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

This is a Phase 1a/b, multicenter, open-label, first-in-human, dose escalation, expansion and extension study to evaluate the safety, tolerability, and DLTs to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) and preliminary efficacy of IBI343 (study drug) in participants with locally advanced unresectable or metastatic solid tumors.


Eligibility Criteria:
Inclusion Criteria:

Enrollment 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: Has at least 1 evaluable lesion according to RECIST v1.1; Phase Ia dose expansion and dose optimization phase, 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\&#39;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: serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min (using the Cockcroft-Gault formula); Urine protein \&lt; 2 + or 24h total urine protein \&lt; 1 g;).
   * 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 and 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).

Enrollment 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.

Enrollment 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.

Enrollment 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.

Enrollment 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.

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. Has received live vaccine within 4 weeks prior to the first dose of study drug or plans to during the study.
6. 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).
7. Has undergoundergone 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.
8. Has received whole pelvic radiotherapy.
9. Has gastric pyloric obstruction and/or persistent recurrent vomiting (≥ 3 episodes in 24 hours).
10. 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.
11. 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.
12. 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.
13. Has uncontrolled medical conditions, such as:

    * 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.
    * Participants infected with human immunodeficiency virus (HIV) (HIV 1/2 antibody positive).
    * 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 \[hepatitis C virus antibody (HCVAb) positive with HCV RNA \&gt; 103 copies/mL\]. 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.
    * Has active COVID-19 infection.
    * 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.
    * Has active syphilis or latent syphilis requiring treatment.
    * Has symptomatic congestive heart failure (New York Heart Association classification NYHA class II-IV), symptomatic or uncontrolled arrhythmia, QTc interval \&gt; 480 ms, or personal or family history of congenital long/short QT syndrome.
    * Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg) by standard treatment.
14. 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.
15. Has tumor invasion of surrounding vital structures or organs (e.g., great vessels, trachea, etc.) or risk of gastrointestinal/respiratory fistula.
16. Has received stent implantation in tracheal or digestive tract.
17. 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).
18. 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.
19. 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.
20. 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 \&#34;serious\&#34; venous thromboembolism).
21. Has hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh B or more severe cirrhosis.
22. 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\&#39;s disease, ulcerative colitis, and chronic diarrhea.
23. Has significant malnutrition (loss of more than 5% of body weight within 1 month or more than 15% of body weight within 3 months, or loss of more than 50% or more food intake within 1 week, if intravenous nutrition is required). Participants with malnutrition corrected over 4 weeks before the first dose of study drug are allowed.
24. 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.
25. Is underHas 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\&#39;s ability to provide written ICF.
26. Has a history of other primary malignancies, with the following exceptions:

    * Curatively treated malignancy with no known active disease for ≥ 2 years prior to study enrollment and is at minimal risk of recurrence;
    * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease recurrence;
    * Adequately treated carcinoma in situ with no evidence of disease recurrence.
27. Has a known history of immunodeficiency.
28. Has a history of allogeneic organ transplantation and history of allogeneic hematopoietic stem cell transplantation.
29. Has a history of severe allergic reaction to other monoclonal antibodies and/or hypersensitivity to any of the formulation components of IBI343.
30. Female participants who are pregnant or lactating.
31. Has other conditions considered not eligible to participate in this study per the Investigator's judgement.