| 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.
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