A Study to Evaluate the Efficacy and Safety of Toripalimab Injection in the Treatment of Recurrent or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Who Have Failed at Least Two Prior Lines of Therapy and Are Positive Specific Markers
A Study to Evaluate the Efficacy and Safety of Toripalimab Injection in the Treatment of Recurrent or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Who Have Failed at Least Two Prior Lines of Therapy and Are Positive Specific Markers
This is a single-arm, multicenter, phase 2 study to assess the efficacy and safety of
 Toripalimab Injection (JS001) in patients with advanced recurrent or metastatic gastric or
 gastroesophageal junction adenocarcinoma who have failed at least 2 prior lines of therapy
 and are positive for specific markers.

 Patients who meet the requirements will be treated with Toripalimab injection 240 mg once
 every 3 weeks (q3w) until disease progression based on imaging according to RECIST 1.1
 criteria judged by the investigator, or intolerable toxicity, or withdrawal of informed
 consent, or withdrawal of treatment judged by the investigator, or voluntarydiscontinuation
 of treatment by the patient with CR of more than 6 months, or up to 2 years of treatment for
 JS001, whichever occurs first.

 For the case that the patient shows disease progression on imaging according to RECIST 1.1,
 as long as the investigator judges that the patient can still benefit from continued
 medication, the treatment with Toripalimab Injection can be continued until the progression
 on imaging assessed by the investigator for the second time. The clinical benefit is based on
 the results of comprehensive assessment by the investigator in combination with imaging
 findings and clinical condition when the patient has no intolerable toxicity or the symptoms
 worsen due to disease progression.

 Tumor assessments are performed at screening (as the baseline), every 6 weeks from the first
 dose in the first year, and every 9 weeks from the second year until radiologically
 documented progressive disease (PD), or second disease progression judged by the investigator
 (for patients with disease progression shown by first imaging, but who can continue treatment
 judged by the investigator), or withdrawal of informed consent by the patient, or loss to
 follow-up, or start of a new anti-tumor therapy, or the termination of the study. If a
 patient withdraws from the study for reasons other than disease progression (including due to
 the AE or because the treatment interval is beyond the window) and no disease progression
 occurs at the time of withdrawal, radiographic assessments should be continued until disease
 progression, death, or start of a new anti-tumor therapy. Patient medication management is
 based on the investigator's tumor assessment.
1. Patients voluntarily participate in this study after full informed consent and sign a
 written informed consent form; 2. Age ≥18 years and ≤75 years at the time of signing
 informed consent; 3. Histologically or cytologically confirmed gastric or gastroesophageal
 junction adenocarcinoma; 4. Disease progression after at least two lines of previous
 treatment for recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma:

 1. First-line treatment must be combination regimen of two or more chemotherapy drugs and
 disease progression occurs; or distant metastasis or local recurrence within 6 months
 after completion of radical neoadjuvant chemotherapy or adjuvant chemotherapy (or
 chemoradiotherapy) based on platinum-based combination chemotherapy, which can be
 considered as progression after first-line treatment;

 2. Second-line treatment includes but is not limited to chemotherapy, anti-angiogenic
 therapy and disease progression occurs;

 3. Patients known to be HER2-positive require treatment with approved anti-HER2 targeted
 agents.

 4. The interval between the end of systemic treatment and the first study drug
 administration is at least 4 weeks (the washout period of oral fluorouracil drugs is 2
 weeks); 5. Previous tumor samples or fresh tumor tissue biopsy samples can be
 provided, and any of the following biomarkers are confirmed positive by the central
 laboratory:

 1)PD-L1 positive: defined as PD-L1 staining positive at any intensity in ≥5% tumor cells
 (TC) or ≥10% immune cells (IC); 2)Epstein-Barr virus (EBV) positive: defined as positive
 for EBV-encoded small RNA in situ hybridization (EBER-ISH); 3)Tumor mutation burden-high
 (TMB-H): tumor tissues will be detected by whole exome sequencing (WES), with tumor
 mutation burden ≥12 Muts/Mb; 4)Microsatellite instability-high (MSI-H): Tumor tissue is
 tested by whole exome sequencing (WES) to confirm MSI-H positivity; 6. at least one
 measurable lesion according to RECIST 1.1 assessment criteria; 7. expected survival ≥3
 months; 8. According to the Eastern Cooperative Oncology Group (ECOG) criteria (Section
 11.2 Appendix 2), the performance status score is 0 or 1; 9. Good organ function:

 1. Hematology (no blood transfusion or colony-stimulating factor and thrombopoietin 14
 days before the first study drug administration) Neutrophil count≥1.5×109/L;
 Thrombocyte count≥100×109/L; Hemoglobin≥90 g/L;

