| Eligibility |
Inclusion Criteria:
- The subjects voluntarily participate in the study and agree to sign the informed
consent form, are compliant, and cooperate with follow-up.
- They are over 18 years of age and gender is not restricted when signing the informed
consent form.
- They have histologically confirmed unresectable advanced or metastatic biliary tract
adenocarcinoma, including intrahepatic or extrahepatic cholangiocarcinoma and
gallbladder cancer.
- Patients who are diagnosed with unresectable or metastatic disease and have not
received prior treatment are eligible for inclusion.
- Patients who have undergone curative surgery and experienced disease recurrence after
more than 6 months; or patients who have completed adjuvant therapy (chemotherapy
and/or radiotherapy) and have been disease-free for more than 6 months after
completing adjuvant therapy are eligible for inclusion.
- They have at least one measurable lesion (as defined by RECIST 1.1, the measurable
lesion is a spiral CT scan long diameter =10mm or lymph node short diameter =15mm).
- Their ECOG score is 0-1 in the week prior to enrollment.
- Based on the investigator's assessment, their estimated survival time is =3 months.
- Patients with active hepatitis B or C require relevant antiviral treatment, with
HBV-DNA <2000 IU/ml (<104 copies/ml), and have received at least 14 days of antiviral
treatment before participating in the study. HCV RNA-positive patients must follow
local standard treatment guidelines for antiviral therapy, and their liver function is
within CTCAE Grade 1 elevation.
- Their hematological and organ functions are adequate, based on laboratory test results
obtained within 14 days before the start of the study (unless otherwise specified):
- Hematology: (no blood transfusion, no G-CSF, no drug correction within 14 days prior
to screening) Hb =90 g/L; neutrophil count =1.5×109/L; PLT =100×109/L.
- Biochemistry: (no albumin transfusion within 14 days) Appropriate liver function: ALT
and AST =2.5×ULN; for patients with liver metastases, ALT and AST =5 × ULN.
Serum bilirubin =2.0×ULN; these conditions do not apply to patients with confirmed
Gilbert's syndrome. Any clinically significant biliary obstruction should be resolved
before randomization.
Appropriate renal function: creatinine =1.5×ULN, or creatinine clearance rate (CCr)
>50mL/min (using the standard Cockcroft-Gault formula):
Female: CrCl = ((140 - age) x weight (kg) x 0.85) / 72 x serum creatinine (mg/dL) Male:
CrCl = ((140 - age) x weight (kg) x 1.00) / 72 x serum creatinine (mg/dL)
?Women of childbearing potential: agree to abstain from sexual intercourse or use
contraceptive methods with a failure rate of less than 1% during the treatment period and
for at least 6 months after the last dose.
If a female patient has menstruation and has not reached menopause (continuous absence of
menstruation for =12 months without other reasons), and has not undergone sterilization
surgery (removal of ovaries and/or uterus), she is considered to be of childbearing
potential.
Examples of contraceptive methods with a failure rate of less than 1% include bilateral
tubal ligation, male sterilization, hormone-based contraceptives that inhibit ovulation,
hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual restraint should be evaluated relative to the duration of the
clinical trial and the patient's preferred lifestyle and daily routine. Periodic abstinence
(such as calendar day, ovulation period, symptom temperature, or post-ovulation method) and
ejaculation outside the vagina are unacceptable contraceptive methods.
?Male: agree to abstain from sexual intercourse or use contraceptive measures, agree not to
donate sperm, as defined below: When the female partner is of childbearing potential, male
patients must abstain during the treatment period and for 6 months after the last dose, or
use a condom plus other contraceptive methods to achieve a failure rate of less than 1%.
Male patients must also agree not to donate sperm during the same period. When the female
partner is already pregnant, male patients must abstain or use a condom to prevent fetal
exposure to the study during the treatment period and for 6 months after the last dose.
The reliability of sexual restraint should be evaluated relative to the duration of the
clinical trial and the patient's preferred lifestyle and daily routine. Periodic abstinence
(such as calendar day, ovulation period, symptom temperature, or post-ovulation method) and
ejaculation outside the vagina are unacceptable contraceptive methods.
Exclusion Criteria:
- Previous systemic treatment received.
- ECOG score > 1.
- Pancreatic cancer.
- Pregnant (positive pregnancy test before medication) or breastfeeding women.
- Known allergy or intolerance to recombinant humanized PD-1 monoclonal antibody drugs,
lenvatinib and its components (or any excipients).
- Received local anti-tumor treatment within 4 weeks before the first study drug
treatment, including but not limited to surgery, radiotherapy, hepatic artery
embolization, TACE, hepatic artery infusion, radiofrequency ablation, cryoablation, or
percutaneous ethanol injection (allowing palliative radiotherapy for bone metastases
at least 2 weeks before study drug treatment).
- Previous or existing grade 3 or higher gastrointestinal fistula or
non-gastrointestinal fistula (such as skin) according to CTCAE 5.0 criteria.
Multiple factors affecting oral administration of lenvatinib (such as inability to swallow,
chronic diarrhea and intestinal obstruction, or other conditions that significantly affect
drug intake and absorption).
