PD1 Combined With Chemotherapy for Adjuvant Treatment of Gastric Cancer

Study Overview
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Brief Summary
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This international, multicenter, randomized, double-blind phase III study intends to recruit 680 patients who have received radical gastrectomy (R0 resection, D2 or more extended lymphadenectomy) with postoperative pathological stage II or III (AJCC Cancer Staging Manual, 8th Edition) gastric or EGJ adenocarcinoma to evaluate the efficacy and safety of JS001 combined with postoperative adjuvant chemotherapy versus placebo combined with postoperative adjuvant chemotherapy.

Detailed Description
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This is an international, multicenter, randomized, double-blind phase III study, plans to recruit 680 patients who received radical gastrectomy (R0, D2 or higher lymphadenectomy) with postoperative pathological stage II (T4aN0M0) or III (the 8th Edition American Joint Committee on Cancer [AJCC] Cancer Staging Manual) gastric adenocarcinoma and gastroesophageal junction adenocarcinoma, and the study intends to evaluate the efficacy and safety of JS001 combined with postoperative adjuvant chemotherapy versus placebo combined with postoperative adjuvant chemotherapy. Patients meeting the inclusion criteria will be 1:1 randomized into JS001-chemotherapy group and placebo-chemotherapy group. The random stratification factors include adjuvant chemotherapeutic regimens (XELOX versus SOX) and tumor anatomical sites (gastric adenocarcinoma versus gastroesophageal junction adenocarcinoma). The study treatment will be initiated 4-6 weeks after surgery, and the investigator will select XELOX (Oxaliplatin + capecitabine) or SOX (Oxaliplatin + S-1, tegafur, gimeracil and oteracil potassium) as the adjuvant chemotherapeutic regimen given as 3-week cycles for up to 8 cycles based on each patient's condition; JS001/placebo will be given for up to 17 cycles after surgery, until intolerable toxicity, disease recurrence, patient's withdrawal of consent, investigator's judgment that the patient needs to be withdrawn from the study treatment, or death, whichever comes first. Safety evaluation, including vital signs, ECOG score, physical examination and laboratory examinations, will be performed on a regular basis during the treatment. This study will end after the main analysis node of DFS and unblinding for analysis are achieved, or 5 years after enrollment of the last patient, whichever comes first. The Sponsor is entitled to terminate the study at any time due to specific reasons (e. g, major safety issues, force majeure, etc.). Radiological follow-up: tumor response evaluation will be performed once every 12 weeks ±7 days within the first 5 years after randomization, and once per year subsequently, until disease recurrence or death. When symptoms or signs of suspected recurrence/metastasis occur, the radiological evaluation can be performed at any time. Disease recurrence is defined as local recurrence or distant metastases with clear radiological evidence (CT or MRI). Survival follow-up: it will be performed once every 12 weeks after disease recurrence, until patient's withdrawal of informed consent, loss to follow-up or death, whichever comes first. Safety follow-up: adverse events will be closely followed up and recorded, until 60 days after the last dose of treatment or the end of study follow-up (death, loss to follow-up, withdrawal of consent form and the end of study), whichever comes first. 

Official Title
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An International, Multicenter, Randomized, Double-blind, Phase III Clinical Study to Evaluate the Efficacy and Safety of Toripalimab Injection Combined With Postoperative Adjuvant Chemotherapy Versus Placebo Combined With Postoperative Adjuvant Chemotherapy in Patients With Gastric or Gastroesophageal Junction Adenocarcinoma After Radical Gastrectomy

Conditions
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Gastric or Esophagogastric Junction Adenocarcinoma

Intervention / Treatment
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* Biological: JS001/Placebo
* Biological: JS001/placebo combine with Postoperative Adjuvant Chemotherapy


