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

Refametinib will be administered orally at the starting dose of 50 mg twice daily on a continuous daily dosing schedule.

Self-administration of refametinib tablets will take place on an outpatient basis. Patients experiencing dose-limiting toxicity attributed to study medication should have at least 1-week treatment breaks inserted into the continuous daily dosing period as needed and/or may be interrupted or reduced depending on individual tolerability.

Inclusion criteria

• age ≥ 18
• histologically or cytologically confirmed adenocarcinoma of biliary tract
• unresectable or metastatic
• ECOG performance status of 0~2
• measurable lesion per RECIST 1.1 criteria
• adequate marrow, hepatic, renal functions
• normal range of cardiac function confirmed by echocardiogram within 1 year (LVEF ≥50)
• Child-Pugh Class A in case of liver cirrhosis
• One prior treatment of cytotoxic chemotherapy (including adjuvant treatment within 12 months)
• Resolution of all acute toxic effects of any prior therapy to Common Toxicity Criteria for Adverse Events (CTCAE 4.03) ≤ grade 1.
• provision of a signed written informed consent

Exclusion criteria

• History of cardiac disease
• Ongoing infection > Grade 2 according to NCI-CTCAE version 4.03. Hepatitis B is allowed if no active replication (defined as abnormal ALT >2xULN associated with HBV DNA >20,000 IU/mL) is present
• Severe co-morbid illness and/or active infections including active hepatitis C and human immunodeficiency virus (HIV) infection
• History of interstitial lung disease (ILD).
• Any cancer curatively treated < 3 years prior to study entry, except cervical carcinoma in situ, treated basal cell carcinoma, and superficial bladder tumors (Staging: Ta, Tis and T1).
• Renal failure requiring hemo- or peritoneal dialysis.
• Clinically significant GI bleeding (CTCAE 4.03 grade 3 or higher) within 30 days prior to start of screening
• Thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) within 6 months prior to start of screening.
• History of organ allograft, cornea transplantation will be allowed
• Active CNS metastases not controllable with radiotherapy or corticosteroids
• Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for RVO or CSR.
• Known history of hypersensitivity to study drugs
• Any condition that was unstable or which could jeopardize the safety of the patient and his/her compliance in the study
• Non-healing wound, ulcer, or bone fracture.
• Patients with seizure disorder requiring medication.
• Use of strong inhibitors of CYP3A4 and strong inducers of CYP3A4 should be stopped 2 weeks before start of screening (see Appendix 1).
• Acute steroid therapy or taper for any purpose (chronic steroid therapy is acceptable provided that the dose is stable for 1 month before start of screening and thereafter).
• Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
• Pregnant or lactating women. Women of childbearing potential not employing adequate contraception. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to start of study treatment and a negative result must be documented before first dose of study drug.