Inclusion Criteria includes:
- Age ≥ 18 years
- Histologically confirmed diagnosis of advanced GIST
- ECOG performance status of 0-1
- Measurable disease as per modified RECIST 1.1
- Prior disease progression on at least imatinib and sunitinib. Maximum of 3 prior kinase inhibitors allowed for treatment of advanced disease. Patients with prior exposure to pazopanib or MEK inhibitors are not eligible.
- Adequate organ systems function within 14 days (and 72 hours) prior to start of protocol therapy
- Patients must provide written informed consent prior to performance of study-specific procedures or assessments and must be willing to comply with treatment and follow-up.
- Women of childbearing potential must have a negative urine or blood pregnancy test within 7 days of Cycle 1 Day 1. Fertile men and women of childbearing potential must agree to use effective contraception as defined in Section 7 during the study and for 4 months following the last dose of study drugs in both sexes.
- Life expectancy of ≥ 3months
Exclusion Criteria includes:
- Prior malignancy.
- Central nervous system (CNS) metastases at baseline, with the exception of those patients who have previously-treated CNS metastases (surgery +/- radiotherapy, radiosurgery, or gamma knife) and who meet both of the following criteria:
are asymptomatic and have no requirement for steroids or enzyme-inducing anticonvulsants in at least 3 months prior to screening.
- Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding
- Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product
- QTcB interval > 480 msec
- History of one or more of the following cardiovascular conditions within the past 6 months:
Cardiac angioplasty or stenting Myocardial infarction Unstable angina Coronary artery bypass graft surgery Symptomatic peripheral vascular disease Class II, III, or IV congestive heart failure, as defined by the New York Heart Association (NYHA) Uncontrolled arrhythmias
- Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥ 140 mm Hg or diastolic blood pressure (DBP) of ≥ 90 mmHg].
- History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
- Major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement are not considered to be major surgery).
- Evidence of active bleeding or bleeding diathesis.
- Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage.
- Recent hemoptysis (≥ 1/2 teaspoon of red blood within 8 weeks before first dose of study drug)
- Any serious and or unstable pre-existing medical, psychiatric, or other condition that could interfere with the patient's safety, provision of informed consent, or compliance to study procedures.
- Unable or unwilling to discontinue use of prohibited medications listed in Section 5.2.4 for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study.
- Treatment with any of the following anti-cancer therapies:
- Radiation therapy or tumor embolization within 14 days prior to the first dose of OR
- Chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug.
- Ipilimumab must have been discontinued at least 8 weeks prior to initiation of treatment with trametinib
- Administration of any non-oncologic investigational drug within 30 days or five half-lives (whichever is longer) prior to the first dose of study drug.
- Any ongoing toxicity from prior anti-cancer therapy that is ≥ Grade 1 and/or that is progressing in severity, except alopecia.
- Inability to swallow and retain oral medication
- Known or suspected allergy or hypersensitivity to pazopanib, trametinib (GSK1120212), or excipients of the formulations given during the course of this trial.
- History of interstitial lung disease or pneumonitis, intracardiac defibrillators, known HIV, active HBV or HCV infections, history of retinal vein occlusion, symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.