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

There are two parts in the study. Part I is mono-therapy dose escalation and dose expansion study, and Part II is dose escalation and dose expansion study of combination therapy.

The dose escalation study will be conducted utilizing 3+3 design with two dosing regimens, i.e. "once every 2 weeks (Q2W)" and "once every 3 weeks (Q3W)".

After MTD/RP2D determined, three cohorts may be included in the expansion plan, with about 30 (20-40) subjects with positive CLDN18.2 expression be treated in each cohort, as shown below (during the study, the treatment cohorts may be adjusted or added based on the clinical and pre-clinical study data).

Approximately 320-540 treated subjects in total

Inclusion criteria

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

• Sign the Informed Consent Form (ICF) voluntarily, understand the study and be willing and able to comply with all study procedures;
• Male or female ≥ 18 years at signing the ICF;
• 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:

• Mono-therapy dose escalation study: The subjects who have no option of or are intolerable to SOC.
• 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

• 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;

• 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;

• ECOG performance status of 0-1;
• Life expectancy ≥ 3 months;
• The results of laboratory examinations at screening must meet all the following criteria:

• Absolute neutrophil count (ANC) ≥ 1.5×109/L;
• Absolute white blood cell (WBC) count ≥2.5×109/L;
• Platelets ≥ 100×109/L;
• Haemoglobin ≥ 9 g/dL;
• 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);
• INR ≤ 2.5 times ULN / or APTT ≤ 2.5 times ULN (for the test with anticoagulant);
• Total bilirubin <= 1.5 x ULN (except participants with Gilbert Syndrome who must have a total bilirubin level of < 3.0 mg/dL).;
• 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;
• Albumin ≥ 30g/L;
• Serum creatinine ≤ 1.5 times ULN, or creatinine clearance rate ≥ 60 ml/min (creatinine clearance rate will be calculated using Cock-croft-Gault Equation);
• 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;
• (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:

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

• 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;
• 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);
• 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.
• 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;
• 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);

• 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.)
• 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;
• The subjects who have evidenced risk of gastric haemorrhage or gastric perforation will be excluded from the study at the discretion of the investigators;
• The subjects with documented obstruction pyloric and persistent repeated vomiting defined as ≥ 3 episodes within 24 hours;
• Documented active colitis within 4 weeks prior to study entry, including infectious colitis, radiation colitis and ischemic colitis.
• History of ulcerative colitis or Crohn's disease;
• Uncontrolled diarrhea is present;
• The subjects who are known to have > Grade 1 peripheral sensory neuropathy, unless a lack of deep tendon reflexes is the only neurological abnormality;
• Active infection requiring systematically intravenous antibiotic therapy within 2 weeks prior to dosing;
• HIV infection history or positive HIV viral test;
• The subjects who are known to have the history of hepatitis C or chronic active hepatitis B;

Except for:

• 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.
• Subjects with hepatitis C infection that is stable after medications (HCV-RNA test negative);
• 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);
• 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);

• 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);
• Subjects vaccinated live vaccine within 4 weeks before the first dose of the investigational drug;
• Pregnant or lactating women;
• 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