Ivonescimab in Combination With Liposomal Irinotecan and 5-FU/LV in Potentially Resectable Biliary Tract Malignancies

Prior treatment

• Prior treatment for cholangiocarcinoma, including chemotherapy, molecularly targeted agents, traditional Chinese medicine with antitumor properties, radiotherapy, or interventional therapy (excluding percutaneous transhepatic cholangial drainage \[PTCD\] or common bile duct stenting). This also includes prior immunotherapy for cholangiocarcinoma.
• Major surgery, active ulceration, or incomplete wound healing within 1 month prior to the first administration of the study drug (excluding central venous catheter placement, tumor biopsy, or nasogastric tube insertion).
• Planned elective surgery during the study period.
• Blood product transfusion or administration of hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF, M-CSF) within 14 days prior to the first dose of the study drug.
• Live-attenuated vaccine administration within 30 days prior to the first dose of the study drug.
• Use of immunosuppressive medications within 14 days prior to the first dose. Exceptions include:
  • Topical, inhaled, or intra-articular corticosteroids.
  • Systemic corticosteroid doses ≤10 mg/day of prednisone or equivalent.
  • Prophylactic corticosteroid use for hypersensitivity reactions (e.g., premedication for CT scans).
• History of severe bleeding tendency or coagulopathy; clinically significant bleeding symptoms (e.g., gastrointestinal bleeding, hemoptysis) within 1 month prior to the first dose; or ongoing anticoagulation therapy within 10 days prior to the first dose.
• Arterial thromboembolic events within 6 months prior to the first dose, or venous thromboembolic events graded ≥Grade 3 per NCI CTCAE v5.0.
• History of another primary malignancy, except:
  • Malignancies treated with curative intent, with no evidence of active disease ≥5 years prior to the first dose and a low risk of recurrence.
  • Non-melanoma skin cancer or malignant melanocytic nevi with no evidence of disease.
  • In situ carcinoma fully treated and with no evidence of disease.
• Participation in another interventional clinical trial within 1 month prior to the first dose of the study drug.
• Thromboembolic events (arterial or venous) within 6 months prior to the first dose, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, or cerebral infarction), deep vein thrombosis, or pulmonary embolism.
• Concomitant illnesses deemed by the investigator to pose a significant risk to participant safety or interfere with study completion (e.g., severe diabetes).
• Residual liver volume ≥40% in patients with cirrhosis or ≥30% in patients without cirrhosis after R0 resection.

Other illness

• Exclusion Criteria for Study Enrollment
  • Participants with any of the following conditions are not eligible for this study:
• History of allogeneic organ transplantation.
• Active autoimmune or inflammatory diseases, or a history thereof, including inflammatory bowel disease (e.g., colitis, Crohn's disease), diverticulitis (excluding diverticulosis), systemic lupus erythematosus, sarcoidosis, Wegener's syndrome, granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, or uveitis. Exceptions include:
  • Vitiligo or alopecia.
  • Stable hypothyroidism managed with hormone replacement (e.g., post-Hashimoto's thyroiditis).
  • Chronic skin conditions not requiring systemic therapy.
  • Celiac disease controlled by diet.
  • Patients with no active disease within the past 5 years, after consultation with the study investigator.
• Uncontrolled medical conditions, including but not limited to: persistent or active infections (other than HBV or HCV), symptomatic congestive heart failure, uncontrolled diabetes, uncontrolled hypertension, unstable angina, uncontrolled arrhythmias, active interstitial lung disease, severe chronic gastrointestinal diseases with diarrhea, or psychiatric/social conditions that may limit adherence to study requirements, increase the risk of adverse events (AEs), or impair the ability to provide written informed consent.
• Active infections, including tuberculosis or human immunodeficiency virus (HIV 1/2 antibody positivity).
• Known hypersensitivity or allergic reaction to any component of the study drug or its excipients.
• Other conditions deemed by the investigator to disqualify the participant from study enrollment.
  • Conversion Success Criteria for Surgical Eligibility
  • After evaluation by a surgeon, participants meeting the following criteria are considered to have achieved conversion success and are eligible for surgical treatment:

Other

• Presence of unresectable extrahepatic metastases.
• Active primary immunodeficiency.
• Participants or their partners who are pregnant or planning pregnancy, or participants who are breastfeeding.
• ECOG performance status ≤1.
• No extrahepatic lesions, or extrahepatic lesions deemed resectable, with no new lesions identified during treatment.
• Tumor vascular occlusion reduced to branch vessels.

• Patients eligible for inclusion in this study must meet all of the following criteria:
  • Informed Consent: Able to provide written informed consent and understand and agree to comply with study requirements and the assessment schedule.
  • Age and Gender: Age ≥18 years and ≤75 years on the day of signing the Informed Consent Form (ICF), male or female.
  • Disease Status: Potentially resectable, previously untreated biliary tract malignancy confirmed by histological or cytological evidence.
  • Tumor Assessment: Tumor evaluated by a hepatobiliary surgeon with sufficient objective evidence to determine irresectability.
  • Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
  • Life Expectancy: Estimated survival of more than 12 weeks.
  • Body Weight: Weight \>30 kg.
  • Prior Therapy: No prior anti-tumor therapy, including but not limited to anti-CTLA-4, anti-VEGF, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies.
  • EnEnough Organ Function
  • Coagulation: Prothrombin time (PT) ≤1.5×ULN, international normalized ratio (INR) ≤1.5×ULN, and activated partial thromboplastin time (aPTT) ≤1.5×ULN.
  • Blood Pressure: Systolic blood pressure ≤150 mmHg and diastolic blood pressure ≤90 mmHg during the screening period, with or without antihypertensive medication. No changes to antihypertensive therapy within 1 week prior to the first administration of the study drug.
  • Contraception: Sexually active males and females of childbearing potential (not surgically sterilized) must agree to use a medically accepted method of contraception (e.g., intrauterine device, contraceptive pill, or condom) during the study treatment period and for 6 months after the last dose of study treatment.
  • Females of childbearing potential must have a negative serum β-human chorionic gonadotropin (β-HCG) test within 7 days prior to study enrollment and must not be breastfeeding.
  • HBV Management: Patients with detectable HBV DNA levels (≥10 IU/mL or above the limit of detection) and HBV infection (defined as positive hepatitis B surface antigen \[HBsAg\] and/or hepatitis B core antibody \[anti-HBc\]) must receive antiviral therapy according to clinical practice prior to study treatment to ensure adequate viral suppression. Antiviral therapy must be continued during the study period and for 6 months after the last dose of study treatment. Patients with positive anti-HBc but undetectable HBV DNA (\<10 IU/mL or below the limit of detection) do not require antiviral therapy unless HBV DNA exceeds 10 IU/mL or the limit of detection during the study. Patients with active HBV and HCV co-infection (defined by positive anti-HCV antibody) or active HBV and hepatitis D virus co-infection are excluded.
  • Voluntary Participation: Willing to voluntarily participate in the clinical trial, comply with study visits and procedures, understand the study requirements, and have signed the informed consent form.