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Age 18-75 years. No residual tumor (R0) after D2 or greater lymphadenectomy through laparotomy. According to the definition of the 8th edition of the AJCC Cancer Staging Manual, patients with gastric adenocarcinoma confirmed by histopathology, pathological stage II (T4aN0M0) and stage III, including gastroesophageal junction adenocarcinoma (GEJ) patients. ECOG performance status 0-1. No metastasis or recurrence as radiologically confirmed. Patients must have adequate organ function as assessed in the laboratory tests. Patients must provide informed consent for this study, and sign the written informed consent form voluntarily before the initiation of the study, and are willing and able to comply with the scheduled visits, treatment plan, laboratory examinations and other study procedures in the study. Female patients of childbearing age must take a serum pregnancy test within 7 days before randomization with negative results, and agree to adopt reliable and effective contraceptive methods during the study. 4.2 EXCLUSION CRITERIA Previous use of non-surgical therapy for gastric adenocarcinoma. Having liver, peritoneal or distant metastasis. Inability to take the drug orally. Having postoperative complications that are not relieved at the time of randomization. Uncontrolled pericardial effusion or pleural effusion which required invasive treatment, and grade II or above peritoneal effusion (diagnosed clinically) present at screening. Presence of contraindicated chemotherapeutic drugs in this study and failure to receive the adjuvant therapeutic regimen in any group specified in the protocol. Having received any surgery not for gastric adenocarcinoma requiring general anesthesia within 28 days prior to randomization. Having malignant tumors other than gastric adenocarcinoma within 5 years before randomization. Active autoimmune disorders requiring systemic treatment. Patients with immunodeficiency or receiving long-term systemic steroid therapy. Concurrent diverticulitis or symptomatic gastrointestinal ulcer disease. Patients who are receiving or requiring anticoagulant therapy. Patients with serious cardiovascular and cerebrovascular diseases. Diabetes mellitus that is not effectively controlled. Active infections requiring treatment. ≥Grade 2 peripheral neuropathy. Patients with active tuberculosis or having received anti-tuberculosis therapy within one year prior to randomization. Patients currently having interstitial lung disease or having a history of interstitial lung disease. Hepatitis B, known positive for hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (HBcAb), and HBV DNA≥1000cps/ml; hepatitis C, positive HCV RNA or RNA ≥1000cps/ml. Human immunodeficiency virus (HIV) antibody positive. Vaccination of any live vaccine within 4 weeks before randomization. Previous allogeneic bone marrow transplantation or solid organ transplantation. Previous treatment targeting PD-1 receptor or its ligand PD-L1 or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptor; Previous history of serious allergy to monoclonal antibody or other biological preparations. Having participated in other interventional clinical studies within 28 weeks before randomization. Having clinically significant underlying medical disease that may affect administration of study drug or compliance to the protocol, as judged by investigators. Other patients who are considered by investigators as inappropriate for enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: JS001 240mg, Q3W with XELOX regimen or SOX regimen<br>JS001 240mg, will be intravenously administered once every 3 weeks, until 17 cycles XELOX regimen (oxaliplatin + capecitabine) or SOX regimen (oxaliplatin + S-1), given in one therapeutic cycle of 3 weeks for up to 8 cycles XELOX regimen: Oxaliplatin, 130mg/m2, intravenous drip for over 3 hours, day 1, Q3W; capecitabine, 1000mg/m2, orally, twice per day, from day 1 to day 14, Q3W. SOX regimen: Oxaliplatin, 130mg/m2, intravenous drip for over 3 hours, day 1, Q3W; S-1 Capsules, 40-60mg, orally, twice per day, from day 1 to day 14, Q3W. | Biological: JS001/Placebo<br>* JS001/placebo combine with Postoperative Adjuvant Chemotherapy<br>* Other names: Postoperative Adjuvant Chemotherapy;|
| Placebo Comparator: Placebo combine with chemotherapy<br>XELOX regimen (oxaliplatin + capecitabine) or SOX regimen (oxaliplatin + S-1), given in one therapeutic cycle of 3 weeks for up to 8 cycles XELOX regimen: Oxaliplatin, 130mg/m2, intravenous drip for over 3 hours, day 1, Q3W; capecitabine, 1000mg/m2, orally, twice per day, from day 1 to day 14, Q3W. SOX regimen: Oxaliplatin, 130mg/m2, intravenous drip for over 3 hours, day 1, Q3W; S-1 Capsules, 40-60mg, orally, twice per day, from day 1 to day 14, Q3W. | Biological: JS001/placebo combine with Postoperative Adjuvant Chemotherapy<br>* JS001/placebo combine with Postoperative Adjuvant Chemotherapy<br>* Other names: Postoperative Adjuvant Chemotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DFS evaluated by the BICR based on RECIST v1.1 | To evaluate the disease-free survival (DFS) as per RECIST v1.1 by the blind independent central review (BICR) for toripalimab injection (JS001) combined with adjuvant chemotherapy versus placebo combined with adjuvant chemotherapy in patients with gastric or EGJ adenocarcinoma after radical gastrectomy. | Through study completion, average of 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DFS evaluated by the investigator based on RECIST v1.1 | To evaluate the disease-free survival (DFS) evaluated by the investigator for Toripalimab Injection (JS001) combined with adjuvant chemotherapy versus placebo combined with adjuvant chemotherapy in patients with gastric or gastroesophageal junction adenocarcinoma after radical gastrectomy. | Through study completion, average of 60 months | 
