PD-1 Antibody + Apatinib Mesylate in 2+ Line Serum AFP-elevated Gastric Adenocarcinoma

Inclusion Criteria:

• Patients must volunteer to participate in the study, signed informed consent, and wereable to comply with the program requirements of visits and related procedures.
• Age and gender: ≥18 years old and≤75 years old, both men and women.
• All subjects must have unresectable, local advanced recurrent or metastatic gastriccancer, and have histologically confirmed predominant adenocarcinoma with serumAFP-elevated (serum AFP > 20 ng/ml).
• Subject must have at least received first-line antitumor therapy or whose standardtreatment is intolerable.
• Subject must have at least one measurable lesion or evaluable disease by CT or MRI periRECIST 1.1 criteria.
• Subject must be previously untreated with anti-angiogenesis molecular targeted therapyand immunotherapy for gastric cancer (including anti-CTLA-4, PD-1/PD-L1 monoclonalantibody immunotherapy).
• ECOG performance status score of 0 or 1.
• Child-Pugh score < 6 (Child-Pugh A), and no history of hepatic encephalopathy.
• Expected survival: ≥12 weeks.
• Adequate bone marrow, hepatic and renal function as assessed by the followinglaboratory requirements conducted within 7 days of starting study treatment: Neutrophil count≥1.5×10^9/L; Platelet count≥80×10^9/L; Hemoglobin≥90g/L; Serumalbumin≥28g/L; Total bilirubin (TBI)≤1.5×ULN; Alanine aminotransferase (ALT)≤3×ULN (or≤5×ULN if liver metastases are present); Aspartate aminotransferase (AST)≤1.5×ULN (or≤5×ULN if liver metastases are present); Alkaline phosphatase (ALP)≤2.5×ULN Thyrotropin (TSH) ≤1×ULN (FT3 and FT4 levels should be examined at the same time if abnormal, such asFT3 and FT4 levels are normal, can be included in the group); Serum creatinine≤1.5×ULN orcalculated creatinine clearance≥40 mL/min (using the Cockcroft-Gault formula) Female CrCl = (140- age in years) × weight in kg × 0.85 / 72 × serum creatinine in mg/ dL Male CrCl = (140- age in years) × weight in kg × 1.00 / 72 × serum creatinine in mg/ dL Subjects notreceiving anticoagulation therapy: INR or APTT ≤ 2×ULN; Urine protein < 2+; 24-hour urinaryprotein content <1.0g/24-hour if urinary protein ≥2+;
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancytest within 72 hours prior to the start of study drug. WOCBP must agree to followinstructions for method(s) of contraception (e.g. intrauterine devices, contraceptivesor condoms) for the duration of study treatment and 3 months after the last dose ofstudy treatment. Subjects must be non-lactating. Males who are sexually active withWOCBP must agree to follow instructions for method(s) of contraception for theduration of study treatment and 3 months after the last dose of study treatment.
• If HBsAg (+) and/or HBcAb (+), HBV DNA is required to be <500 IU/mL, and the originalanti-HBV treatment is continued throughout the study period, or start to anti-HBVtreatment throughout the study.

Exclusion Criteria:

• With history of active autoimmune disease or autoimmune disease (For example, thefollowing, but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis,enteritis, hepatitis, pituitary, vasculitis, nephritis, hyperthyroidism; patients withvitiligo; in childhood asthma has been completely alleviated, adults without anyintervention can be included; asthma with medical intervention could not be included).Substitution therapy is not considered as systemic therapy. Patients with thefollowing diseases are not excluded and may proceed to further screening:

