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 withprotocol-specified visits and related procedures.

2. Phase Ia dose escalation phase, Phase Ia part 3 metabolite profiling cohort，Phase Iapart 3 1L G/GEJ AC and 1L PDAC cohorts Safety Lead-in stage: Has at least 1evaluable lesion according to RECIST v1.1; Phase Ia dose expansion and doseoptimization phase, Phase Ia part 3 1L G/GEJ AC and 1L PDAC cohorts Doseoptimization stage, Phase Ib: Has at least 1 measurable lesion according to ResponseEvaluation 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 ≥ 9.0g/dL, participants must not have received transfusion of blood products (includingred blood cell suspension, apheresis platelets, cryoprecipitate, etc.),erythropoietin (EPO), G-colony stimulating factor (G-CSF) or granulocyte-macrophagecolony stimulating factor (GM-CSF) within 7 days prior to blood sample collection;

• Hepatic function: TBIL ≤ 1.5 × ULN (TBIL ≤ 3 × ULN is allowed for participantswith Gilbert's syndrome); ALT and AST ≤ 2.5 × ULN for participants withoutliver 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 activatedpartial thromboplastin time (APTT) ≤ 1.5 × ULN (participants receivinganticoagulant therapy with coagulation function within the above range areallowed).

7. Female participants of childbearing potential or male participants whose partnersare female of childbearing potential are required to use effective contraceptivemeasures throughout the treatment period and for 6 months after the final treatmentperiod.

Inclusion Criteria for Phase Ia Dose Escalation:

1. Participants with histopathologically confirmed unresectable locally advanced ormetastatic malignant solid tumors that have failed or were intolerant to standardtherapy 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 ormetastatic G/GEJ AC, PDAC, BTC, or other solid tumors (For Phase Ia Part 3metabolite profiling cohort, only PDAC allowed) who have failed or were intolerantto 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/GEJAC preferentially enrolled **high expression of CLDN18.2 and PDAC preferentiallyenrolled ***moderate to high expression of CLDN18.2). For participants with previousanti-CLDN18.2 treatment (including but not limited to monoclonal antibodies, ADCs,CAR-T, etc.), tumor samples should be obtained post anti-CLDN18.2 therapy forCLDN18.2 expression evaluation.

Inclusion Criteria for Phase Ia Part 3 1L G/GEJ AC Cohort:

1. Participants with histopathologically confirmed unresectable locally advanced ormetastatic G/GEJ AC who has not received previous systemic therapy. (For SafetyLead-in stage, participants who has received previous systemic therapy arepermitted.) A prior (neo)adjuvant systemic therapy completed within 6 months priorto disease relapse or progression will be considered as having received previoussystemic therapy.

2. Confirmed Her 2-negative (defined as IHC 0 or 1+, or IHC 2+ and negative by in situhybridization) disease.

3. Confirmed combined positive score (CPS) <5 as determined by local IHC testing.

4. Participants must not have previously received topoisomerase inhibitor-basedantibody-drug conjugate(s), unless given peri-operatively without evidence ofresistance.

5. Participants must not have previously received anti-CLDN18.2 therapy.

6. *CLDN18.2-positive confirmed by pathological examination by central laboratory (ForDose optimization stage, G/GEJ AC enrolled participants with Claudin18.2immunohistochemical 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 receivedprevious 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 relapseor 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-basedantibody-drug conjugate(s), unless given peri-operatively without evidence ofresistance.

4. *CLDN18.2-positive confirmed by pathological examination by central laboratory (ForDose 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 HER2overexpression (defined as 3 + or 2 + by immunohistochemistry and ISH +) must havereceived anti-HER2 therapy, and participants who have not received prioranti-PD-(L)1 or anti-HER2 therapy must have had a contraindication or reasonablereason 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-overexpressingparticipants must have received prior anti-HER2 therapy unless contraindicated orjustified 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 anyintensity in tumor tissue by immunohistochemistry, when tested previously, at thestudy site, or at the central laboratory.

• High expression of CLDN18. 2: Claudin18.2 immunohistochemical membrane stainingintensity ≥ 2 + in ≥ 75% of tumor cells.

