Combined HAIC, Lenvatinib and Pucotenlimab As Conversion Therapy for Unresectable Intrahepatic Cholangiocarcinoma

Inclusion Criteria:

• Histologically confirmed intrahepatic cholangiocarcinoma.

• Age ≥18 years.

• ECOG performance status score of 0 or 1.

• Not suitable for radical surgery (including radical hepatic resection, livertransplantation or ablation) after evaluation by the MDT expert group of treatinghepatobiliary cancer. Specifically, any of the following conditions are met：

1. R0 resection is not feasible.

2. in subjects without cirrhosis, the volume of normal liver parenchyma is lessthan 30% of the total volume, or in patients with cirrhosis, the volume ofnormal liver parenchyma is less than 40% of the total volume, or ICG-R15>15%.

3. Number of lesions >1.

• No prior systemic anti-tumor treatment for intrahepatic cholangiocarcinoma beforethe first dose.

• According to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTV1.1), at least 1 measurable lesion, or a measurable lesion that has clearlyprogressed (based on RECIST V1.1 criteria) after local treatment.

• Subjects with portal vein tumor thrombus (PVTT):

1. Chen's group A and B, or Cheng's type I-III can be enrolled.

2. Chen's group C, or Cheng's type IV (superior vena cava tumor thrombus) cannotbe enrolled.

• Subjects with hepatic vein tumor thrombus:

1. VV1 and VV2 types can be enrolled.

2. VV3 type, or Sakamoto type I (inferior vena cava tumor thrombus) can also beenrolled.

3. Sakamoto type II (inferior vena cava tumor thrombus extending above thediaphragm), or Sakamoto type III (inferior vena cava tumor thrombus reachingthe right atrium) cannot be enrolled.

• Subjects with oligometastases outside the liver can be enrolled: Oligometastasesoutside the liver are defined as up to three metastatic lesions in a maximum of twoorgans, with the largest diameter being 3cm.

• Child-Pugh score less than or equal to 7.

• Adequate organ and bone marrow function, with laboratory test values meeting thefollowing requirements within 7 days prior to inclusion (no blood components, cellgrowth factors, albumin, or other intravenous or subcutaneous corrective treatmentdrugs are allowed within 14 days prior to obtaining laboratory tests):

1. Complete blood count: Absolute Neutrophil Count (ANC) ≥1.5×10^9/L; Plateletcount (PLT) ≥75×10^9/L; Hemoglobin (HGB) ≥9.0 g/dL.

2. Liver function: Total Bilirubin (TBIL) ≤2×Upper Limit of Normal Value (ULN);Alanine Aminotransferase (ALT) and Aspartate Transferase (AST) ≤5×ULN; Serumalbumin ≥28 g/L; Alkaline Phosphatase (ALP) ≤5×ULN.

3. Kidney function: Serum Creatinine (Cr) ≤ 1.5×ULN or Clearance of Creatinine (CCr) ≥50mL/min (Cockcroft-Gault formula); Urinalysis shows proteinuria <2+;For subjects with baseline urinalysis showing proteinuria ≥2+, a 24-hour urinecollection should be performed and 24-hour urinary protein quantification <1g.

4. Coagulation function: International Normalized Ratio (INR) ≤2.3 or ProthrombinTime (PT) extension ≤6 seconds.

• Estimated life expectancy of ≥12 weeks.

• Female subjects of childbearing age or male subjects whose sexual partners are ofchildbearing age need to take effective contraceptive measures during the entiretreatment period and for 6 months after the last medication.

• Signed written informed consent, and able to comply with the visit and relatedprocedures stipulated in the protocol.

Exclusion Criteria:

• Histologically/cytologically confirmed sarcomatoid intrahepatic cholangiocarcinoma,mixed hepatocellular carcinoma, etc.

• History of hepatic encephalopathy or liver transplantation.

• Clinically symptomatic pleural effusion, ascites, or pericardial effusion requiringdrainage. Patients with only radiologically detected minimal pleural effusion,ascites, or pericardial effusion without symptoms can be included.

• Acute or chronic active hepatitis B or C infection, with hepatitis B virus (HBV) DNA >2000IU/ml or 10^4 copies/ml; hepatitis C virus (HCV) RNA >10^3 copies/ml;co-positive for hepatitis B surface antigen (HbsAg) and anti-HCV antibody. Patientswho meet the above criteria after antiviral treatment with nucleoside analogs can beincluded.

• Presence of central nervous system metastases.

• History of esophageal or gastric variceal bleeding due to portal hypertension withinthe past 6 months. Patients assessed by the investigator to be at high risk ofbleeding.

• Any life-threatening bleeding event within the past 3 months, including thoserequiring blood transfusion, surgery or local treatment, or continuous drugtreatment.

• History of arterial or venous thromboembolic events within the past 6 months,including myocardial infarction, unstable angina, cerebrovascular accident ortransient ischemic attack, pulmonary embolism, deep vein thrombosis, or any otherserious thromboembolic events. Exceptions are made for thrombosis formation relatedto implanted venous infusion ports or catheters, or superficial vein thrombosis thathas stabilized after routine anticoagulation treatment. Preventive use of low-doselow molecular weight heparin (such as enoxaparin 40 mg/day) is allowed.

• Continuous use of aspirin (>325 mg/day) or other known platelet function inhibitorssuch as clopidogrel or ticlopidine for 10 days within 2 weeks prior to the firstdose.

• Uncontrolled hypertension, with systolic blood pressure ≥150mmHg or diastolic bloodpressure ≥100mmHg after optimal medical treatment, history of hypertensive crisis orhypertensive encephalopathy.

