A Phase IIa Study of the MEK Inhibitor Trametinib Monotherapy in the Treatment of Biliary Tract Cancers

This is a Phase IIa, open-label, single-arm, multi-center study to evaluate the efficacy and safety of orally administered MEK inhibitor trametinib as the second line in subjects with advanced or metastatic biliary tract cancers (BTC) in Japanese population. The primary endpoint of this study is 12 week non-progressive disease (PD) rate defined as the percentage of subjects without progression at Week 12. As a sub-study, pharmacokinetics (PK) of four tablets of 0.5 milligram (mg) tablet, or one tablet of 2 mg tablet to achieve 2 mg daily regimen will be assessed to evaluate the pharmacokinetics of trametinib in Japanese population.

Eligible subjects will be randomized to receive trametinib at the recommended Phase II dose of 2 mg every day as one 2 mg tablet or four 0.5 mg tablets on Day 1. From Day 2 until disease progression or withdrawal from the study treatment, all subjects will receive one tablet of 2 mg trametinib . Disease assessment will be performed every 8 week. Translational research is also planned to evaluate the potential blood or tumor tissue-derived biomarkers for biological activity, and sensitivity or resistance to treatment with trametinib .


Eligibility Criteria:
Inclusion Criteria:

* Male or female of age 20 years or older inclusive, at the time of signing the informed consent.
* Japanese patients with histologically or cytologically confirmed cholangiocarcinoma (intra- or extrahepatic) or gallbladder cancer or ampulla of Vater cancer are eligible for which all of the following criteria have to be met: Nonresectable, recurrent, and/or metastatic disease.
* Disease progression after up to two lines of systemic chemotherapies including no more than one line of gemcitabine-based chemotherapy. Note: Systemic therapy in adjuvant setting is not allowed as prior therapy.
* More than 21 days have elapsed since any prior anti-tumor therapy.
* At least one of the tumor samples for archived tissue at initial diagnosis or archived tissue at recent progression or fresh biopsy at recent progression (collect within 21 days from randomization if none of the archived tissues are available) is available prior to randomization to provide for translational research.
* Measurable disease, i.e. presenting with at least one measurable lesion per the RESIST 1.1.
* Performance status score of ≤1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
* Estimated life expectancy of at least 12 weeks.
* All prior treatment- related toxicities must be common terminology criteria for adverse events (CTCAE) (Version 4.0) ≤ Grade 1 (except alopecia) at the time of randomization.
* Negative for hepatitis C virus (HCV) test, hepatitis B surface (HBs) antigen, hepatitis virus Bc (HBc) antibody, and HBs antibody. HBs antigen-negative subjects who test positive for both HBc antibody and HBs antibody or either of them may be eligible when their HBV DNA quantification result is negative.
* Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
* Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment and agree to use effective contraception throughout the treatment period, and for 4 months after the last dose of study treatment.
* Adequate baseline organ function for haematological, hepatic, renal, cardiac systems.

Exclusion Criteria:

* History of another malignancy.
* Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
* Radiotherapy completed within 2 weeks prior to randomization.
* History of interstitial lung disease or pneumonitis.
* Having a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).
* Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 28 days prior to randomization and/or chemotherapy without the potential for delayed toxicity within 21days prior to randomization.
* Any prior use of any MEK inhibitors (including but not limited to trametinib, AZD6244 (selumetinib), RDEA119).
* Current use of a prohibited medication.
* History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
* Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.
* Known Human Immunodeficiency Virus (HIV) infection. History or evidence of cardiovascular risk including a QT interval corrected for heart rate using the Bazett's formula (QTcB) interval \>480 msec, history or evidence of current clinically significant uncontrolled arrhythmias, history of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization, history or evidence of current \> or = Class II congestive heart failure as defined by New York Heart Association, treatment refractory hypertension defined as a blood pressure of systolic\> 140 mmHg and/or diastolic \> 90 mmHg which cannot be controlled by anti-hypertensive therapy, subjects with intra-cardiac defibrillators or permanent pacemakers.
* Known cardiac metastases.