Overview

This study is a single-arm Phase II clinical trial aiming to evaluate the safety and efficacy of HAIC combined with Cadonilimab and Regorafenib as second-line treatment for unresectable intrahepatic cholangiocarcinoma.

The study plans to enroll approximately 45 participants. All enrolled participants will receive continuous treatment: HAIC-Gemox: Gemcitabine 1000mg/m2 on Day 1 + Oxaliplatin 85mg/m2 on Day 1, every 3 weeks (Q3W), for up to 6 treatment cycles, Cadonilimab(6mg/kg, D2, Q3W) and Regorafenib (80mg QD, Q3W) until the investigator determines that there is no longer any clinical benefit (based on comprehensive assessment including RECIST v1.1 imaging evaluation and clinical condition), intolerable toxicity, initiation of new anti-tumor therapy, or meeting other criteria for treatment discontinuation, whichever occurs first.

Eligibility

Inclusion Criteria:

        To be eligible for enrollment in the study, participants must meet the following inclusion
        criteria:
          1. Voluntarily provide written informed consent.
          2. Age at enrollment is ≥18 years and ≤75 years, both males and females.
          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
          4. Expected survival period of ≥3 months.
          5. Patients with histologically or cytologically confirmed unresectable intrahepatic
             cholangiocarcinoma. Patients who have failed standard treatment (standard treatment
             includes gemcitabine plus cisplatin plus pembrolizumab, gemcitabine plus gemcitabine
             plus oxaliplatin, capecitabine plus oxaliplatin, chemotherapy mainly based on
             albumin-bound paclitaxel, 5-fluorouracil (5-FU) plus platinum-based therapy) or are
             intolerant to standard treatment, or patients for whom standard treatment is not
             accessible. Note: Patients who have received adjuvant/neoadjuvant chemotherapy
             targeting non-metastatic disease with curative intent and experience disease
             progression within ≤6 months after the last treatment are eligible.
          6. At least one measurable lesion according to RECIST v1.1 that can be accurately
             measured repeatedly. Note: Brain metastases cannot be considered as target lesions.
          7. Adequate organ function determined by the following requirements:
               1. Hematology (no use of any blood components or growth factors within 7 days prior
                  to starting the study treatment): i. Absolute Neutrophil Count (ANC) ≥ 1.5 ×
                  109/L (1,500/mm3). ii. Platelet count ≥ 80 × 109/L (100,000/mm3). iii. Hemoglobin
                  ≥ 90 g/L.
               2. Kidney:
             i. Serum creatinine ≤ 1.5 × Upper Limit of Normal (ULN). ii. Calculated creatinine
             clearance* (CrCl) ≥ 50 mL/min.
             * CrCl will be calculated using the Cockcroft-Gault formula (Cockcroft-Gault formula).
             CrCl (mL/min) = {(140 - age) × body weight (kg) × F} / (SCr (mg/dL) × 72) For males, F
             = 1; for females, F = 0.85; SCr = serum creatinine. iii. Urine protein ≤ 1+ or 24-hour
             urinary protein quantification < 1.0 g. c) Liver: i. Total bilirubin (TBil) ≤ 3 × ULN.
             ii. AST and ALT ≤ 5 × ULN. iii. Serum albumin (ALB) ≥ 28 g/L. d) Coagulation function:
             i. International Normalized Ratio (INR) and Activated Partial Thromboplastin Time
             (APTT) ≤ 1.5 × ULN (unless the subject is receiving anticoagulant therapy and
             coagulation parameters [PT/INR and APTT] are within the expected range for
             anticoagulant treatment at screening).
             e) Cardiac function: i. Left Ventricular Ejection Fraction (LVEF) ≥ 50%.
          8. Female participants of childbearing potential must undergo urine or serum pregnancy
             testing within 3 days prior to the first dose of study medication (if the urine
             pregnancy test results cannot be confirmed as negative, a serum pregnancy test must be
             conducted, with the serum pregnancy test result being definitive). If female
             participants of childbearing potential engage in sexual activity with a nonsterilized
             male partner, they must use an acceptablemethod of contraception from the start of
             screening and agree to continue using contraception for up to 120 days after the last
             dose of the study medication. The decision to stop contraception after this time
             should be discussed with the investigator.
          9. Male participants with a female partner of childbearing potential must use effective
             contraception from the start of screening until 120 days after the last dose of the
             study medication. The decision to stop contraception after this time should be
             discussed with the investigator.
