The purpose of this study is to test the safety and tolerability of the combination of pexidartinib and MEK162. This study tests different doses of pexidartinib in combination with different doses of MEK162 to see which dose combination of these drugs is safe and best tolerated in people.

Inclusion Criteria:

• Patients must have pathologically confirmed GIST.

• In the Phase I dose escalation study, must have locally advanced, unresectable or metastatic GIST and have progressed on imatinib.

• In the dose expansion portion of the phase I study, patients must have locally advanced, unresectable or metastatic GIST that is resistant to imatinib. This population includes patients who have not been treated with imatinib (imatinib-naïve) but considered to have primary resistance to imatinib, i.e. KIT/PDGFRA wild-type GIST, and patients with imatinib-refractory disease, i.e. has had prior treatment with imatinib.

• Patients must be at least 18 years of age.

• Disease must be measurable by RECIST 1.1.

• ECOG Performance Status 0 or 1.

• Patient must be able to take oral medications.

• Patients must sign an informed consent document.

• Adequate renal, hepatic, and hematologic function defined by:

  • 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/mm^3
  • Platelets ≥ 100,000/mm^3
  • Hemoglobin ≥ 9g/dL

• Patients of childbearing potential are permitted in the study so long as they consent to avoid getting their partner pregnant or becoming pregnant, respectively, by using a reliable methods of contraception during and for 3 months following the last dose of the study drugs.

• Females of childbearing potential must have a negative serum pregnancy test within 14 days of treatment.

• Women of non-childbearing potential may be included if they are either surgically sterile or considered postmenopausal. Women who have documentation of at least 12 months of spontaneous amenorrhea and have an FSH level >40mIU/mL will be considered postmenopausal.

Exclusion Criteria:

• Patients have a severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection).
• Patients have known active brain metastasis.
• Leptomeningeal disease
• Patients have known chronic liver disease (i.e., cirrhosis)
• Active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus or known active or chronic infection with human immunodeficiency virus. Prior hepatitis infection that has been treated with highly effective therapy with no evidence of residual infection (including undetectable viral loads while on antiviral therapy) and with normal liver function (ALT, AST, total and direct bilirubin \