 2. Kidney function Serum creatinine≤1.5 x upper limit of normal (ULN) or Calculated
 creatinine clearance by referring to the Cockcroft-Gault formula (Section 11.6
 Appendix 6) or site practice≥50 mL/min;

 3. Hepatic function Bilirubin total≤1.5 x ULN or ≤3 x ULN (patients with known Gilbert's
 disease) ; ALT/AST≤3 x ULN (without liver metastasis) or ≤5 x ULN (in case of liver
 metastases) ; Alkaline phosphatase≤3 x ULN (without liver and bone metastasis) or ≤5 x
 ULN (in case of liver or bone metastasis) ; Albumin≥30 g/L;

 4. Coagulation function:International normalized ratio (INR) or prothrombin time (PT) or
 activated partial thromboplastin time (aPTT) ≤1.5 x ULN.

 10. Adverse events and/or complications caused by any previous treatment, including surgery
 or radiotherapy, have been fully relieved and must have been relieved to grade 0 or 1
 [according to the National Cancer Institute Common Terminology Criteria for Adverse Events
 (NCI-CTCAE 5.0)]; except for alopecia/pigmentation of any grade and long-term toxicity
 caused by other treatments, which cannot be recovered and does not affect the study drug
 administration/compliance and patient safety in the judgment of the investigator; 11.
 Within 7 days before the first dose, women of childbearing age must confirm that the serum
 pregnancy test is negative and agree to use effective contraceptive measures during the use
 of the study drug and within 60 days after last dose. A female of childbearing potential in
 this protocol is defined as a sexually mature female who:

 1. No hysterectomy or bilateral oophorectomy,

 2. Spontaneous menopause does not last for 24 consecutive months (amenorrhea after cancer
 treatment and not rule out fertility) (i.e., menstruation at any time within the
 previous 24 consecutive months).

 Male patients with partners of childbearing potential must agree to use effective
 contraception during the use of the study drug and within 60 days after last dose.

 Exclusion criteria:

 1. With pathologically diagnosed squamous cell carcinoma or sarcoma or undifferentiated
 carcinoma of the stomach or gastroesophageal junction;

 2. Patients with necrotic lesions, judged by the investigator to have a risk of massive
 hemorrhage;

 3. Symptomatic spinal cord compression, or untreated patients expected to have symptoms
 of spinal cord compression; or for previously diagnosed and treated spinal cord
 compression, there is no evidence that the disease is clinically stable for ≥4 weeks
 before the first study drug administration; 1)Patients with asymptomatic spinal cord
 compression indicated by imaging, which is assessed as stable by specialists, unless
 treatment for spinal cord compression is not required temporarily;

 4. Poorly controlled pleural effusion, pericardial effusion or ascites requiring regular
 drainage;

 5. Accompanied by severe peritoneal metastasis, mainly manifested as: clinically
 significant intestinal obstruction; moderate to large amount of ascites; barium enema
 revealed small intestinal stenosis;

 6. Poorly controlled tumor-related pain; 1)For patients requiring analgesics, treatment
 must be on a stable dose prior to study participation; 2)Symptomatic lesions suitable
 for palliative radiotherapy (e.g., bone metastasis or metastasis resulting in nerve
 injury) should be treated before enrollment; 3)Prior to enrollment, local treatment of
 asymptomatic metastatic lesions that may cause functional deficit or intractable pain
 due to further growth (e.g., current epidural metastases not associated with spinal
 cord compression) should be considered if appropriate;

 7. Active or untreated CNS metastases as determined by computed tomography (CT) or
 magnetic resonance imaging (MRI) assessment during screening and previous imaging
 assessment; 1)Patients who have previously received treatment for CNS metastases,
 shown to be stable for ≥4 weeks by imaging examination during the screening period,
 and stopped systemic hormone therapy (prednisone or other hormones with equal efficacy
 at a dose > 10 mg/day) for ≥4 weeks before the first study drug administration can
 participate in the study;

 8. Patients with a history of carcinomatous meningitis;

 9. Patients with a weight loss of more than 10% within 2 months before signing the
 informed consent form;

 Exclusion criteria for concurrent other diseases or concomitant conditions:

 10. Patients with other malignant tumors except for gastric cancer (except for cured
 cervical carcinoma in situ, basal or squamous cell skin cancer, localized prostate
 cancer with radical treatment, ductal carcinoma in situ with radical treatment) within
 5 years before the first study drug administration;

 11. Within 28 days prior to the first study drug administration, there are other major
 surgeries except for the diagnosis of gastric cancer, or major surgeries are expected
 to be performed during the study, unless assessed by researchers and specialists that
 they have fully recovered from the complications of major surgery;