         10. Participants must be willing and able to comply with the scheduled visits, treatment
             plan, laboratory tests, and other study requirements.
        Exclusion Criteria:
        Subjects meeting any of the following criteria will be ineligible to participate in this
        study:
          1. Diagnosis of malignant tumors with non-biliary cancers such as hepatocellular
             carcinoma, mixed-cell carcinoma, or fibrolamellar carcinoma.
          2. History of other malignant tumors within the past 3 years, except for cured localized
             tumors (e.g., basal cell carcinoma, squamous cell carcinoma of the skin, superficial
             bladder cancer, cervical carcinoma in situ).
          3. Concurrent participation in another clinical study unless it is an observational,
             non-interventional study or follow-up period of an interventional study.
          4. Palliative local therapy performed on non-target lesions within 2 weeks prior to the
             first dose; non-specific immune modulating therapy (e.g., interleukins, interferons,
             thymosin, excluding IL-11 for thrombocytopenia) within 2 weeks prior to the first
             dose; use of traditional Chinese medicine or herbal remedies with anti-tumor
             indications within 1 week prior to the first dose.
          5. Previous receipt of any immune anti-tumor therapy, including immune checkpoint
             stimulants (e.g., ICOS, CD40, CD137, GITR, OX40 antibodies), immune cell therapy.
          6. Previous receipt of targeted therapy.
          7. Active autoimmune diseases requiring systemic treatment within the past two years
             (e.g., medications for disease improvement, corticosteroids, immunosuppressive
             therapy); replacement therapy (e.g., thyroid hormones, insulin, physiological
             corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not
             considered systemic treatment.
          8. History of active or prior documented inflammatory bowel disease (e.g., Crohn's
             disease, ulcerative colitis, or chronic diarrhea).
          9. History of immunodeficiency; positive HIV antibody test; current long-term use of
             systemic corticosteroids or other immunosuppressive agents.
         10. Known active tuberculosis (TB) or suspected active TB requiring clinical evaluation;
             known active syphilis infection.
         11. History of allogeneic organ transplantation or allogeneic hematopoietic stem cell
             transplantation.
         12. History of or current non-infectious pneumonitis/interstitial lung disease requiring
             systemic corticosteroid therapy.
         13. Severe infection within 4 weeks prior to the first dose, including complications
             requiring hospitalization, sepsis, or severe pneumonia; active infection requiring
             systemic anti-infective treatment within 2 weeks prior to the first dose (excluding
             antiviral therapy for hepatitis B or C).
         14. Subjects with active hepatitis B (positive HBsAg and HBV-DNA >1000 copies/mL [200
             IU/mL] or above the lower limit of detection, whichever is higher). Note: Subjects
             with hepatitis B should receive antiviral therapy during the study treatment period.
         15. Subjects with active hepatitis C (positive HCV antibody and HCV-RNA above the lower
             limit of detection).
         16. Presence of obstructive jaundice (eligible if actively treated with biliary drainage
             or stenting and liver function has recovered).
             Major surgery or significant traumatic injury within 30 days prior to the first dose,
             or planned major surgery within 30 days after the first dose (as determined by the
             investigator); minor surgical procedures within 3 days prior to the first dose
             (excluding placement of peripheral intravenous catheters and implantation of venous
             infusion ports).
         17. Subjects with active central nervous system (CNS) metastases. Note: Subjects with
             previously treated brain metastases (e.g., surgery, radiotherapy) may be eligible if
             clinically stable for at least two weeks after treatment (from the start of study drug
             administration) and off corticosteroids for three days prior to study drug
             administration. Subjects with untreated, asymptomatic brain metastases (i.e., no
             neurological symptoms, no requirement for corticosteroids, and no brain metastases
             with a longest diameter >1.5 cm) may be eligible and should have regular assessments
             of brain metastases during the course of the study treatment.
         18. Known brainstem, meningeal, spinal cord, or leptomeningeal metastases or compression.
             Subjects with clinically significant symptoms or requiring repeated drainage of
