A Trial to Evaluate Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of TST001 in Advanced or Metastatic Solid Tumors

Inclusion Criteria:

The subjects who meet all inclusion criteria can be enrolled into the trial:

1. Sign the Informed Consent Form (ICF) voluntarily, understand the study and bewilling and able to comply with all study procedures;

2. Male or female ≥ 18 years at signing the ICF;

3. Suffer from histologically confirmed locally unresectable advanced or metastaticsolid tumors and meet the criteria of corresponding cohort as follows: Part I - Mono-therapy dose escalation and expansion phase:

4. Mono-therapy dose escalation study: The subjects who have no option of or areintolerable to SOC.

5. Mono-therapy dose expansion study: The subjects with positive CDLN18.2expression in tumor tissue (defined as CLDN18.2 membranous staining ≥1+ in ≥10%of tumor cells by immunohistochemistry (IHC) in the central laboratory)confirmed by the central laboratory at enrollment. The dose expansion study mayinclude the following 3 cohorts: Cohort A: Subjects with G/GEJ adenocarcinoma who have no option of or areintolerable to SOC; Cohort B: Subjects with ductal adenocarcinoma of pancreas whohave no option of or are intolerable to SOC; Cohort E: Subjects with other locallyadvanced or metastatic solid tumors excluding G/GEJ adenocarcinoma (limited tobiliary tract neoplasms, lung adenocarcinoma or colorectal cancer) who have nooption of or are intolerable to SOC; Part II - Dose escalation and expansion phasefor combination medication

6. Dose escalation study of combination medication (dose escalation part):Cohort C/G: Subjects with HER2 negative or unknown G/GEJ adenocarcinoma whohave not received prior systemic chemotherapy. The subjects who have completedneoadjuvant or adjuvant chemotherapy within at least 6 months prior to theinitial dosing of the study can be enrolled.Cohort D: The subjects with G/GEJ adenocarcinoma who have received at leastprior first-line systemic chemotherapy; Cohort F: The subjects with biliaryneoplasm who have not received prior systematic chemotherapy. The subjects whohave completed neoadjuvant or adjuvant chemotherapy within at least 6 monthsprior to the initial dosing of the study can be enrolled.Cohort H: The subjects with G/GEJ adenocarcinoma who have received at leastprior second-line systemic chemotherapy;

7. Dose expansion study of combination medication (dose expansion part): The subjects with positive CDLN18.2 expression in tumor tissue confirmed by thecentral laboratory will be enrolled as follows: Cohort C/G: Subjects with HER2 negative or unknown G/GEJ adenocarcinoma who have notreceived prior systemic chemotherapy. The subjects who have completed neoadjuvant oradjuvant chemotherapy within at least 6 months prior to the initial dosing of thestudy can be enrolled. Cohort D: The subjects with G/GEJ adenocarcinoma who have received at least priorfirst-line systemic chemotherapy; Cohort F: The subjects with biliary neoplasm whohave not received prior systematic chemotherapy. The subjects who have completedneoadjuvant or adjuvant chemotherapy within at least 6 months prior to the initialdosing of the study can be enrolled. Cohort H: The subjects with G/GEJ adenocarcinoma who have received at least priorsecond-line systemic chemotherapy;

8. ECOG performance status of 0-1;

9. Life expectancy ≥ 3 months;

10. The results of laboratory examinations at screening must meet all the followingcriteria:

11. Absolute neutrophil count (ANC) ≥ 1.5×109/L;

12. Absolute white blood cell (WBC) count ≥2.5×109/L;

13. Platelets ≥ 100×109/L;

14. Haemoglobin ≥ 9 g/dL;

15. International normalized ratio (INR) ≤ 1.5 times upper limit of normal (ULN) /or activated partial thromboplastin time (APTT) ≤ 1.5 times ULN (for the testwithout anticoagulant);

16. INR ≤ 2.5 times ULN / or APTT ≤ 2.5 times ULN (for the test withanticoagulant);

17. Total bilirubin <= 1.5 x ULN (except participants with Gilbert Syndrome whomust have a total bilirubin level of < 3.0 mg/dL).;

18. AST and ALT ≤ 2.5 times ULN (≤ 5 times ULN for subjects with hepatic cancer orliver metastases); ALT/AST ≤ 3xULN regardless of liver metastasis for cohort Gand H only;

