Overview

This is an open-label, multi-center, Phase I trial of TST001. Subjects with locally advanced or metastatic solid tumors will be enrolled. The study will consist of two parts: Part A is dose escalation and dose expansion phase for mono-therapy, and Part B is dose escalation and dose expansion phase for combination therapy in gastric, gastroesophageal junction(G/GEJ) and biliary tract cancer, etc.

Eligibility

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 be willing 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 metastatic solid tumors and meet the criteria of corresponding cohort as follows:

   Part I - Mono-therapy dose escalation and expansion phase:

   1. Mono-therapy dose escalation study: The subjects who have no option of or are intolerable to SOC.
   2. Mono-therapy dose expansion study: The subjects with positive CDLN18.2 expression 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 may include the following 3 cohorts:

             Cohort A: Subjects with G/GEJ adenocarcinoma who have no option of or are intolerable
             to SOC; Cohort B: Subjects with ductal adenocarcinoma of pancreas who have no option
             of or are intolerable to SOC; Cohort E: Subjects with other locally advanced or
             metastatic solid tumors excluding G/GEJ adenocarcinoma (limited to biliary tract
             neoplasms, lung adenocarcinoma or colorectal cancer) who have no option of or are
             intolerable to SOC; Part II - Dose escalation and expansion phase for combination
             medication
               1. Dose escalation study of combination medication (dose escalation part):
                  Cohort C/G: Subjects with HER2 negative or unknown G/GEJ adenocarcinoma who have
                  not received prior systemic chemotherapy. The subjects who have completed
                  neoadjuvant or adjuvant chemotherapy within at least 6 months prior to the
                  initial dosing of the study can be enrolled.
                  Cohort D: The subjects with G/GEJ adenocarcinoma who have received at least prior
                  first-line systemic chemotherapy; Cohort F: The subjects with biliary neoplasm
                  who have not received prior systematic chemotherapy. The subjects who have
                  completed neoadjuvant or adjuvant chemotherapy within at least 6 months prior to
                  the initial dosing of the study can be enrolled.
                  Cohort H: The subjects with G/GEJ adenocarcinoma who have received at least prior
                  second-line systemic chemotherapy;
               2. Dose expansion study of combination medication (dose expansion part):
             The subjects with positive CDLN18.2 expression in tumor tissue confirmed by the
             central laboratory will be enrolled as follows:
             Cohort C/G: Subjects with HER2 negative or unknown G/GEJ adenocarcinoma who have not
             received prior systemic chemotherapy. The subjects who have completed neoadjuvant or
             adjuvant chemotherapy within at least 6 months prior to the initial dosing of the
             study can be enrolled.
             Cohort D: The subjects with G/GEJ adenocarcinoma who have received at least prior
             first-line systemic chemotherapy; Cohort F: The subjects with biliary neoplasm who
             have not received prior systematic chemotherapy. The subjects who have completed
             neoadjuvant or adjuvant chemotherapy within at least 6 months prior to the initial
             dosing of the study can be enrolled.
             Cohort H: The subjects with G/GEJ adenocarcinoma who have received at least prior
             second-line systemic chemotherapy;
          4. ECOG performance status of 0-1;
          5. Life expectancy ≥ 3 months;
          6. The results of laboratory examinations at screening must meet all the following
             criteria:
               1. Absolute neutrophil count (ANC) ≥ 1.5×109/L;
               2. Absolute white blood cell (WBC) count ≥2.5×109/L;
               3. Platelets ≥ 100×109/L;
               4. Haemoglobin ≥ 9 g/dL;
               5. International normalized ratio (INR) ≤ 1.5 times upper limit of normal (ULN) / or
                  activated partial thromboplastin time (APTT) ≤ 1.5 times ULN (for the test
                  without anticoagulant);
               6. INR ≤ 2.5 times ULN / or APTT ≤ 2.5 times ULN (for the test with anticoagulant);
               7. Total bilirubin <= 1.5 x ULN (except participants with Gilbert Syndrome who must
                  have a total bilirubin level of < 3.0 mg/dL).;
               8. AST and ALT ≤ 2.5 times ULN (≤ 5 times ULN for subjects with hepatic cancer or
                  liver metastases); ALT/AST ≤ 3xULN regardless of liver metastasis for cohort G
                  and H only;
               9. Albumin ≥ 30g/L;
              10. Serum creatinine ≤ 1.5 times ULN, or creatinine clearance rate ≥ 60 ml/min
                  (creatinine clearance rate will be calculated using Cock-croft-Gault Equation);
          7. Male and female of childbearing age should agree to take effective contraception
             measures (refer to Appendix 3. Contraception) from signing the ICF till at least 120
             days post the last dose of TST001 and other study drugs except nivolumab; female of
             childbearing age should agree to take effective contraception measures (refer to
             Appendix 3. Contraception) from signing the ICF till at least 5 months post the last
             dose of nivolumab; Serum β-HCG test for women of childbearing age within 72 hours
             prior to the initial dosing must be negative;
          8. (For dose expansion phase only) At least one measurable lesion conforming to per
             RECIST 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 are supposed
             to be enrolled into the combination therapy cohorts with CAPOX and CAPOX+nivolumab
             (Cohort C and G) have previously received systemic chemotherapy; and the subjects in
             the Cohort G have previously received PD1/PD-L1/CTLA4 antibody treatment. The subjects
             will be eligible provided that they have completed neoadjuvant or adjuvant
             chemotherapy at least 6 months prior to the initial dosing of the study; The subjects
             with locally advanced or metastatic G/GEJ adenocarcinoma who 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 the initial
             dosing of the investigational drug (the subjects who previously received local
             radiotherapy for bone metastases treatment within 4 weeks with the radiotherapy
             related AE resolved to ≤ Grade 1 will be eligible);
