A Phase IIa Study of the MEK Inhibitor Trametinib Monotherapy in the Treatment of Biliary Tract Cancers
Condition: Cancer
MeSH terms: Biliary Tract Neoplasms
Intervention: Trametinib (single tablet); Trametinib (Multiple tablet)
Intervention description: The drug substance is blended with inert; The drug substance is blended with inert
Intervention MeSH terms: Trametinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 20 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: pharmacokinetics; second line monotherapy; GSK1120212 (trametinib); MEK inhibitor; locally advanced or metastatic biliary tract cancers

Summary:

      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.