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 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 :

1. Participants with histopathologically confirmed unresectable locally advanced or metastatic G/GEJ AC, PDAC, BTC, or other solid tumors 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 , 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.

Exclusion Criteria:

Exclusion criteria common to Phases Ia and Ib:

1. Is participating in another interventional clinical study other than an observational (non-interventional) clinical study or is in the survival follow-up phase of an interventional study.
2. Has received the last dose of antineoplastic therapy within 4 weeks or 5 half-lives of an antineoplastic therapy (whichever is shorter) prior to the first dose of study drug.
3. Plans to receive other anti-tumor therapy during treatment with the study drug \[palliative radiotherapy for symptomatic relief (e.g., pain) that does not affect response assessment is allowed\].
4. Has received a strong cytochrome P450 3A4 (CYP3A4) inhibitor within 2 weeks or 5 half-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 NCI CTCAE 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 the investigator).
6. Has undergone major surgical procedure (craniotomy, thoracotomy, laparotomy or others 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; Or plans to undergo major surgery during the study period; Note: Local surgical treatment of isolated lesions for palliative purposes is acceptable.
7. Has gastric pyloric obstruction and/or persistent recurrent vomiting (≥ 3 episodes in 24 hours).
8. Has a history of gastrointestinal perforation and/or fistula within 6 months that has not resolved surgically prior to the first dose of study drug.
9. Has symptomatic central nervous system metastases. Participants with asymptomatic brain metastases (i.e., no neurological symptoms, no need for glucocorticoid treatment, all brain metastasis ≤ 1. 5 cm) or stable symptoms after treatment of brain metastases must meet all of the following criteria to participate in the study: no metastasis in the midbrain, pons, cerebellum, meninges, medulla oblongata or spinal cord; Stable clinical status for at least 4 weeks with definitive clinical evidence of no new or enlarging brain metastasis and discontinuation of corticosteroids and anticonvulsants for at least 2 weeks prior to the first dose of study drug. Note: lesions of the central nervous system will not be considered as a target lesion
10. Has a history of pneumonitis requiring corticosteroids therapy, or a history of interstitial lung disease, non-infectious pneumonitis, severely impaired lung function or uncontrolled lung disease, such as pulmonary fibrosis, severe radiation pneumonitis, acute lung injury, or suspected of having the above diseases during the screening period.
11. Has uncontrolled medical conditions, such as:
12. Active or clinically uncontrolled serious infection requiring treatment with systemic anti-infectives (antibiotics, antivirals, or antifungals) within 1 week prior to the first dose of study drug, including but not limited to the infection of respiratory tract, urinary system, biliary tract infection, etc.
13. Participants infected with human immunodeficiency virus (HIV) (HIV 1/2 antibody positive).
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 or chronic active hepatitis C \[hepatitis C virus antibody (HCVAb) positive with HCV RNA \> 103 copies/mL\]. Participants whose test results are below the above criteria after receiving antiviral therapy with nucleotides, or participants with positive serology but negative HCV-RNA test result are eligible.
15. Has active pulmonary tuberculosis, is being treated with anti-tuberculosis therapy or having received anti-tuberculosis therapy within 1 year prior to the first dose of study drug.
16. Has active syphilis or latent syphilis requiring treatment.
17. Has symptomatic congestive heart failure (New York Heart Association classification NYHA class II-IV), symptomatic or uncontrolled arrhythmia, QTc interval \> 480 ms, or personal 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 the average of triplicate screening ECG (using Appendix 4 Calculation Formula of QTcF)
18. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 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 6 months 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 reinfusion therapy \[CART\]). Asymptomatic participants with a small amount of pleural effusion, ascites or pericardial effusion on imaging are allowed. (Drainage and CART are not allowed 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 the opinion of the investigator or consulting gastroenterologist or hepatologist. Participants with evidence of portal hypertension (including splenomegaly on imaging) or a history of prior variceal bleeding must undergo endoscopic evaluation within 3 months prior to the first dose of study drug.
23. Has one or more life-threatening bleeding event or Grade 3 or 4 gastrointestinal/variceal bleeding requiring blood transfusion, endoscopic or surgical 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 serious venous thromboembolism within 3 months prior to the first dose of study drug (implantable venous access port or catheter-derived thrombosis, or superficial vein thrombosis is not considered "serious" venous thromboembolism).
25. Has hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh B or more severe cirrhosis.
26. Has complete or incomplete intestinal or bowel obstruction at the time of screening or a history of complete or incomplete intestinal or bowel obstruction within 3 months prior to first dose, or is at risk of intestinal perforation (including but not limited to acute diverticulitis, history of intra-abdominal abscess), or a history of any of the following disease: inflammatory bowel disease or extensive bowel resection (partial colectomy or extensive small bowel resection with concurrent chronic diarrhea), Crohn's disease, ulcerative colitis, and chronic diarrhea.
27. Has other acute or chronic disease or laboratory abnormality that may result in increased risk associated with study participation or study drug administration, or interfere with the interpretation of study results, and is considered unfit for this study per the Investigator's judgement.
28. Has a neurological or psychiatric illness or a social situation that affects compliance with study requirements, significantly increases the risk of AE, or affects 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 to study enrollment and is at minimal risk of recurrence;
31. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease 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 allogeneic hematopoietic stem cell transplantation.
35. Has a history of severe allergic reaction to other monoclonal antibodies and/or hypersensitivity to any of the formulation components of IBI343 or mFOLFOX or Irinotecan or liposomal Irinotecan (For phase 1a part 3 1L G/GEJ AC and 1L PDAC cohort).
36. Female participants who are pregnant or lactating.
37. Has other conditions considered not eligible to participate in this study per the Investigator's judgement.
38. Has known dihydropyrimidine dehydrogenase deficiency (DPD). (NOTE: Screening for DPD deficiency should be conducted per local requirements.)
39. Has known peripheral sensory neuropathy \> grade 1 unless the absence of deep tendon reflexes is the sole neurological abnormality.