- Major surgery (except biopsy) has been performed within 4 weeks before the first study
drug treatment, or the surgical incision has not completely healed; minor surgery
(such as simple excision, biopsy, etc.) was performed within 7 days before the first
study intervention.
- Significant cardiovascular and cerebrovascular diseases, including but not limited to
acute myocardial infarction, severe/unstable angina pectoris, cerebrovascular
accidents or transient ischemic attacks within 6 months before enrollment, congestive
heart failure (New York Heart Association classification =2), arrhythmia requiring
antiarrhythmic drugs (except beta blockers or digoxin), and repeated electrocardiogram
showing QTc interval >480 milliseconds (ms).
Hepatic or renal dysfunction, with manifestations such as jaundice, ascites, and/or
bilirubin >3×ULN, creatinine ratio >3.5g/24 hours, or renal failure requiring blood or
peritoneal dialysis, and/or urinary routine showing urine protein =++ or confirmed 24-hour
urine protein quantification >1.0g.
- Persistent infection > grade 2 (CTCAE 5.0).
- History of thrombotic events (including stroke and/or transient ischemic attacks)
within the past 6 months.
- Poorly controlled hypertension (systolic blood pressure >160mmHg, diastolic blood
pressure >100mmHg) despite treatment with antihypertensive medications.
Active autoimmune disease or history of autoimmune disease within the past 2 years;
participants with active, known, or suspected autoimmune diseases that may affect important
organ function or require systemic immunosuppressive therapy are excluded, including but
not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, antiphospholipid syndrome associated with thrombosis,
Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis,
vasculitis, or glomerulonephritis. However, participants with type 1 diabetes,
hypothyroidism requiring only hormone replacement, skin diseases that do not require
systemic treatment (such as vitiligo, psoriasis, or alopecia) or participants who will not
relapse without external triggering factors are allowed. Replacement therapy (such as
thyroid hormone, insulin, or physiological corticosteroid replacement therapy for adrenal
or pituitary insufficiency) is not considered a form of systemic treatment.
?Known active central nervous system (CNS) metastasis and/or carcinomatous meningitis.
Participants with previously treated brain metastases may participate as long as they are
stable (evidence of no progression on imaging at least 4 weeks before the first trial
treatment and any neurological symptoms have returned to baseline), have no evidence of new
or enlarging brain metastases, and have not used steroids for at least 7 days before trial
treatment. This exception does not include carcinomatous meningitis, which is excluded
regardless of clinical stability. Participants with known or untreated brain metastases or
epilepsy requiring medication are also excluded.
Planned or prior organ or allogeneic bone marrow transplantation. Known history of active
tuberculosis (Mycobacterium tuberculosis). History of gastrointestinal bleeding within the
past 6 months or clear evidence of gastrointestinal bleeding tendencies, such as bleeding
esophageal varices, locally active gastrointestinal ulcerative lesions, fecal occult blood
=(++), cannot be included; if fecal occult blood (+), gastroscopy is required; evidence or
history of bleeding mechanism disorders of grade =3 (CTCAE 5.0), or other bleeding
disorders.
- Known human immunodeficiency virus (HIV) infection.
- Known active hepatitis B or C infection and not receiving regular treatment.
- During the screening period, HBV DNA =2000 IU/ml (or =104 copies/ml) must be reduced
to <2000 IU/ml (or <104 copies/ml) with entecavir before enrollment. For eligible
participants with Anti-HBc (+)/HBsAg (+)/HBV DNA< 2000 IU/ml or Anti-HBc (+)/HBsAg
(-)/HBV DNA< 2000 IU/ml, antiviral therapy must be administered during the trial
period using the original medication or entecavir or tenofovir.
- Severe non-healing wounds, ulcers, or fractures.
- History of substance abuse or any medical, psychological, or social condition that may
affect the study, patient compliance, or endanger patient safety.
- Unresolved toxicity of grade >1 (CTCAE 5.0) caused by any prior treatment/procedure,
except for hair loss, anemia, and hypothyroidism.
- Severe non-healing wounds, ulcers, or fractures.
- Objective evidence of severe pulmonary impairment, such as a history of severe
pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, or
drug-related pneumonia.
- Treatment with a strong CYP3A4 inhibitor (e.g., clarithromycin, indinavir,
itraconazole, lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole,
etc.) within 7 days before participating in the study, or treatment with a strong
CYP3A4 inducer (e.g., phenytoin, phenobarbital, primidone, carbamazepine, rifampin,
rifabutin, rifapentine, or St. John's Wort) within 12 days before participating in the
study.
- Concomitant malignancy, except for previously treated skin basal cell carcinoma,
squamous cell carcinoma, carcinoma in situ of the breast or cervix, superficial
bladder cancer that has been treated, and prostate cancer that has been treated with
surgery and has a normal range of PSA tumor markers, or any other malignancy that has
not been cured within the past 5 years.
- The investigator determines that the participant is unsuitable for the study based on
overall medical condition.
- Concurrent participation in another clinical study.
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