          3. The subjects who previously received other systematic anti-tumor drug therapies within
             4 weeks or 5 half-lives prior to the initial dosing of the investigational drug
             (whichever is shorter); The medication (such as zoledronic acid) for bone metastases
             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 are
             expected to undergo major surgery, or who are in the conditions such as severe
             unhealed wound, trauma, and ulcer;
          5. The subjects who previously received targeted CLDN18.2 therapy (including CLDN18.2
             monoclonal antibody, ADC, double antibody, CART);
          6. The subjects who have previous serious allergic reactions, or are intolerable to the
             known component of TST001 or other monoclonal antibodies (including humanized or
             chimeric antibodies);
          7. The subjects who are known to have immediate or delayed hypersensitivity to, be
             intolerable to or be forbidden from any component of the investigational drugs;
          8. The subjects who have previous serious allergic reaction or intolerance to taxane
             drugs (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 following
             conditions can be enrolled:
             The subjects with brain metastasis who have not received to any treatment and are
             asymptomatic, or who are radiologically stable for at least 8 weeks following
             treatment and do not require hormone or anti epilepsy treatment at least within 8
             weeks;
         10. The subjects with body cavity effusion (hydrothorax, ascites and pericardial effusion)
             requiring local treatment or repeated drainage which is not well controlled at the
             discretion of the investigators;
         11. The subjects with concurrent malignant tumors within 3 years other than adequately
             treated cervical carcinoma in situ, localized squamous cell cancer of the skin, basal
             cell carcinoma, prostate cancer with no treatment required (with or without
             resection), 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 as
             per CTCAE v5.0 (exclusive of alopecia and anaemia) before the initial dosing of the
             investigational drug. If the adverse reaction has no clinical influence, the Sponsor
             and investigators will decide whether the subject can be enrolled in the study after
             discussion.
         13. The subjects who received growth factor, transfusion or other blood products in
             treatment of anaemia or decreased platelet within 14 days prior to the initial dose;
         14. The subjects who experienced clinically significant cardiovascular and cerebrovascular
             diseases within 6 months before the initial dosing of the investigational drug,
             including:
             i. Myocardial infarction, ii. Unstable angina pectoris, iii. Cerebrovascular accident
             or iv. Other acute uncontrollable cardiovascular diseases; Clinically significant
             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 (Naring A, 2012); The
             subjects with heart rhythm disorders requiring the treatment with antiarrhythmic drugs
             (The subjects who suffer from atrial fibrillation with heart rate controllable more
             than 1 month before the initial dosing of the investigational drug 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 resolution documented
             by endoscopy or colonoscopy;
         17. The subjects who have evidenced risk of gastric haemorrhage or gastric perforation
             will be excluded from the study at the discretion of the investigators;
         18. The subjects with documented obstruction pyloric and persistent repeated vomiting
             defined as ≥ 3 episodes within 24 hours;
         19. Documented active colitis within 4 weeks prior to study entry, including infectious
             colitis, 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 a
             lack of deep tendon reflexes is the only neurological abnormality;
         23. Active infection requiring systematically intravenous antibiotic therapy within 2
             weeks 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 active
             hepatitis B;
             Except for:
               1. HBV virus carriers or subjects with hepatitis B infection that is stable after
                  medications (HBV-DNA titer should be no more than 1000 copies [cps]/mL or 200
                  IU/mL); Patients who are not currently on viral suppressive therapy may be
                  eligible and should be discussed with the Medical Monitor and if enrolled,
                  antiviral therapy is required throughout study treatment.
               2. Subjects with hepatitis C infection that is stable after medications (HCV-RNA
                  test negative);
         26. Subjects with active autoimmune disorders requiring systemic immunosuppressive therapy
             within the past 2 years (Subjects with type 1 diabetes mellitus (TD1M), hypothyroidism
             requiring hormone replacement therapy only, or skin diseases that do not require
             systemic treatment are eligible);
         27. Any disease requiring systemic treatment with corticosteroids (> 10 mg/day prednisone
             or equivalent drugs) or other immunosuppressive drugs for ≤14 days prior to 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 systemic
             absorption Preventive corticosteroids (e.g. prevention of contrast media allergy) for
             short term (≤ 7 days), or corticosteroids for the treatment of non-autoimmune
             disorders (e.g. delayed type hypersensitivity caused by contactant);
         28. Any conditions that the investigators judge that the patient is not appropriate for
             PD-1 antibody treatment, including but not limited to a history of interstitial lung
             disease or non-infectious pneumonia, uncontrollable lung diseases, such as pulmonary
             fibrosis, active pneumonia, etc. (Cohort G and H);
         29. Subjects vaccinated live vaccine within 4 weeks before the first dose of the
             investigational drug;
         30. Pregnant or lactating women;
         31. Subject with other conditions (such as psychological, geographic or medical
             conditions) that do not allow them to follow the study schedule and follow-up
             procedures. Or the subjects who are unsuitable to be enrolled into the study at the
             discretion 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