| DFS rate at 3 years evaluated by the BICR based on RECIST v1.1 | To evaluate the postoperative DFS rate and overall survival (OS) rate at 3 years for Toripalimab Injection (JS001) combined with adjuvant chemotherapy versus placebo combined with adjuvant chemotherapy in patients with gastric or gastroesophageal junction adenocarcinoma after radical gastrectomy. | 36 months | 
| DFS rate at 5 years evaluated by the BICR based on RECIST v1.1 | To evaluate the postoperative DFS rate and overall survival (OS) rate at 5 years for Toripalimab Injection (JS001) combined with adjuvant chemotherapy versus placebo combined with adjuvant chemotherapy in patients with gastric or gastroesophageal junction adenocarcinoma after radical gastrectomy. | 60 months | 
| OS | To evaluate the OS for Toripalimab Injection (JS001) combined with adjuvant chemotherapy versus placebo combined with adjuvant chemotherapy in patients with gastric or gastroesophageal junction adenocarcinoma after radical gastrectomy. | 5 years | 
| Overall survival rate (OS rate) at 3 years and 5 years | To evaluate the postoperative overall survival (OS) rate at 3 for Toripalimab Injection (JS001) combined with adjuvant chemotherapy versus placebo combined with adjuvant chemotherapy in patients with gastric or gastroesophageal junction adenocarcinoma after radical gastrectomy. | 3 years and 5 years | 
| Time to local recurrence (TTLR) | To evaluate the time to local recurrence (TTLR) for Toripalimab Injection (JS001) combined with adjuvant chemotherapy versus placebo combined with adjuvant chemotherapy in patients with gastric or gastroesophageal junction adenocarcinoma after radical gastrectomy. | Through study completion, average of 60 months | 
| Time to response (TTR) | To evaluate thetime to recurrence (TTR) for Toripalimab Injection (JS001) combined with adjuvant chemotherapy versus placebo combined with adjuvant chemotherapy in patients with gastric or gastroesophageal junction adenocarcinoma after radical gastrectomy. | Through study completion, average of 60 months | 
| Incidence and severity of adverse events (AE),clinically significant abnormal changes in vital signs, ECOG scores, physical examination, electrocardiogram (ECG), echocardiography and laboratory examinations | To evaluate the safety of Toripalimab Injection (JS001) combined with adjuvant chemotherapy versus placebo combined with adjuvant chemotherapy in patients with gastric or gastroesophageal junction adenocarcinoma after radical gastrectomy. | Through study completion, average of 60 months | 
| To explore the correlation of PD-L1 status, tumor mutation burden (TMB) status, microsatellite status and EBV status with DFS, DFS rate , OS, OS rate at ,TTLR and TTR[efficacy] of adjuvant therapy. | To evaluate the correlation of PD-L1 status, tumor mutation burden (TMB) status, microsatellite status and EBV status with the efficacy of adjuvant therapy. | Within 6 Months after C1D1 | 
| To evaluate the potential correlation of the incidence of ADA of Toripalimab Injection (JS001) with incidence and severity of adverse events (AE)[safety] and DFS, DFS rate , OS, OS rate ,TTLR and TTR[efficacy]. | To evaluate the incidence and titer of anti-drug antibody (ADA) of Toripalimab Injection (JS001). | At every other cycle（each cycle is 21 days）up to 17 cycles | 
| To evaluate the quality of life in the two groups using the EORTC QLQ-C30 questionnaires | To evaluate the disease-related symptoms and health-related quality of life (HRQoL) in the two groups through the European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life questionnaire (EORTC QLQ-C30) a. The EORTC QLQ-C30 consists of three subscales with 30 questions. The EORTC QLQ-C30 have three subscales in the scale include functioning scales (15 questions), symptom scales (13 questions), and global health status (2 questions). The reliability and validity of Cronbach'α was 0.81-0.94. The functional scale and the global health status , the higher the total score, the better the quality of life; the lower the score in the symptom scale, the better the quality of life. | From date of randomization, until disease progression , loss of clinical benefit ,withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first. Up to 1 approximately years | 
| To evaluate the quality of life in the two groups using the EORTC QLQ-STO22 questionnaires | To evaluate the disease-related symptoms and health-related quality of life (HRQoL) in the two groups through the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Stomach (QLQ-STO22).The EORTC QLQ-STO22 consists of one subscale with 22 questions.The EORTC QLQ-STO22 scale include symptom scales (22 questions) The Cronbach'α was 0.70-0.94.The lower the score in the symptom scale, the better the quality of life. | From date of randomization, until disease progression , loss of clinical benefit ,withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first. Up to 1 approximately years |