             pleural effusion, pericardial effusion, or ascites.
             Inability to swallow tablets, malabsorption syndrome, or any condition that could
             affect gastrointestinal absorption.
         19. Current uncontrolled concurrent illness, including but not limited to decompensated
             cirrhosis, nephrotic syndrome, uncontrolled metabolic disorder, severe active peptic
             ulcer disease or gastritis, or any psychiatric/social condition that would limit
             compliance with study requirements or affect the subject's ability to provide written
             informed consent.
         20. History of myocarditis, cardiomyopathy, malignant arrhythmia. Subjects with unstable
             angina, myocardial infarction, congestive heart failure (New York Heart Association
             functional class II or higher), or vascular disease with a risk of rupture requiring
             hospitalization within 12 months prior to the first dose of study drug, or other
             cardiac damage (e.g., poorly controlled arrhythmias, myocardial ischemia) that may
             affect the assessment of the safety of the study drug.
         21. History within 6 months prior to the first dose of study drug of esophageal or gastric
             variceal bleeding, severe ulceration, unhealed wound, gastrointestinal perforation,
             fistula, intra-abdominal abscess, or acute gastrointestinal bleeding; any arterial
             thromboembolic event within 6 months prior to the first dose of study drug, grade 3 or
             higher venous thromboembolism according to NCI CTCAE version 5.0, transient ischemic
             attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy;
             current hypertension with a systolic blood pressure ≥160 mmHg or diastolic blood
             pressure ≥100 mmHg after oral antihypertensive therapy.
         22. History of severe bleeding diathesis or coagulation disorder; clinically significant
             bleeding symptoms within 1 month prior to the first dose of study drug, including but
             not limited to gastrointestinal bleeding, bleeding gastric ulcer, hemoptysis (defined
             as coughing or spitting up ≥1 teaspoon of fresh blood or small clots or coughing blood
             without sputum, subjects with blood-tinged sputum are allowed), epistaxis (excluding
             nosebleeds and regurgitant epistaxis); subjects receiving continuous anticoagulant
             therapy within 10 days prior to the first dose of study drug.
         23. Screening imaging showing tumor encasement or invasion of major blood vessels or
             organs (such as heart and pericardium, trachea, esophagus, aorta, superior vena cava,
             etc.) or presence of significant necrosis, cavitation, and the investigator determines
             that entry into the study would pose a risk of bleeding.
         24. Previous unresolved toxicity from anticancer treatment, defined as toxicity not
             recovered to grade 0 or 1 according to NCI CTCAE version 5.0 or as specified in the
             inclusion/exclusion criteria, except for alopecia and residual neurotoxicity related
             to previous platinum-based treatment. Subjects with irreversible toxicity that is not
             expected to worsen with study drug administration (e.g., hearing loss) may be
             considered for inclusion in the study after consultation with the investigator.
             Subjects with late toxicities caused by radiotherapy that the investigator deems
             irrecoverable may be considered for inclusion in the study.
         25. Administration of live vaccines within 30 days prior to the first dose or planned
             administration of live vaccines during the study is not allowed, but the use of
             inactivated vaccines is permitted.
         26. Known allergies to any component of the investigational drug or a history of severe
             hypersensitivity reactions to other monoclonal antibodies.
         27. Known history of mental illness, substance abuse, alcoholism, or drug addiction.
         28. Pregnant or lactating women.
         29. Previous or current presence of any condition, treatment, or laboratory abnormalities
             that may confound study results, affect the subject's full participation in the study,
             or be contrary to the subject's best interests.
         30. Non-malignant diseases causing local or systemic symptoms or conditions secondary to
             the tumor, leading to higher medical risks and/or uncertainty in survival assessment,
             such as tumor-related leukemic reaction (white blood cell count >20 × 109/L),
             manifestations of cachexia (e.g., known weight loss exceeding 10% in the 3 months
             before screening), etc.