• Moderate to high expression of CLDN18.2: Claudin18.2 immunohistochemicalmembrane staining intensity ≥ 2 + in ≥ 40% of tumor cells.

• Specified expression of CLDN18.2: Claudin18.2 immunohistochemicalmembrane staining intensity 1+/2+/3+ in ≥50% of tumor cells.

Exclusion Criteria:

Exclusion criteria common to Phases Ia and Ib:

1. Is participating in another interventional clinical study other than anobservational (non-interventional) clinical study or is in the survival follow-upphase of an interventional study.

2. Has received the last dose of antineoplastic therapy within 4 weeks or 5 half-livesof an antineoplastic therapy (whichever is shorter) prior to the first dose of studydrug.

3. Plans to receive other anti-tumor therapy during treatment with the study drug [palliative radiotherapy for symptomatic relief (e.g., pain) that does not affectresponse assessment is allowed].

4. Has received a strong cytochrome P450 3A4 (CYP3A4) inhibitor within 2 weeks or 5half-lives (whichever is longer) prior to the first dose of study drug.

5. Toxicities due to prior therapy that have not recovered to Grade 0 or 1 per NCICTCAE v5.0 prior to the first dose of study drug (excluding alopecia, asthenia,hyperpigmentation, and other conditions with no safety risk per the judgment of theinvestigator).

6. Has undergone major surgical procedure (craniotomy, thoracotomy, laparotomy orothers per the investigator, excluding needle biopsy) or has unhealed wounds,ulcers, or bone fracture within 4 weeks prior to the first dose of study drug; Orplans to undergo major surgery during the study period; Note: Local surgicaltreatment of isolated lesions for palliative purposes is acceptable.

7. Has gastric pyloric obstruction and/or persistent recurrent vomiting (≥ 3 episodesin 24 hours).

8. Has a history of gastrointestinal perforation and/or fistula within 6 months thathas not resolved surgically prior to the first dose of study drug.

9. Has symptomatic central nervous system metastases. Participants with asymptomaticbrain metastases (i.e., no neurological symptoms, no need for glucocorticoidtreatment, all brain metastasis ≤ 1. 5 cm) or stable symptoms after treatment ofbrain metastases must meet all of the following criteria to participate in thestudy: no metastasis in the midbrain, pons, cerebellum, meninges, medulla oblongataor spinal cord; Stable clinical status for at least 4 weeks with definitive clinicalevidence of no new or enlarging brain metastasis and discontinuation ofcorticosteroids and anticonvulsants for at least 2 weeks prior to the first dose ofstudy drug. Note: lesions of the central nervous system will not be considered as atarget lesion

10. Has a history of pneumonitis requiring corticosteroids therapy, or a history ofinterstitial lung disease, non-infectious pneumonitis, severely impaired lungfunction or uncontrolled lung disease, such as pulmonary fibrosis, severe radiationpneumonitis, acute lung injury, or suspected of having the above diseases during thescreening period.

11. Has uncontrolled medical conditions, such as:

12. Active or clinically uncontrolled serious infection requiring treatment withsystemic anti-infectives (antibiotics, antivirals, or antifungals) within 1 weekprior to the first dose of study drug, including but not limited to the infection ofrespiratory tract, urinary system, biliary tract infection, etc.

13. Participants infected with human immunodeficiency virus (HIV) (HIV 1/2 antibodypositive).

14. Acute or chronic active hepatitis B (defined as hepatitis B surface antigen (HBsAg)and/or hepatitis B core antibody positive (HBcAb) with hepatitis B virus DNA copies ≥ 104 copies/mL or ≥ 2000 IU/mL or above the lower limit of detection) or acute orchronic active hepatitis C [hepatitis C virus antibody (HCVAb) positive with HCV RNA > 103 copies/mL]. Participants whose test results are below the above criteria afterreceiving antiviral therapy with nucleotides, or participants with positive serologybut negative HCV-RNA test result are eligible.

15. Has active pulmonary tuberculosis, is being treated with anti-tuberculosis therapyor having received anti-tuberculosis therapy within 1 year prior to the first doseof study drug.

