Lenvatinib Plus Paclitaxel for Patients With Advanced Biliary Tract Cancer Who Failed to Gemcitabine-based Treatment

Inclusion Criteria:

• 1. Patients with age ≧20 years old.
• 2.Histologically confirmed biliary tract cancer which is locally advanced, recurrentor metastatic disease. The disease entities include intrahepatic cholangiocarcinoma,perihilar cholangiocarcinoma, distal bile duct cholangiocarcinoma, Ampulla of Vatercancer, and gallbladder cancer. 3.Documented disease progression during or within 6 months after gemcitabine-based (regimens containing gemcitabine plus cisplatin, gemcitabine plus S-1, or gemcitabineplus oxaliplatin) chemotherapy. Patient who has received antiangiogenetic agent (bevacizumab, ramucirumab, lenvatinib), taxane-based chemotherapy, or more than 1 lineof chemotherapy for locally advanced or metastatic biliary tract cancer is ineligible.

4. Documented measurable disease as defined by RECIST v1.1. 5. Baseline EasternCooperative Oncology Group performance status score 0-1. 6. Patient has lifeexpectancy of at least 12 weeks. 7. Adequate hematologic parameters, and hepatic andrenal functions defined as 7.1: Hepatic: alanine aminotransferase (ALT) and aspartateaminotransferase (AST) 2.5 x upper limit of normal (ULN) ( 5.0 x ULN if attributableto liver metastases), total bilirubin 3 mg/dL.

7.2: Renal: serum creatinine level 1.5 x ULN or creatinine clearance > 30 ml/min [calculated by either Cockcroft-Gault equation [(140-age) x body weight (kg) x (1 if maleor 0.85 if female) / (72 x serum creatinine level, mg/dl)] or 24-hour urine test].

7.3: Hematological: white blood cell 3,000/ul, absolute neutrophil count (ANC) 1,500/ul,hemoglobin 9 g/dl and platelet count 90,000/ul. 8. Adequate controlled blood pressure (BP), defined as BP≦140/90 mmHg at screening and nochange in antihypertensive medication within 1 week prior to the cycle1/day 1. 9. Adequate blood coagulation function, defined as prothrombin time internationalnormalized ratio (PT INR)≦ 2.3. 10. Normal ECG or ECG without any clinical significant findings 11. Able to understand andsign an informed consent (or have a legal representative who is able to do so). 12. Women or men of reproductive potential should agree to use an effective contraceptivemethod

Exclusion Criteria:

• 1. Patients who have major abdominal surgery, radiotherapy or other investigatingagents within 2 weeks are not eligible. Patients who have palliative radiotherapy willbe eligible if the irradiated area does not involve the only lesion of measurable /evaluable disease.

2. Patients having liver dysfunction with Child-Pugh score ≧7. 3. Patients withgastrointestinal malabsorption or condition that might affect the absorption oflenvatinib in the opinion of the investigator.
3. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage.Patients with tumor invasion/infiltration of major blood vessels should be excludedbecause of the potential risk of severe hemorrhage associated with tumorshrinkage/necrosis following therapy.
4. Uncontrolled blood pressure (systolic BP>140 mmHg or diastolic BP>90 mmHg) in spiteof an optimized regimen of antihypertensive medication.
5. Significant cardiovascular impairment: history of congestive heart failure greaterthan New York Heart Association (NYHA) Class II, unstable angina, myocardialinfarction or stroke within 6 months, or cardiac arrhythmia requiring medicaltreatment.
6. Patients having > 1+ proteinuria on urine dipstick testing will undergo 24 h urinecollection for quantitative assessment of proteinuria. Subjects with urine protein≧ 1g/24 h will be ineligible.
7. Patients with electrolyte abnormalities that have not been corrected. 9. Patientswith metastatic lesion in central nervous system. 10. Patients with active infection.
8. Subjects who have not recovered adequately from any toxicity from other anti-cancer treatment regimens and/or complications from major surgery prior to startingtherapy.
9. Patients who have peripheral neuropathy > grade I of any etiology 13. Patients whohave serious concomitant systemic disorders incompatible with the study, i.e. poorlycontrolled diabetes mellitus, auto-immune disorders, or other condition that in theopinion of the investigator would preclude the subject's participation in the study.
10. Patients who have other prior or concurrent malignancy except for adequatelytreated in situ carcinoma or basal cell carcinoma of skin, or any malignancy whichremains disease-free for 3 or more years after curative treatment.
11. Females who are breastfeeding or pregnant at screening or baseline. 16. Patientswith psychiatric illness which would preclude study compliance.