• Presence of any toxicity caused by previous treatment that has not recovered tograde 0 or 1 according to the National Cancer Institute Common Terminology Criteriafor Adverse Events version 5.0 (NCI CTCAE 5.0) before the first dose of studytreatment (excluding alopecia, non-clinically significant and asymptomaticlaboratory abnormalities).

• Symptomatic congestive heart failure (New York Heart Association class II-IV), leftventricular ejection fraction (LVEF) <50% as indicated by echocardiography.

• Symptomatic or poorly controlled arrhythmia. History of congenital long QT syndromeor corrected QTc >500 ms (calculated using the Fridericia formula) at screening.

• Severe bleeding tendency or coagulation disorder, or currently receivingthrombolytic therapy.

• History of gastrointestinal perforation and/or fistula, intestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition),extensive intestinal resection (partial colectomy or extensive small bowel resectionwith chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrheawithin the past 6 months.

• Received radiotherapy within 3 weeks prior to the first dose of study treatment. Forpatients who received radiotherapy more than 3 weeks prior to the first dose ofstudy treatment, all of the following conditions must be met for inclusion: nocurrent radiation-related toxicities, no need for corticosteroids, and exclusion ofradiation pneumonitis, radiation hepatitis, radiation enteritis, etc.

• History or current diagnosis of pulmonary fibrosis, interstitial pneumonia,pneumoconiosis, drug-related pneumonia, severe impairment of lung function, andother lung diseases.

• Active pulmonary tuberculosis, currently receiving anti-tuberculosis treatment, orreceived anti-tuberculosis treatment within 1 year prior to the first dose.

• Infection with human immunodeficiency virus (HIV) (HIV 1/2 antibody positive), knownsyphilis infection requiring treatment.

• Active or clinically uncontrolled severe infection. Severe infection within 4 weeksprior to the first dose, including but not limited to hospitalization forcomplications of infection, sepsis, or severe pneumonia.

• Active autoimmune disease requiring systemic treatment (such as disease-modifyingdrugs, corticosteroids, or immunosuppressants) within 2 years prior to the firstdose. Replacement therapy (such as thyroxine, insulin, or physiologicalcorticosteroids for adrenal or pituitary insufficiency, etc.) is allowed. History ofprimary immunodeficiency. Patients with only autoantibody positivity need to beconfirmed by the investigator whether there is an autoimmune disease.

• Use of immunosuppressive drugs within 4 weeks prior to the first dose, excludingintranasal, inhaled, or other local corticosteroids or physiological doses ofsystemic corticosteroids (i.e., no more than 10mg/day prednisone or equivalent dosesof other corticosteroids). Temporary use of corticosteroids for the treatment ofdyspnea symptoms due to allergies or diseases such as asthma, chronic obstructivepulmonary disease, etc., is allowed.

• Received a live attenuated vaccine within 4 weeks prior to the first dose or plannedto receive one during the study period.

• Major surgery (craniotomy, thoracotomy, or laparotomy) or unhealed wound, ulcer, orfracture within 4 weeks prior to the first dose. Minor surgical procedures or tissuebiopsy within 7 days prior to the first dose, excluding venous puncture for thepurpose of intravenous infusion, are excluded.

• Local treatment for hepatocellular carcinoma within 4 weeks prior to the first dose.

• Use of traditional Chinese medicine with anti-tumor indications or drugs withimmunomodulatory effects (including thymosin, interferon, interleukin, etc., exceptfor local use to control pleural effusion or ascites, etc.) within 2 weeks prior tothe first dose.

• Uncontrolled/uncorrectable metabolic disorders or other non-malignant neoplasticorgan diseases or systemic diseases or secondary reactions to cancer that couldresult in higher medical risk and/or uncertainty in survival evaluation, or thepresence of other conditions that, in the judgment of the investigator, makeenrollment inappropriate.

• Diagnosis of other malignancy within 5 years prior to first dose, excludingradically treated basal cell carcinoma of the skin, squamous cell carcinoma of theskin, and/or radically resected carcinoma in situ. If other malignancy was diagnosedmore than 5 years prior to dosing, even if the liver lesion meets the EASL-ILCAclinical diagnostic criteria for intrahepatic cholangiocarcinoma, the liver lesionmust still be diagnosed pathologically or cytologically and those who aredefinitively intrahepatic cholangiocarcinoma may be enrolled.

• Previous treatment with any anti-PD-1 antibody, anti-PD-L1/L2 antibody, anti-CTLA-4antibody, or other immunotherapy. Previous treatment with targeted therapy againstVEGF and/or VEGFR, RAF, MEK, PDGFR, FGFR, etc.

• Known allergy to any component of oxaliplatin, 5-fluorouracil, calcium folinate,lenvatinib, or pucotenlimab; or severe allergic reaction to other monoclonalantibodies in the past.

• Patients diagnosed with aortic dissection aneurysm, celiac trunk and superiormesenteric artery dissection aneurysm.

• Received treatment in other clinical trials within 4 weeks prior to the first dose.

• Pregnant or breastfeeding women.

• Patients with systemic multiple metastases, portal vein tumor thrombus involving thesuperior mesenteric vein, inferior vena cava tumor thrombus extending above thediaphragm or reaching the right atrium.

• Other acute or chronic diseases, mental illnesses, or laboratory test abnormalitiesthat may result in the following outcomes: increased risk associated with studyparticipation or study drug administration, or interference with the interpretationof study results, and other conditions that, in the investigator's judgment, makethe patient ineligible to participate in the study.