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, orgemcitabine plus oxaliplatin) chemotherapy. Patient who has receivedantiangiogenetic agent (bevacizumab, ramucirumab, lenvatinib), taxane-basedchemotherapy, or more than 1 line of chemotherapy for locally advanced or metastaticbiliary 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, andhepatic and renal functions defined as 7.1: Hepatic: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2.5 x upper limit of normal (ULN) ( 5.0 x ULN if attributable to 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 male or 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 andno change 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 understandand sign an informed consent (or have a legal representative who is able to do so).

11. Women or men of reproductive potential should agree to use an effectivecontraceptive method

Exclusion Criteria:

1. Patients who have major abdominal surgery, radiotherapy or other investigatingagents within 2 weeks are not eligible. Patients who have palliativeradiotherapy will be eligible if the irradiated area does not involve the onlylesion 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 beexcluded because of the potential risk of severe hemorrhage associated withtumor shrinkage/necrosis following therapy.

4. Uncontrolled blood pressure (systolic BP>140 mmHg or diastolic BP>90 mmHg) inspite of an optimized regimen of antihypertensive medication.

5. Significant cardiovascular impairment: history of congestive heart failuregreater than New York Heart Association (NYHA) Class II, unstable angina,myocardial infarction or stroke within 6 months, or cardiac arrhythmiarequiring medical treatment.

6. Patients having > 1+ proteinuria on urine dipstick testing will undergo 24 hurine collection for quantitative assessment of proteinuria. Subjects withurine protein≧ 1 g/24 h will be ineligible.

7. Patients with electrolyte abnormalities that have not been corrected. 9.Patients with metastatic lesion in central nervous system. 10. Patients withactive infection. 11. Subjects who have not recovered adequately from anytoxicity from other anti- cancer treatment regimens and/or complications frommajor surgery prior to starting therapy.

8. Patients who have peripheral neuropathy > grade I of any etiology 13. Patientswho have serious concomitant systemic disorders incompatible with the study,i.e. poorly controlled diabetes mellitus, auto-immune disorders, or othercondition that in the opinion of the investigator would preclude the subject'sparticipation in the study.

9. Patients who have other prior or concurrent malignancy except for adequatelytreated in situ carcinoma or basal cell carcinoma of skin, or any malignancywhich remains disease-free for 3 or more years after curative treatment.

10. Females who are breastfeeding or pregnant at screening or baseline. 16.Patients with psychiatric illness which would preclude study compliance.