Inclusion Criteria:
* Patients must have pathologically confirmed GIST.
* In the Phase Ib portion, must have locally advanced or metastatic GIST and have progressed on imatinib.
* In the Phase II portion, patients must be newly diagnosed or treatment naïve, or have been off adjuvant imatinib therapy for at least 3 months. Patients with newly diagnosed GIST and who had been on imatinib for up to 4 weeks prior to signing the consent are allowed to enroll in order to expedite accrual.
* Patients must be at least 18 years of age.
* Disease must be measurable by RECIST 1.1.
* ECOG Performance Status 0 or 1.
* Adequate renal, hepatic, and hematologic function as the following: Serum Creatinine ≤ 1.5 mg/dL, Total Serum Bilirubin ≤ 1.5 x upper limit of normal (ULN), Serum AST (SGOT) and/or ALT (SGPT) ≤ 2.5 x ULN (or ≤ 5.0 x ULN if considered due to tumor)ANC ≥ 1500/mm3, Platelets ≥ 100,000/mm3, and hemoglobin ≥ 10g/dL.
* Patients of childbearing potential must have a negative serum pregnancy test within 14 days of treatment. Patients must agree to use a reliable barrier method of birth control during and for 3 months following the last dose of study drug.
* Patient must have adequate cardiac function (left ventricular ejection fraction (LVEF) ≥50% as determined by a multigated acquisition (MUGA) scan or echocardiogram; and QTc interval≤480 ms.
* Patient must be able to take oral medications.
* Patients must sign an informed consent document.
Exclusion Criteria:
* In the phase II portion of the study, patients that have been previously treated with any systemic therapy for GIST are not permitted to enroll, with the exception of adjuvant imatinib systemic therapy or exposure to imatinib within 4 weeks of signing consent.
* Patients have a severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection).
* Patients have known brain metastasis.
* Patients have known chronic liver disease (i.e., cirrhosis)
* Known positive serology for HIV, active Hepatitis B, and/or active Hepatitis C infection.
* Other active malignancy (other than malignancies, which the investigator determines are unlikely to interfere with treatment and safety analysis).
* Patients have a history or current evidence of Central Serous Retinopathy (CSR) or retinal vein occlusion (RVO) or predisposing factors to CSR or RVO (i.e. uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, hyperviscosity or hypercoagulability syndromes).
* History of retinal degenerative disease.
* History of Gilbert's syndrome.
* Patients have clinically significant cardiovascular disease, including any of the following:
1\) History of acute coronary syndrome including myocardial infarction, unstable angina, CABG, coronary angioplasty or stenting \< 6 months prior to screening; 2) symptomatic chronic heart failure (New York Heart Association Criteria, Class II-IV); 3) evidence of clinically significant cardiac arrhythmias and/or conduction abnormalities \< 6 months prior to screening except atrial fibrillation (AF) and paroxysmal supraventricular tachycardia (PSVT).
* Uncontrolled arterial hypertension despite appropriate medical therapy.
* Patients who have neuromuscular disorders that are associated with elevated creatinine phosphokinase (i.e. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
* Uncontrolled impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome). Patients who have ulcerative colitis or other gastrointestinal diseases that are well controlled are allowed to proceed with this study.
* Prior therapy with a MEK inhibitor.
* Patients had a major surgery within 3 weeks prior to study entry or who have not recovered from side effects of such procedure.
* Women who are pregnant or lactating.
* Sexually active males unless they use a condom during intercourse while taking the drug and for 15 days after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
* Patients with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.
