Pembrolizumab With or Without Lenvatinib or Chemotherapy in First-Line Treatment of Advanced Biliary Tract Cancer

Inclusion Criteria:

• • The subjects voluntarily participate in the study and agree to sign the informedconsent form, are compliant, and cooperate with follow-up.

• They are over 18 years of age and gender is not restricted when signing theinformed consent form.

• They have histologically confirmed unresectable advanced or metastatic biliarytract adenocarcinoma, including intrahepatic or extrahepatic cholangiocarcinomaand gallbladder cancer.

• Patients who are diagnosed with unresectable or metastatic disease and have notreceived prior treatment are eligible for inclusion.

• Patients who have undergone curative surgery and experienced disease recurrenceafter more than 6 months; or patients who have completed adjuvant therapy (chemotherapy and/or radiotherapy) and have been disease-free for more than 6months after completing adjuvant therapy are eligible for inclusion.

• They have at least one measurable lesion (as defined by RECIST 1.1, themeasurable lesion is a spiral CT scan long diameter ≥10mm or lymph node shortdiameter ≥15mm).

• Their ECOG score is 0-1 in the week prior to enrollment.

• Based on the investigator's assessment, their estimated survival time is ≥3months.

• 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 daysof antiviral treatment before participating in the study. HCV RNA-positivepatients 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 testresults obtained within 14 days before the start of the study (unless otherwisespecified):

• Hematology: (no blood transfusion, no G-CSF, no drug correction within 14 daysprior to screening) Hb ≥90 g/L; neutrophil count ≥1.5×109/L; PLT ≥100×109/L.

• Biochemistry: (no albumin transfusion within 14 days) Appropriate liverfunction: 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 patientswith confirmed Gilbert's syndrome. Any clinically significant biliaryobstruction should be resolved before randomization. Appropriate renalfunction: creatinine ≤1.5×ULN, or creatinine clearance rate (CCr) >50mL/min (using the standard Cockcroft-Gault formula): Female: CrCl = ((140 - age) xweight (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 intercourseor use contraceptive methods with a failure rate of less than 1% duringthe treatment period and for at least 6 months after the last dose. If afemale patient has menstruation and has not reached menopause (continuousabsence of menstruation for ≥12 months without other reasons), and has notundergone sterilization surgery (removal of ovaries and/or uterus), she isconsidered to be of childbearing potential. Examples of contraceptivemethods with a failure rate of less than 1% include bilateral tuballigation, male sterilization, hormone-based contraceptives that inhibitovulation, hormone-releasing intrauterine devices, and copper intrauterinedevices. The reliability of sexual restraint should be evaluated relativeto the duration of the clinical trial and the patient's preferredlifestyle and daily routine. Periodic abstinence (such as calendar day,ovulation period, symptom temperature, or post-ovulation method) andejaculation outside the vagina are unacceptable contraceptive methods.

• Male: agree to abstain from sexual intercourse or use contraceptivemeasures, agree not to donate sperm, as defined below: When the femalepartner is of childbearing potential, male patients must abstain duringthe treatment period and for 6 months after the last dose, or use a condomplus other contraceptive methods to achieve a failure rate of less than 1%. Male patients must also agree not to donate sperm during the sameperiod. When the female partner is already pregnant, male patients mustabstain or use a condom to prevent fetal exposure to the study during thetreatment period and for 6 months after the last dose. The reliability ofsexual restraint should be evaluated relative to the duration of theclinical trial and the patient's preferred lifestyle and daily routine.Periodic abstinence (such as calendar day, ovulation period, symptomtemperature, or post-ovulation method) and ejaculation outside the vaginaare 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 antibodydrugs, lenvatinib and its components (or any excipients).

• Received local anti-tumor treatment within 4 weeks before the first study drugtreatment, including but not limited to surgery, radiotherapy, hepatic arteryembolization, TACE, hepatic artery infusion, radiofrequency ablation,cryoablation, or percutaneous ethanol injection (allowing palliativeradiotherapy for bone metastases at least 2 weeks before study drug treatment).

• Previous or existing grade 3 or higher gastrointestinal fistula or nongastrointestinal 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 firststudy drug treatment, or the surgical incision has not completely healed; minorsurgery (such as simple excision, biopsy, etc.) was performed within 7 days beforethe first study intervention.

• Significant cardiovascular and cerebrovascular diseases, including but not limitedto acute myocardial infarction, severe/unstable angina pectoris, cerebrovascularaccidents or transient ischemic attacks within 6 months before enrollment,congestive heart failure (New York Heart Association classification ≥2), arrhythmiarequiring antiarrhythmic drugs (except beta blockers or digoxin), and repeatedelectrocardiogram showing QTc interval >480 milliseconds (ms). Hepatic or renaldysfunction, with manifestations such as jaundice, ascites, and/ or bilirubin >3×ULN, creatinine ratio >3.5g/24 hours, or renal failure requiring blood orperitoneal 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 bloodpressure >100mmHg) despite treatment with antihypertensive medications. Activeautoimmune disease or history of autoimmune disease within the past 2 years;participants with active, known, or suspected autoimmune diseases that may affectimportant 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 syndromeassociated 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 hormonereplacement, skin diseases that do not require systemic treatment (such as vitiligo,psoriasis, or alopecia) or participants who will not relapse without externaltriggering 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 carcinomatousmeningitis. Participants with previously treated brain metastases may participate aslong as they are stable (evidence of no progression on imaging at least 4 weeksbefore the first trial treatment and any neurological symptoms have returned tobaseline), have no evidence of new or enlarging brain metastases, and have not usedsteroids for at least 7 days before trial treatment. This exception does not includecarcinomatous meningitis, which is excluded regardless of clinical stability.Participants with known or untreated brain metastases or epilepsy requiringmedication are also excluded. Planned or prior organ or allogeneic bone marrowtransplantation. Known history of active tuberculosis (Mycobacterium tuberculosis).History of gastrointestinal bleeding within the past 6 months or clear evidence ofgastrointestinal bleeding tendencies, such as bleeding esophageal varices, locallyactive gastrointestinal ulcerative lesions, fecal occult blood ≥(++), cannot beincluded; if fecal occult blood (+), gastroscopy is required; evidence or history ofbleeding 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 bereduced to <2000 IU/ml (or <104 copies/ml) with entecavir before enrollment.For eligible participants with Anti-HBc (+)/HBsAg (+)/ HBV DNA< 2000 IU/ml orAnti-HBc (+)/HBsAg (-)/HBV DNA< 2000 IU/ ml, antiviral therapy must beadministered during the trial period using the original medication or entecaviror tenofovir.

• Severe non-healing wounds, ulcers, or fractures.

• History of substance abuse or any medical, psychological, or social conditionthat may affect the study, patient compliance, or endanger patient safety.

• Unresolved toxicity of grade >1 (CTCAE 5.0) caused by any priortreatment/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 severepulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiationpneumonitis, 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, ortreatment 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 cellcarcinoma, squamous cell carcinoma, carcinoma in situ of the breast or cervix,superficial bladder cancer that has been treated, and prostate cancer that hasbeen treated with surgery and has a normal range of PSA tumor markers, or anyother malignancy that has not been cured within the past 5 years.

• The investigator determines that the participant is unsuitable for the studybased on overall medical condition.

• Concurrent participation in another clinical study.