19. Albumin ≥ 30g/L;

20. Serum creatinine ≤ 1.5 times ULN, or creatinine clearance rate ≥ 60 ml/min (creatinine clearance rate will be calculated using Cock-croft-Gault Equation);

21. Male and female of childbearing age should agree to take effective contraceptionmeasures (refer to Appendix 3. Contraception) from signing the ICF till at least 120days post the last dose of TST001 and other study drugs except nivolumab; female ofchildbearing age should agree to take effective contraception measures (refer toAppendix 3. Contraception) from signing the ICF till at least 5 months post the lastdose of nivolumab; Serum β-HCG test for women of childbearing age within 72 hoursprior to the initial dosing must be negative;

22. (For dose expansion phase only) At least one measurable lesion conforming to perRECIST v1.1;

Exclusion Criteria:

The subjects who meet any one of the following criteria will be excluded from participation in this study:

1. The subjects with locally advanced or metastatic G/GEJ adenocarcinoma who aresupposed to be enrolled into the combination therapy cohorts with CAPOX andCAPOX+nivolumab (Cohort C and G) have previously received systemic chemotherapy; andthe subjects in the Cohort G have previously received PD1/PD-L1/CTLA4 antibodytreatment. The subjects will be eligible provided that they have completedneoadjuvant or adjuvant chemotherapy at least 6 months prior to the initial dosingof the study; The subjects with locally advanced or metastatic G/GEJ adenocarcinomawho are supposed to be enrolled into the combination therapy cohort with paclitaxel (Cohort D) have previously received taxane drugs.

2. The subjects who previously received radiotherapy within 4 weeks prior to theinitial dosing of the investigational drug (the subjects who previously receivedlocal radiotherapy for bone metastases treatment within 4 weeks with theradiotherapy related AE resolved to ≤ Grade 1 will be eligible);

3. The subjects who previously received other systematic anti-tumor drug therapieswithin 4 weeks or 5 half-lives prior to the initial dosing of the investigationaldrug (whichever is shorter); The medication (such as zoledronic acid) for bonemetastases related events will not influence on the enrollment;

4. The subjects who previously received major surgery (exclusive of aspiration biopsy)within 8 weeks prior to the initial dosing of the investigational drug, or who areexpected to undergo major surgery, or who are in the conditions such as severeunhealed wound, trauma, and ulcer;

5. The subjects who previously received targeted CLDN18.2 therapy (including CLDN18.2monoclonal antibody, ADC, double antibody, CART);

6. The subjects who have previous serious allergic reactions, or are intolerable to theknown component of TST001 or other monoclonal antibodies (including humanized orchimeric antibodies);

7. The subjects who are known to have immediate or delayed hypersensitivity to, beintolerable to or be forbidden from any component of the investigational drugs;

8. The subjects who have previous serious allergic reaction or intolerance to taxanedrugs (Cohort D only) or any component of CAPOX (Cohort C and G), PD1 antibody (Cohort G and H) or GP (Cohort F);

9. The subjects in whom symptoms of brain or leptomeningeal metastases are present; The subjects with central nerve system (CNS) metastasis who meets the followingconditions can be enrolled: The subjects with brain metastasis who have not received to any treatment and areasymptomatic, or who are radiologically stable for at least 8 weeks followingtreatment and do not require hormone or anti epilepsy treatment at least within 8weeks;

10. The subjects with body cavity effusion (hydrothorax, ascites and pericardialeffusion) requiring local treatment or repeated drainage which is not wellcontrolled at the discretion of the investigators;

11. The subjects with concurrent malignant tumors within 3 years other than adequatelytreated cervical carcinoma in situ, localized squamous cell cancer of the skin,basal cell carcinoma, prostate cancer with no treatment required (with or withoutresection), ductal carcinoma in situ of the breast, or ≤ T1 urothelial carcinoma (for the dose expansion phase only);

12. Any adverse reactions caused by previous treatment have not resolved to ≤ Grade 1 asper CTCAE v5.0 (exclusive of alopecia and anaemia) before the initial dosing of theinvestigational drug. If the adverse reaction has no clinical influence, the Sponsorand investigators will decide whether the subject can be enrolled in the study afterdiscussion.