 12. Clinically significant underlying medical conditions (e.g., dyspnea, pneumonia,
 pancreatitis, poorly controlled diabetes, active or poorly controlled infection, drug
 or alcohol abuse, or psychiatric disorders) that, in the opinion of the investigator,
 can affect study drug administration and protocol compliance;

 13. Presence of severe neurological or psychiatric disorders, including dementia and
 epileptic seizures;

 14. Have NCI-CTCAE ≥grade 2 peripheral neuropathy;

 15. Pregnant or lactating female patients;

 16. Patients with major cardiovascular diseases, such as heart disease of New York Heart
 Association (NYHA) functional class II or above (see Section 11.5 Appendix 5),
 myocardial infarction within 3 months before the first study drug administration,
 poorly controlled arrhythmia or unstable angina;

 1)Patients with known coronary artery disease, congestive heart failure not meeting the
 above criteria, or left ventricular ejection fraction < 50% must be treated with an
 optimized stable medical regimen at the discretion of the treating physician, with
 consultation with a cardiologist, as appropriate;

 Exclusion criteria for medication:

 17. Previous history of hypersensitivity to other monoclonal antibodies or any component of
 Toripalimab Injection (JS001); 18. Previous treatment targeting PD-1 receptor or its ligand
 PD-L1 or cytotoxic T-lymphocyte-associated protein 4 (CTLA4) receptor; 19. Participated in
 or planned to participate in other intervention studies within 4 weeks before the first
 study drug administration.

 20. Treatment with systemic immunostimulatory drugs (including but not limited to
 interferon or IL-2) within 2 weeks or 5 half-lives of the drug (whichever is longer) before
 the first study drug administration; 21. Received systemic corticosteroids (> 10 mg/day
 prednisone equivalent drug) or other systemic immunosuppressive agents (including but not
 limited to cyclophosphamide, azathioprine, methotrexate, thalidomide and anti-tumor
 necrosis factor drugs [anti-TNF]) within 2 weeks before the first study drug administration
 ;

 1. Topical, ocular, intra-articular, intranasal, and inhaled corticosteroids are
 permitted;

 2. Patients receiving acute low-dose systemic immunosuppressive agents (e.g., a single
 dose of dexamethasone for nausea) can be enrolled after discussion with and approval
 by the medical monitor;

 3. Patients who need baseline and follow-up MRI/CT tumor assessment can use steroids
 prophylaxis if they have previous allergic reactions to intravenous contrast media.

 4. Inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids
 (e.g., fludrocortisone) for orthostatic hypotension, and low-dose corticosteroids for
 maintenance treatment of adrenocortical insufficiency are permitted;

 Exclusion criteria for special immune status:

 22. History of autoimmune diseases, including but not limited to myasthenia gravis,
 myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
 inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome,
 Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barre syndrome, multiple sclerosis,
 vasculitis, or glomerulonephritis (see Section 11.7, Appendix 7 for a more comprehensive
 list of autoimmune diseases);

 1. Patients with autoimmune-related hypothyroidism on stable doses of thyroid hormone
 replacement are eligible for this study;

 2. Patients with type 1 diabetes controlled on a stable insulin regimen are eligible for
 this study; 23. Patients with previous allogeneic bone marrow transplantation or
 previous solid organ transplantation; 24. Any live vaccine (e.g., vaccines against
 infectious diseases, such as influenza vaccine, varicella vaccine, etc.) within 4
 weeks (28 days) before the first study drug administration; 25. Active infection,
 including tuberculosis (clinical diagnosis including clinical history, physical
 examination and imaging findings, as well as TB tests according to local medical
 routine), hepatitis B, hepatitis C or human immunodeficiency virus (HIV antibody
 positive);

 1)Patients who are positive for hepatitis B surface antigen (HBsAg+) and/or hepatitis B
 core antibody (HBcAb+) are required to undergo hepatitis B virus deoxyribonucleic acid (HBV
 DNA) test. If HBV DNA copy number is ˂1000 cps/mL, or less than the lower limit of
 detectable value at the study site, the patients can participate in this study; 2)Patients
 who are positive for hepatitis C antibody (HCV Ab+) are required to have an HCV RNA test
 and are eligible for this study only if they are negative for HCV RNA (defined as below the
 lower limit of detectable value at the study site); 26. History of idiopathic pulmonary
 fibrosis, drug-induced pneumonia, organized pneumonia (i.e., bronchiolitis obliterans),
 idiopathic pneumonia, or evidence of active pneumonia on chest CT scan at screening.