mg solution intravenously once daily, Q3W.<br>Drug: Oxaliplatin<br>* CapeOx: 130 mg/m2 (body surface area) solution intravenously once-daily, followed by 20 days off. FOLFOX: 85 mg/m2 (body surface area) solution intravenously once-daily, followed by 13 days off.<br>Drug: Capecitabine<br>* CapeOx: 1000 mg2 (body surface area) bid orally in 14 days, followed by 7 days off.<br>Drug: Tegafur-gimeracil-oteracil potassium<br>* SOX: 40 - 60 mg bid orally in 14 days, followed by 7 days off<br>Drug: 5-FU<br>* FOLFOX：2400-2800mg/m2/d continuous intravenous pumping for 48h, Q2W<br>Radiation: Radiotherapy<br>* 1.8 Gy/Fx, 45-50.4 Gy<br>Drug: Chemotherapy<br>* Capecitabine 625mg/m2 bid orally with radiotherapy; ORegafur-gimeracil-oteracil potassium combination drug 40-60mg bid orally with radiotherapy<br>|
| Active Comparator: Chemotherapy<br>Chemotherapy: CapeOx or SOX or FOLFOX therapy determined by investigator. CapeOX: Oxaliplatin 130 mg/m2 (body surface area) solution intravenously once-daily, followed by 20 days off. Capecitabine 1000 mg2 (body surface area) bid orally in 14 days, followed by 7 days off. SOX: Oxaliplatin 130 mg/m2 (body surface area) solution intravenously once-daily, followed by 20 days off. Tegafur-gimeracil-oteracil potassium combination drug 40 - 60 mg bid orally in 14 days, followed by 7 days off. FOLFOX: Oxaliplatin 85 mg/m2 (body surface area) solution intravenously once-daily, followed by 13 days off. 5-FU 2400-2800mg/m2/d continuous intravenous pumping for 48h, Q2W. | Drug: Oxaliplatin<br>* CapeOx: 130 mg/m2 (body surface area) solution intravenously once-daily, followed by 20 days off. FOLFOX: 85 mg/m2 (body surface area) solution intravenously once-daily, followed by 13 days off.<br>Drug: Capecitabine<br>* CapeOx: 1000 mg2 (body surface area) bid orally in 14 days, followed by 7 days off.<br>Drug: Tegafur-gimeracil-oteracil potassium<br>* SOX: 40 - 60 mg bid orally in 14 days, followed by 7 days off<br>Drug: 5-FU<br>* FOLFOX：2400-2800mg/m2/d continuous intravenous pumping for 48h, Q2W<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year DFS rate | Defined as the time from randomization to the date of first documented progression or death from any cause. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year OS rate | Defined as the time from randomization to death from any cause. | Up to 3 years | 
| 3-year local recurrence free survival rate | Defined as the time from randomization to the date of first documented recurrence or death from any cause. | Up to 3 years | 
| Percentage of participants with treatment-related acute adverse events as assessed by CTCAE v5.0 |  | Up to 28 days from last dose | 
| Quality of life as assessed by Quality of Life Scale (range 0-60) | It evaluates the quality of life from 12 aspects, including appetite, mental status, sleep quality, fatigue, etc. The higher scores mean a better quality of life. | Through study completion, up to 10 years |