13. The subjects who received growth factor, transfusion or other blood products intreatment of anaemia or decreased platelet within 14 days prior to the initial dose;

14. The subjects who experienced clinically significant cardiovascular andcerebrovascular diseases within 6 months before the initial dosing of theinvestigational drug, including: i. Myocardial infarction, ii. Unstable angina pectoris, iii. Cerebrovascularaccident or iv. Other acute uncontrollable cardiovascular diseases; Clinicallysignificant ventricular arrhythmia history (such as ongoing ventricular tachycardia,ventricular fibrillation and torsade de pointes); New York Heart Association (NYHA)Class III or IV congestive cardiac failure; QTc ≥470ms (female) or QTc ≥450ms (male), or medical history or family history of congenital long-QT syndrome (NaringA, 2012); The subjects with heart rhythm disorders requiring the treatment withantiarrhythmic drugs (The subjects who suffer from atrial fibrillation with heartrate controllable more than 1 month before the initial dosing of the investigationaldrug will be eligible);

15. The subjects who are known to have dihydropyrimidine dehydrogenase (DPD) deficiency. (Note: DPD deficiency screening should be performed according to local requirement.) (The screening will be performed only in the subjects receiving CAPOX.)

16. Subjects with recent gastrointestinal bleeding as evidenced by hematemesis,hematochezia, or melena in the past 3 months without evidence of resolutiondocumented by endoscopy or colonoscopy;

17. The subjects who have evidenced risk of gastric haemorrhage or gastric perforationwill be excluded from the study at the discretion of the investigators;

18. The subjects with documented obstruction pyloric and persistent repeated vomitingdefined as ≥ 3 episodes within 24 hours;

19. Documented active colitis within 4 weeks prior to study entry, including infectiouscolitis, radiation colitis and ischemic colitis.

20. History of ulcerative colitis or Crohn's disease;

21. Uncontrolled diarrhea is present;

22. The subjects who are known to have > Grade 1 peripheral sensory neuropathy, unless alack of deep tendon reflexes is the only neurological abnormality;

23. Active infection requiring systematically intravenous antibiotic therapy within 2weeks prior to dosing;

24. HIV infection history or positive HIV viral test;

25. The subjects who are known to have the history of hepatitis C or chronic activehepatitis B; Except for:

26. HBV virus carriers or subjects with hepatitis B infection that is stable aftermedications (HBV-DNA titer should be no more than 1000 copies [cps]/mL or 200IU/mL); Patients who are not currently on viral suppressive therapy may beeligible and should be discussed with the Medical Monitor and if enrolled,antiviral therapy is required throughout study treatment.

27. Subjects with hepatitis C infection that is stable after medications (HCV-RNAtest negative);

28. Subjects with active autoimmune disorders requiring systemic immunosuppressivetherapy within the past 2 years (Subjects with type 1 diabetes mellitus (TD1M),hypothyroidism requiring hormone replacement therapy only, or skin diseases that donot require systemic treatment are eligible);

29. Any disease requiring systemic treatment with corticosteroids (> 10 mg/dayprednisone or equivalent drugs) or other immunosuppressive drugs for ≤14 days priorto the first dose of the investigational drug, except for: Adrenal replacement steroids (≤10 mg/day prednisone or equivalent drugs) Topical,ophthalmic, intra-articular, intranasal or inhaled corticosteroids with low systemicabsorption Preventive corticosteroids (e.g. prevention of contrast media allergy)for short term (≤ 7 days), or corticosteroids for the treatment of non-autoimmunedisorders (e.g. delayed type hypersensitivity caused by contactant);

30. Any conditions that the investigators judge that the patient is not appropriate forPD-1 antibody treatment, including but not limited to a history of interstitial lungdisease or non-infectious pneumonia, uncontrollable lung diseases, such as pulmonaryfibrosis, active pneumonia, etc. (Cohort G and H);

31. Subjects vaccinated live vaccine within 4 weeks before the first dose of theinvestigational drug;

32. Pregnant or lactating women;

33. Subject with other conditions (such as psychological, geographic or medicalconditions) that do not allow them to follow the study schedule and follow-upprocedures. Or the subjects who are unsuitable to be enrolled into the study at thediscretion of the investigators.

As of protocol version 4.2, enrollment of subjects on the combination protocol no longer requires a positive CLDN18.2 expression result, but enrolled subjects must provide sufficient formalin-fixed paraffin-embedded (FFPE) wax blocks of tumor tissue specimens or at least 10 consecutive white slices) for retrospective CLDN18.2 and PD-L1 testing. (Patients may be enrolled if they have less than 10 specimens, but not less than 7, and meet the requirements of the other inclusion criteria and receive approval from the sponsor's medical ombudsman).

Other protocol defined inclusion/exclusion criteria could apply