Study of SYSA1801 in the Treatment of Claudin( CLDN) 18.2 Positive Advanced Malignant Solid Tumor

Inclusion Criteria:

1. Subjects provide documented informed consent voluntarily;
2. Male or female subjects ≥ 18 years and ≤ 75 years;
3. Subjects with locally advanced unresectable or metastatic malignant solid tumors confirmed by histology and/or cytology and CLDN 18.2 positive expression in the tumor tissue confirmed by the central laboratory: dose-escalation phase defined as IHC ≥ 1+ by central laboratory IHC assay; dose-expansion phase and extension cohort studies defined as CLDN18.2 expression in ≥ 40% of tumor cells, the IHC ≥ 2+);
4. Subjects met following requirements according to the different stages: Stage I: subjects have no standard treatment, or the standard treatment failed or was intolerant, or have no condition to receive standard treatment; Stage II: Subjects had received at least one prior line of systemic chemotherapy with clear disease progression confirmed by investigator or documented by medical records, in the following phase II cohorts:

   Cohort A: Gastric cancer/adenocarcinoma of gastroesophageal junction Cohort B: Pancreatic cancer Cohort C: Non-small cell lung cancer Cohort D: Other solid tumors expressing CLDN 18.2;
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0 or 1, and life expectancy ≥ 3 months;
6. At least one measurable lesion according to RECIST1.1;
7. The main organ function met the following criteria within 7 days before enrollment (no blood transfusion, EPO, G-CSF or other medical support treatment within 14 days before administration of study drug): neutrophil ≥ 1.5 × 10\^9 /L, platelet ≥ 100 × 109/L, hemoglobin ≥ 90 g/L or ≥ 5.6 mmol/L; International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × Upper limit of normal range (ULN), activated partial thrombin time (APTT) ≤ 1.5 × ULN, serum creatinine ≤ 1.5 × ULN, total bilirubin (TBIL) ≤ 1.5 × ULN (≤ 3 × ULN for subjects with Gilbert's syndrome or liver metastasis), Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN for subjects with liver metastasis);
8. Fertile women must have negative pregnancy tests before study entry;
9. Men and fertile women must agree to take effective contraceptive measures from signing informed consent to 6 months after the last administration;
10. Understand the trial requirements, and willing to follow the trial and follow-up procedures.

Exclusion Criteria:

1. Pregnant or lactating women;
2. Subjects who have not recovered from the adverse reactions caused by previous anti-tumor treatment (refer to NCI CTCAE 5.0, ≤ grade 1 or at baseline), except for the toxicity of alopecia, pigmentation and other conditions have no safety risk according to investigators' opinion;
3. Antitumor therapy such as chemotherapy, radiotherapy, biotherapy, targeted therapy, immunotherapy and other anti-tumor treatment within 4 weeks before administration of the study drug, and the following items: Nitrosourea (such as carmustine, lomustine, etc.) or mitomycin C were within 6 weeks before administration of the study drug; Oral fluorouracil and small molecule targeted drugs within 5 half-lives before administration of the study drug; Endocrine therapy or traditional Chinese medicines with anti-tumor indications within 2 weeks before administration of the study drug; Palliative radiotherapy for bone metastasis or local radiotherapy for pain relief within 2 weeks before administration of the study drug; Drugs for bone metastasis related events (such as zoledronic acid, etc.) did not affect the enrollment;
4. Subjects who have undergone major surgery (excluding needle biopsy) within 4 weeks before administration of the study drug, or who are expected to undergo major surgery during the study period, or who have severe unhealed wounds, trauma, ulcers, etc;
5. Subjects with previous intolerance to CLDN 18.2 monoclonal antibody or known components of SYSA1801, or severe allergic reactions;
6. Subjects with symptoms of brain or pia mater metastasis; Subjects with central nervous system (CNS) metastases in the following conditions can be considered: subjects with brain metastases without treatment and without symptoms, or with imaging evidence of progression free status lasting for at least 4 weeks after treatment, and without hormone or antiepileptic treatment for at least 4 weeks;
7. Subjects with body cavity effusion (pleural effusion, ascites, pericardial effusion, etc.) that need local treatment or repeated drainage, and which are poorly controlled by the investigators' judgment;
8. Concurrent other malignant tumors (except history of the following tumors that occurred and were cured 5 years ago: non-melanoma, skin cancer, carcinoma in situ or non-invasive tumor);
9. Clinically significant cardiac disease within 6 months before administration of the study drug, including: myocardial infarction, unstable angina pectoris, cerebrovascular accident or other acute and uncontrollable heart diseases; A history of clinically significant ventricular arrhythmias (such as persistent ventricular tachycardia, ventricular fibrillation, torsade de pointe ventricular tachycardia); New York Heart Association (NYHA) grade III or IV congestive heart failure; QTc \> 470 ms (female) or \> 450 ms (male) or Personal or family history of congenital long QT syndrome (Naring A, 2012); Arrhythmias requiring antiarrhythmic drug treatment (subjects with heart rate controllable atrial fibrillation \> 1 month before the first administration of the study drug were eligible for inclusion);
10. Subjects with evidence of risk of gastric bleeding or gastric perforation are not suitable for inclusion according to the judgment of investigators;
11. Active colitis, including infectious colitis, radiation colitis and ischemic colitis, within 4 weeks before administration of the study drug;
12. Pyloric obstruction or persistent recurrent vomiting (defined as vomiting ≥ 3 times in 24 hours);
13. Peripheral neuropathy ≥ grade 2 (refer to NCI CTCAE 5.0);
14. Subjects with active hepatitis B or C (HBsAg positive and/or HBcAb positive with HBV DNA titer more than 1000 copies/mL or 200 IU/mL; HCV Ab positive with HCV RNA titer higher than the upper limit of normal value);
15. HIV positive or syphilis infection requiring systematic treatment;
16. Subjects who have received systemic immunosuppressive therapy, including glucocorticoids, within 2 weeks before administration of the study drug; Subjects allowed to use physiological replacement dose of hydrocortisone or similar drugs;
17. Subjects with active autoimmune diseases requiring systemic immunosuppressive therapy in the past 2 years;
18. Subjects received other clinical trial drugs within 28 weeks before administration of the study drug;
19. Subjects have received antibody conjugated drugs targeting CLDN 18.2 in the past;
20. Subjects who are not appropriate for this clinical trial at the discretion of the investigator.