16. Has active syphilis or latent syphilis requiring treatment.

17. Has symptomatic congestive heart failure (New York Heart Association classificationNYHA class II-IV), symptomatic or uncontrolled arrhythmia, QTc interval > 480 ms, orpersonal or family history of congenital long/short QT syndrome. For part 3 1L G/GEJ AC and 1L PDAC cohort, the QTc should be calculated based on theaverage of triplicate screening ECG (using Appendix 4 Calculation Formula of QTcF)

18. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic bloodpressure ≥ 100 mmHg) by standard treatment.

19. Has one or more arterial thromboembolic event, including myocardial infarction,unstable angina, cerebrovascular accident, transient ischemic attack, etc., within 6months prior to the first dose of study drug.

20. Has received stent implantation in tracheal or digestive tract.

21. Has symptomatic pleural, ascites, or pericardial effusion requiring intervention (e.g., drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusiontherapy [CART]). Asymptomatic participants with a small amount of pleural effusion,ascites or pericardial effusion on imaging are allowed. (Drainage and CART are notallowed within 2 weeks prior to screening assessment).

22. Has esophageal or gastric varices that require immediate intervention (e.g.,ligature or sclerotherapy) or are considered to be at high risk for bleeding in theopinion of the investigator or consulting gastroenterologist or hepatologist.Participants with evidence of portal hypertension (including splenomegaly onimaging) or a history of prior variceal bleeding must undergo endoscopic evaluationwithin 3 months prior to the first dose of study drug.

23. Has one or more life-threatening bleeding event or Grade 3 or 4gastrointestinal/variceal bleeding requiring blood transfusion, endoscopic orsurgical treatment within 3 months prior to the first dose of study drug

24. Has a history of deep vein thrombosis, pulmonary embolism, or any other seriousvenous thromboembolism within 3 months prior to the first dose of study drug (implantable venous access port or catheter-derived thrombosis, or superficial veinthrombosis is not considered "serious" venous thromboembolism).

25. Has hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh B or more severecirrhosis.

26. Has complete or incomplete intestinal or bowel obstruction at the time of screeningor a history of complete or incomplete intestinal or bowel obstruction within 3months prior to first dose, or is at risk of intestinal perforation (including butnot limited to acute diverticulitis, history of intra-abdominal abscess), or ahistory of any of the following disease: inflammatory bowel disease or extensivebowel resection (partial colectomy or extensive small bowel resection withconcurrent chronic diarrhea), Crohn's disease, ulcerative colitis, and chronicdiarrhea.

27. Has other acute or chronic disease or laboratory abnormality that may result inincreased risk associated with study participation or study drug administration, orinterfere with the interpretation of study results, and is considered unfit for thisstudy per the Investigator's judgement.

28. Has a neurological or psychiatric illness or a social situation that affectscompliance with study requirements, significantly increases the risk of AE, oraffects the participant's ability to provide written ICF.

29. Has a history of other primary malignancies, with the following exceptions:

30. Curatively treated malignancy with no known active disease for ≥ 2 years prior tostudy enrollment and is at minimal risk of recurrence;

31. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence ofdisease recurrence;

32. Adequately treated carcinoma in situ with no evidence of disease recurrence.

33. Has a known history of immunodeficiency.

34. Has a history of allogeneic organ transplantation and history of allogeneichematopoietic stem cell transplantation.

35. Has a history of severe allergic reaction to other monoclonal antibodies and/orhypersensitivity to any of the formulation components of IBI343 or mFOLFOX orIrinotecan or liposomal Irinotecan (For phase 1a part 3 1L G/GEJ AC and 1L PDACcohort).

36. Female participants who are pregnant or lactating.

37. Has other conditions considered not eligible to participate in this study per theInvestigator's judgement.

38. Has known dihydropyrimidine dehydrogenase deficiency (DPD). (NOTE: Screening for DPDdeficiency should be conducted per local requirements.)

39. Has known peripheral sensory neuropathy > grade 1 unless the absence of deep tendonreflexes is the sole neurological abnormality.