A First-in-human Study of IBI343 in Subjects With Locally Advanced Unresectable or Metastatic Solid Tumors

Inclusion criteria

Inclusion criteria to be met for both Phase Ia and Phase Ib: 1. Has signed written Informed Consent Form (ICF), willing and able to comply with protocol-specified visits and related procedures. 2. Phase Ia dose escalation phase, Phase Ia part 3 metabolite profiling cohort，Phase Ia part 3 1L G/GEJ AC and 1L PDAC cohorts Safety Lead-in stage: Has at least 1 evaluable lesion according to RECIST v1.1; Phase Ia dose expansion and dose optimization phase, Phase Ia part 3 1L G/GEJ AC and 1L PDAC cohorts Dose optimization stage, Phase Ib: Has at least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors RECIST v1.1. 3. Age ≥ 18 years, of either sex. 4. Has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. 5. Has an expected survival ≥ 12 weeks. 6. Has adequate bone marrow and organ function. Defined as: • Hematology: ANC ≥ 1.5 × 109/L; Platelet count ≥ 100 × 109/L; Hemoglobin ≥ 9.0 g/dL, participants must not have received transfusion of blood products (including red blood cell suspension, apheresis platelets, cryoprecipitate, etc.), erythropoietin (EPO), G-colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) within 7 days prior to blood sample collection; * Hepatic function: TBIL ≤ 1.5 × ULN (TBIL ≤ 3 × ULN is allowed for participants with Gilbert's syndrome); ALT and AST ≤ 2.5 × ULN for participants without liver metastasis and ≤ 5 × ULN for participants with liver metastasis; Albumin ≥ 28 g/L; * Renal function: estimated creatinine clearance ≥ 30mL/min (using Appendix 5. Calculation of Estimated Creatinine Clearance and Body Surface ). * Coagulation function: international normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (participants receiving anticoagulant therapy with coagulation function within the above range are allowed). 7. Female participants of childbearing potential or male participants whose partners are female of childbearing potential are required to use effective contraceptive measures throughout the treatment period and for 6 months after the final treatment period. Inclusion Criteria for Phase Ia Dose Escalation: 1. Participants with histopathologically confirmed unresectable locally advanced or metastatic malignant solid tumors that have failed or were intolerant to standard therapy or for whom no standard therapy is available. Inclusion Criteria for Phase Ia Dose Expansion, Dose Optimization and Phase Ia Part 3 Metabolite Profiling Cohort: 1. Participants with histopathologically confirmed unresectable locally advanced or metastatic G/GEJ AC, PDAC, BTC, or other solid tumors (For Phase Ia Part 3 metabolite profiling cohort, only PDAC allowed) who have failed or were intolerant to standard therapy or for which no standard therapy is available. 2. \* CLDN18.2-positive confirmed by pathological examination (in dose expansion phase, G/GEJ AC and PDAC preferentially enrolled \*\*\* moderate to high expression of CLDN18. 2; in dose optimization phase and Phase Ia Part 3 metabolite profiling cohort, G/GEJ AC preferentially enrolled \*\*high expression of CLDN18.2 and PDAC preferentially enrolled \*\*\*moderate to high expression of CLDN18.2). For participants with previous anti-CLDN18.2 treatment (including but not limited to monoclonal antibodies, ADCs, CAR-T, etc.), tumor samples should be obtained post anti-CLDN18.2 therapy for CLDN18.2 expression evaluation. Inclusion Criteria for Phase Ia Part 3 1L G/GEJ AC Cohort: 1. Participants with histopathologically confirmed unresectable locally advanced or metastatic G/GEJ AC who has not received previous systemic therapy. (For Safety Lead-in stage, participants who has received previous systemic therapy are permitted.) A prior (neo)adjuvant systemic therapy completed within 6 months prior to disease relapse or progression will be considered as having received previous systemic therapy. 2. Confirmed Her 2-negative (defined as IHC 0 or 1+, or IHC 2+ and negative by in situ hybridization) disease. 3. Confirmed combined positive score (CPS) \<5 as determined by local IHC testing. 4. Participants must not have previously received topoisomerase inhibitor-based antibody-drug conjugate(s), unless given peri-operatively without evidence of resistance. 5. Participants must not have previously received anti-CLDN18.2 therapy. 6. \*CLDN18.2-positive confirmed by pathological examination by central laboratory (For Dose optimization stage, G/GEJ AC enrolled participants with Claudin18.2 immunohistochemical membrane staining intensity 2+/3+ in ≥50% of tumor cells). Inclusion Criteria for Phase Ia Part 3 1L PDAC Cohort: 1. Participants with histopathologically confirmed metastatic PDAC who has not received previous systemic therapy in the metastatic setting. (For Safety Lead-in stage, participants who has received previous systemic therapy are permitted.) A prior (neo)adjuvant systemic therapy completed within 12 months prior to disease relapse or progression will be considered as having received previous systemic therapy. 2. Participants must not have previously received anti-CLDN18.2 therapy. 3. Participants must not have previously received topoisomerase inhibitor-based antibody-drug conjugate(s), unless given peri-operatively without evidence of resistance. 4. \*CLDN18.2-positive confirmed by pathological examination by central laboratory (For Dose optimization stage, PDAC enrolled # specified expression of CLDN 18.2) Inclusion Criteria for Phase Ib Cohort A: 1. Histopathologically confirmed unresectable locally advanced or metastatic G/GEJ AC. 2. Have received at least 2 lines of systemic therapy \[anti-PD-(L)1 + platinum, fluoropyrimidines, paclitaxel/docetaxel, or irinotecan; participants with HER2 overexpression (defined as 3 + or 2 + by immunohistochemistry and ISH +) must have received anti-HER2 therapy, and participants who have not received prior anti-PD-(L)1 or anti-HER2 therapy must have had a contraindication or reasonable reason for no benefit\] and have had disease progression. 3. High expression of \*\*CLDN18. 2 was confirmed by pathological examination. Inclusion Criteria for Phase Ib Cohort B: 1. Histopathologically confirmed unresectable locally advanced or metastatic G/GEJ AC. 2. Disease progression after first-line standard therapy (HER2-overexpressing participants must have received prior anti-HER2 therapy unless contraindicated or justified non-benefit). 3. Confirmed \* CLDN18.2-positive by histopathological examination. Inclusion Criteria for Phase Ib Cohort C: 1. Histopathologically confirmed unresectable locally advanced or metastatic PDAC. 2. Disease progression after at least one prior systemic therapy. Inclusion criteria for Phase Ib Cohort D: 1. Histopathologically confirmed unresectable locally advanced or metastatic BTC. 2. Disease progression after at least one prior systemic therapy. 3. Confirmed \* CLDN18.2-positive by histopathological examination. Notes: * CLDN18.2-positive: defined as ≥ 1% of tumor cells with membranous staining of any intensity in tumor tissue by immunohistochemistry, when tested previously, at the study site, or at the central laboratory. * High expression of CLDN18. 2: Claudin18.2 immunohistochemical membrane staining intensity ≥ 2 + in ≥ 75% of tumor cells. * Moderate to high expression of CLDN18.2: Claudin18.2 immunohistochemical membrane staining intensity ≥ 2 + in ≥ 40% of tumor cells. * Specified expression of CLDN18.2: Claudin18.2 immunohistochemical membrane staining intensity 1+/2+/3+ in ≥50% of tumor cells.