NGS as the First-line Treatment in Advanced Biliary Tract Cancer

The primary endpoint will be evaluating overall response rate (ORR) of nivolumab in combination with gemcitabine and TS-1 in patients with advanced BTC. Simon's two-stage design will be used. If there are 3 or fewer subjects with controlled disease in these 19 patients, the study will be stopped. Otherwise, 25 additional patients will be accrued for a total of 44. The null hypothesis will be rejected if 11 or more subjects with controlled disease are observed in 44 patients.

Inclusion criteria

• histologically confirmed locally advanced or metastatic biliary tract carcinoma (including intrahepatic bile duct, extrahepatic bile duct, gallbladder and ampulla of vater);
• no history of chemotherapy or radiotherapy for biliary tract cancer, except those delivered as adjuvant setting that completed at least 6 months before documentation of recurrence by imaging study.
• presence of at least one measurable tumor lesion which is defined as lesions that can be accurately measured in at least 1 dimension with longest diameter (LD) ≥20 mm using conventional techniques or ≥10 mm with spiral CT and MRI; measurable lymph nodes must be ≥15 mm in the short axis;
• adequate hematopoietic function which is defined as below:

• hemoglobin level ≥ 9 g/dL;
• absolute neutrophil count (ANC) ≥ 1,500/mm3;
• platelet count ≥ 100,000/mm3;
• adequate hepatic function which is defined as below:

• total bilirubin < 2 mg/dL;
• Alanine aminotransferase (ALT) ≤ 3 x ULN; ≤ 5 x ULN if liver metastasis
• adequate renal function: creatinine clearance rate (CCr) ≥ 50 mL/min ((based upon Cockroft-Gault formula or 24-hour urine collection); < Cockroft-Gault formula > Male: ((140 - age) × weight [kg])/(72 × serum creatinine[mg/dL]) Female: 0.85 x estimate for male
• age of 20 years or above;
• ECOG performance status 0-1;
• life expectancy of at least 12 weeks;
• patients with childbearing potential shall have effective contraception for both the patient and his or her partner during the study.
• ability to understand and willingness to sign a written informed consent document.

Exclusion criteria

• other malignancy within the past 5 years except for adequately treated basal or squamous cell skin cancer or cervical cancer in situ;
• history or known presence of brain metastasis;
• presence of grade 2 or above ascites or pleural effusion;
• presence of grade 2 or above diarrhea;
• presence of mental disease or psychotic manifestation;
• active or uncontrolled infection;
• significant medical conditions that is contraindicated to study medication or render patient at high risk from treatment complications based on investigator's discretion;
• pregnant women or nursing mothers, or positive pregnancy test for women of childbearing potential.
• History of active autoimmune disease within 3 years or long-term use of steroid more than prednisolone 10mg/day.