This is a non-randomized, open label, multi-center phase 2 study to evaluate the efficacy and safety of ponatinib in patients with metastatic and/or unresectable GIST after failure of prior TKI therapy. Patients whose tumors have an activating mutation in exon 11 of cellular KIT (KIT) will be enrolled into Cohort A. Patients whose tumors have other activating mutations will be enrolled into in Cohort B.