Phase II Study of Refametinib, a MEK Inhibitor, as Second-line Treatment in Advanced Biliary Tract Adenocarcinoma

Inclusion Criteria:

1. age ≥ 18

2. histologically or cytologically confirmed adenocarcinoma of biliary tract

3. unresectable or metastatic

4. ECOG performance status of 0~2

5. measurable lesion per RECIST 1.1 criteria

6. adequate marrow, hepatic, renal functions

7. normal range of cardiac function confirmed by echocardiogram within 1 year (LVEF ≥50)

8. Child-Pugh Class A in case of liver cirrhosis

9. One prior treatment of cytotoxic chemotherapy (including adjuvant treatment within 12months)

10. Resolution of all acute toxic effects of any prior therapy to Common Toxicity Criteriafor Adverse Events (CTCAE 4.03) ≤ grade 1.

11. provision of a signed written informed consent

Exclusion Criteria:

1. History of cardiac disease

2. Ongoing infection > Grade 2 according to NCI-CTCAE version 4.03. Hepatitis B isallowed if no active replication (defined as abnormal ALT >2xULN associated with HBVDNA >20,000 IU/mL) is present

3. Severe co-morbid illness and/or active infections including active hepatitis C andhuman immunodeficiency virus (HIV) infection

4. History of interstitial lung disease (ILD).

5. Any cancer curatively treated < 3 years prior to study entry, except cervicalcarcinoma in situ, treated basal cell carcinoma, and superficial bladder tumors (Staging: Ta, Tis and T1).

6. Renal failure requiring hemo- or peritoneal dialysis.

7. Clinically significant GI bleeding (CTCAE 4.03 grade 3 or higher) within 30 days priorto start of screening

8. Thrombotic or embolic events such as cerebrovascular accident (including transientischemic attacks) within 6 months prior to start of screening.

9. History of organ allograft, cornea transplantation will be allowed

10. Active CNS metastases not controllable with radiotherapy or corticosteroids

11. Visible retinal pathology as assessed by ophthalmologic exam that is considered a riskfactor for RVO or CSR.

12. Known history of hypersensitivity to study drugs

13. Any condition that was unstable or which could jeopardize the safety of the patientand his/her compliance in the study

14. Non-healing wound, ulcer, or bone fracture.

15. Patients with seizure disorder requiring medication.

16. Use of strong inhibitors of CYP3A4 and strong inducers of CYP3A4 should be stopped 2weeks before start of screening (see Appendix 1).

17. Acute steroid therapy or taper for any purpose (chronic steroid therapy is acceptableprovided that the dose is stable for 1 month before start of screening andthereafter).

18. Substance abuse, medical, psychological or social conditions that may interfere withthe patient's participation in the study or evaluation of the study results.

19. Pregnant or lactating women. Women of childbearing potential not employing adequatecontraception. Women of childbearing potential must have a negative serum pregnancytest performed within 7 days prior to start of study treatment and a negative resultmust be documented before first dose of study drug.