IBI343 Combined With Chemotherapy in Advanced Pancreatic Cancer

Inclusion criteria

• Sign a written Informed Consent Form (ICF) and be willing and able to comply with the visit and related procedures stipulated by the program.
• Histopathologically confirmed unresectable locally advanced, recurrent, or metastatic PAC.
• Progression or intolerance following first-line gemcitabine-based systemic therapy at locally advanced or recurrent/metastatic stages.If the time from the last neoadjuvant/adjuvant therapy to disease recurrence/metastasis is less than 6 months, the treatment is considered first-line therapy.
• The subject must not be suitable for radical treatment methods such as radical chemoradiotherapy and/or surgery.
• According to RECIST v1.1, at least 1 measurable lesion had not received prior radiotherapy.(At baseline, an intravenous contrast agent is preferred by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) to accurately measure nodes with a long diameter ≥10 mm except for the short axis of the lymph nodes≥15 mm Target lesion diameter ≥2 times image layer thickness and lesions suitable for repeated accurate measurement.If a lesion located in a previously irradiated area clearly demonstrates progression to RECIST V1.1 criteria, it can be considered a measurable lesion).
• Age ≥18 years old, gender is not limited.
• Score of 0 or 1 according to the Eastern Cooperative Oncology Group Performance Status (ECOG PS).
• BMI 17 kg/m2.
• Expected survival ≥12 weeks.
• With full bone marrow and organ function:

A. routine blood ANC acuity 1.5 x 109 / L platelet count 100 x 109 or higher acuity 9.0 g/dL/L hemoglobin content subjects in blood sampling may not be received within 7 days before losing blood products (including red suspension, single mining platelet and cryoprecipitate, etc.), Erythropoietin,Granulocyte-colony Stimulating Factor or Granulocyte-Macrophage Colony-Stimulating Factor treatment b. Liver function TBIL≤1.5×ULN Subjects with Gilbert syndrome allowed TBIL≤3×ULN Subjects without liver metastasis ALT and AST≤2.5×ULN Subjects with liver metastasis ALT and AST≤5×ULN albumin ≥30 g/L c. Renal creatinine clearance ≥60 mL/min Urinary protein < 2+ by Cockcroft-Gault formula or total urinary protein < 1 g in 24h d. Coagulation function: International Normalized Ratio≤1.5 and Activated Partial Thromboplastin Time≤1.5×ULN (subjects who are allowed to receive anticoagulation therapy and whose coagulation function is in the above range).

• Female subjects of childbearing age or male subjects whose partners are women of childbearing age are required to take effective contraceptive measures throughout the treatment period and for 6 months after the treatment period.
• The histopathological test confirmed that *CLDN18.2 was positive.For subjects who have previously received any anti-CLDN18.2 treatment, tumor samples should be collected again after the relevant anti-CLDN18.2 treatment has ended.

Note:

*CLDN18.2 positive was defined as Claudin18.2 immunohistochemical membrane staining intensity ≥ acceptance of previous test results, center test results, and laboratory test results in ≥40% of tumor cells.The proportion of CLDN18.2 expression can be dynamically adjusted by sponsors and funders during the study based on newly generated data.

Exclusion criteria

• Participating in another interventional clinical study, other than an observational (non-interventional) clinical study or in the survival follow-up phase of an interventional study.
• Cytochrome P450 3A4 CYP3A4 (cytochrome P450 3A4) suppressant treatment within 2 weeks or 5 half-lives (whichever is longer) prior to the first administration of the study drug.
• Receive the last anti-tumor treatment 4 weeks before the first administration of the study drug or within 5 half-lives of the anti-tumor therapy drug (whichever is shorter) (drugs without an exact half-life need to be eluted for 2 weeks).
• Received therapeutic or palliative radiotherapy within 2 weeks prior to the first administration of the study drug.
• Biliary stenting or PTCD was performed within 7 days prior to the first use of the study drug.
• Plan to receive other anti-tumor therapy during the study drug treatment period [allowing palliative radiotherapy for the purpose of relieving symptoms (such as pain) without compromising the evaluation of efficacy].
• Receive any live vaccines within 4 weeks prior to the first administration of the study drug or during the study period.
• Had a major surgical procedure (craniotomy, thoracotomy, or laparotomy, or other procedure as defined by the investigator, excluding needle biopsy) or had an unhealed wound, ulcer, or fracture within 4 weeks prior to the first administration of the study drug;Or plan to require major surgery during the study.For the purpose of palliative care, local surgical treatment of isolated lesions is acceptable.
• Toxicity from prior treatment that did not return to NCI CTCAE v5.0 before first administration of the investigational drug (excluding alopecia, weakness, pigmentation, and other conditions deemed by the investigator to be of no safety risk).
• A history of gastrointestinal perforation and/or fistula within the 6 months prior to the first administration of the study drug that has not been cured by surgical treatment.
• Presence of pyloric obstruction and/or persistent recurrent vomiting (vomiting ≥ 3 times within 24 hours).
• Digestive tract [refers to the muscular duct from the mouth to the anal canal, including the mouth, pharynx, esophagus, stomach, small intestine (duodenum, jejunum, ileum), large intestine (cecum, appendix, colon, rectum) and anal canal, etc.] or after endotracheal stent implantation.
• Symptomatic central nervous system metastasis.Participants with asymptomatic BMS (i.e., no neurological symptoms, no need for glucocorticoid therapy, all BMS ≤ 1.5 cm) or BMS with stable symptoms after treatment met all of the following criteria to be eligible for participation in this study: no midbrain, pontine, cerebellum, meninges, medulla bulbar, or spinal cord metastases;Clinical status remained stable for at least 4 weeks, clinical evidence confirmed no new or expanded brain metastases, and corticosteroids and anticonvulsants were discontinued for at least 2 weeks before first administration of the study drug.Note: The central nervous system is not a target lesion.
• Bone metastases at risk of paraplegia.
• Interstitial lung disease requiring steroid therapy, or a history of interstitial lung disease, non-infectious pneumonia, severely impaired lung function or uncontrolled lung disease, such as pulmonary fibrosis, severe radiation pneumonia, acute lung injury, etc., or suspected during screening.
• There are uncontrolled diseases such as:

• Investigate the presence of poorly controlled infections that require treatment with systemic anti-infective drugs (antibiotics, antivirals, or antifungals) in the week prior to the first administration of the drug.
• HIV-1/2 antibody positive in people with human immunodeficiency virus (HIV).
• Acute or chronic active Hepatitis B (defined as Hepatitis B surface Antigen HBsAg) and/or hepatitis B Core Antibody HBcAb positive with hepatitis B virusDNA copy number ≥ 104 copies /mL or ≥ 2000 IU/mL or acute or chronic active Hepatitis C [Hepatitis C Virus antibody (HCVAb) positive HCV RNA 103 copies /mL].Subjects below the above criteria after nucleotide antiviral therapy and those with HCV antibody positive but RNA negative tests were admitted.
• Active tuberculosis, receiving antituberculosis therapy or receiving antituberculosis therapy within 1 year prior to the first administration of the investigational drug.
• Active plum poisoning or latent syphilis requires treatment.
• Symptomatic congestive heart failure (NYHA Class II to IV), symptomatic or poorly controlled arrhythmia, QTc interval 480 ms, or a personal or family history of congenital long/short QT syndrome.
• Standardized treatment of poorly controlled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥100 mmHg).
• There is a risk of gastrointestinal/respiratory fistula.
• pleural effusion, ascites, or pericardial effusion that is symptomatic and requires intervention (e.g. drainage).
• Esophageal or gastric varices that require immediate intervention (e.g., lapping or sclerotherapy) or that are considered to have a high risk of bleeding in the opinion of the investigator or in consultation with a gastroenterologist or hepatologist,Subjects with evidence of portal hypertension (including splenomegaly on imaging) or a history of varicose bleeding must undergo endoscopic evaluation within 3 months prior to the first administration of the study drug.
• Any life-threatening bleeding event or grade 3 or 4 gastrointestinal/varicose bleeding event requiring blood transfusion, endoscopic, or surgical treatment occurred in the 3 months prior to the first administration of the study drug.
• Study any arterial thromboembolic events, including myocardial infarction, unstable angina pectoris, cerebrovascular accident, and transient ischemic attack, within 6 months prior to the first administration of the drug.
• History of new or uncontrolled stable deep vein thrombosis, pulmonary embolism, or any other severe venous thromboembolism within the 3 months prior to the first administration of the investigational drug (implantable port of intravenous infusion or catheter-derived thrombosis or superficial venous thrombosis were not considered "severe" venous thromboembolism).
• hepatic encephalopathy, hepatorenal syndrome or Child-Pugh score > 7.
• Risk of intestinal obstruction or perforation (including, but not limited to, a history of acute diverticulitis, abdominal abscess) or a history of inflammatory bowel disease or extensive enterectomy (partial resection of the colon or extensive resection of the small intestine with chronic diarrhea), Crohn's disease, ulcerative colitis, etc.
• Other acute or chronic medical conditions or abnormalities in laboratory tests that may increase the risk associated with study participation or study drug administration, or interfere with the interpretation of study results, and, at the investigator's discretion, classify subjects as ineligible to participate in the study.
• Neurological, psychiatric, or social conditions that affect compliance with study requirements, significantly increase the risk of AE, or affect a subject's ability to provide a written ICF.
• History of other primary malignancies, except the following:

Cured malignancies with no known active disease ≥ 2 years prior to study inclusion and a very low risk of recurrence;Non-melanoma skin cancer or malignant lentigo with adequate treatment and no evidence of disease recurrence;Carcinoma in situ with adequate treatment and no evidence of disease recurrence.

• Known history of immunodeficiency.
• History of allogeneic organ transplantation and hematopoietic stem cell transplantation.
• Previously received antibody drug conjugate therapy based on topoisomerase inhibitors.
• For subjects receiving drug therapy, there is a history of prior allergy to the corresponding drug or preparation.
• There are contraindications for subjects receiving medication.
• For subjects receiving medication, there is a history of drug-related adverse reactions leading to permanent discontinuation.
• Pregnant or lactating female subjects.
• Other investigators did not consider themselves eligible to participate in the study.