1. Controlled Type I diabetes
2. Hypothyroidism (provided it is managed with hormone replacement therapy only)

• Any condition that required systemic treatment with either corticosteroids (> 10 mgdaily of prednisone or equivalent) or other immunosuppressive medication ≤ 14 daysbefore randomization.
• A history of severe allergy to any monoclonal antibody or anti-angiogenesis targeteddrug.
• Patients with known central nervous system metastasis (suspected need to be excludedby MRI scans) or a history of hepatic encephalopathy.
• The total volume of liver metastases>50%, or obvious infiltration of bile duct orportal vein trunk, or patients who have received liver transplantation in the past.
• More than a small amount of pericardial effusion, uncontrollable pleural effusion orascites requiring frequent drainage or medical intervention.
• Uncontrollable hypertension with drugs (systolic pressure ≥140 mmHg or diastolicpressure≥90 mmHg).
• With history of serious cardiovascular and cerebrovascular diseases: Any history of heart failure meeting New York Heart Association Classification III or IV ≤3months before randomization； Left ventricular ejection fraction < 50% by color Dopplerechocardiography； Uncontrolled arrhythmias or unstable angina pectoris； Corrected QTinterval > 500ms (calculated by Fridericia method).
• Abnormal coagulation function (INR > 2.0, PT > 16s), with haemorrhagic tendency orundergoing thrombolytic or anticoagulant therapy, but prophylactic use of low-doseaspirin and low-molecular-weight heparin is allowed.
• Significant clinical bleeding symptoms or definite bleeding tendency occurred within 3months before randomization.
• Arteriovenous thrombosis events occurring within 6 months before randomization.
• Hereditary or Acquired Hemorrhage and Thrombosis Tendency.
• Metastatic diseases involving major airways or blood vessels or large centralmediastinal tumors.
• Urinary routine indicated that urinary protein (++) and confirmed 24-hour urinaryprotein content > 1.0 g.
• Has received any radiotherapy, chemotherapy, hormone therapy, surgery or anyinvestigational therapies within 28 days or 5 half-lives (whichever is longer) of thefirst study drug administration.
• Patients with toxicities (as a result of prior anticancer therapy) which have notrecovered to baseline or ≤ CTCAE 1, except for AEs not considered a likely safety risk (eg, alopecia and specific laboratory abnormalities).
• Systemic immunostimulants (including interferon and IL-2) were administered within 28days or 5 half-lives (whichever is longer) before randomization. Systemicimmunosuppressive drugs (such as glucocorticoids) were administered within 2 weeks, orsystemic immunosuppressive drugs were expected to be used during the study period.Patients who are currently or have previously been on any of the following steroidregimens are not excluded: Acute, low-dose systemic immunosuppressive drugs or single-shot systemic immunosuppressivedrugs (e.g. 48-hour glucocorticoid administration to prevent and treat contrast agentallergy); Treatment of chronic obstructive pulmonary disease or bronchial asthma withcorticosteroids inhalation administration such as fluorocortisone and glucocorticoids;Accept low doses of glucocorticoid to treat postural hypotension or adrenal insufficiency (dose ≤ 10 mg daily of prednisone or equivalent).
• With severe chronic or active infections (including tuberculosis infection, etc.)requiring systemic antibacterial, antifungal or antiviral therapy within 7 days of thefirst study drug administration.
• Abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation,intraperitoneal abscess or intestinal obstruction occurred within 6 months beforerandomization. Subjects with incomplete obstructive/obstructive syndrome/intestinalobstructive symptoms/signs who have undergone definite surgical treatment and whosesymptoms disappear are not excluded.
• Major surgical procedures (craniotomy, thoracotomy or laparotomy, etc.), open biopsyor major trauma, abdominal surgery or major abdominal trauma within 60 days prior tothe start of treatment, or anticipated need for major surgical procedures during thestudy period, and not recovered from side effects. Tissue (hollow needle) biopsy orother minor surgery was performed within 3 days before randomization, except for theplacement of intravenous infusion system devices.
• Congenital or acquired immunodeficiency (e.g. HIV-infected persons).
• Any active malignancy ≤ 5 years before randomization except for the specific cancerunder investigation in this study and any cured limited tumors (eg, carcinoma in situof the cervix or prostate, basal cell skin cancer).
• With history of interstitial lung disease, non-infectious pneumonitis.
• Gastric surgery and/or local treatment or experimental drug therapy for gastric cancerwere performed within 4 weeks before randomization. In patients with bone metastasis,palliative radiotherapy for bone metastasis lesions within 1 week before randomizationcan be included (but the radiotherapy area is required to be less than 5% of the bonemarrow area).
• Received prior therapies targeting PD-1, PD-L1, or PD-L2, or Apatinib mesylate.
• Was administered a live vaccine ≤ 4 weeks before randomization; or plan to livevaccinate during against PD-1 monoclonal antibody treatment or within five monthsafter last administration.
• Concurrent participation in another therapeutic clinical trial, unless participatingin observational (non-interventional) clinical studies or at the follow-up stage ofinterventional studies.
• Other situations that the researchers think should be excluded.