Inclusion Criteria:

          -  Male or female patients ≥18 years old

          -  GIST with failure or intolerance to imatinib or failure / intolerance to all three
             approved TKIs defined as:

          -  Histologically confirmed metastatic and/or unresectable GIST (harboring a primary KIT
             or PDGFRA-mutation) after failure or intolerance of imatinib (cohort A and B) or all
             three approved TKIs (cohort C). If prior TKI treatment was neoadjuvant therapy, then
             relapse must have occurred during the neoadjuvant therapy in order to consider it
             failed therapy

          -  Patients in Cohort A must have evidence of clinical resistance mutations in any other
             exon or no resistance mutation but evidence of progression by CT or MRI imaging.
             Patients in Cohort B must have evidence of an activating resistance mutation in KIT
             exon 13 (by direct sequencing of progressing lesions or by liquid biopsy).

          -  Measurable disease per modified RECIST 1.1 (Demetri et al., 2013). A lesion in a
             previously irradiated area is eligible to be considered as measurable disease as long
             as there is objective evidence of progression of the lesion prior to study enrollment

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

          -  Adequate hepatic function as defined by the following criteria:

          -  Total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert's
             syndrome

          -  ALT (Alanine Aminotransferase) ≤2.5×ULN or ≤5.0xULN if liver metastases are present

          -  AST (Aspartate Aminotransferase) ≤2.5×ULN or ≤5.0xULN if liver metastases are present

          -  Adequate renal function as defined by the following criterion:

          -  Serum creatinine <1.5×ULN

          -  Adequate pancreatic function as defined by the following criterion:

          -  Serum lipase and amylase ≤1.5×ULN

          -  For patients of childbearing potential, a negative pregnancy test must be documented
             prior to enrollment

          -  Female and male patients who are fertile must agree to use an effective form of
             contraception with their sexual partners from signing of the informed consent form for
             this study through 4 months after the End-of-Treatment Provision of written informed
             consent

          -  Willingness and ability to comply with scheduled visits and study procedures

          -  Fully recovered (≤ Grade 1 or returned to baseline or deemed irreversible) from the
             acute effects of prior cancer therapy before initiation of the study drug treatment

        Exclusion Criteria:

          1. Patients lacking primary mutations of KIT or PDGFRA (including
             Succinate-Dehydrogenase(SDH)-deficient GIST)

          2. Major surgery within 28 days prior to initiating therapy

          3. History of bleeding disorder

          4. History of acute pancreatitis within 1 year of study or history of chronic
             pancreatitis

          5. History of alcohol and /or drug abuse

          6. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL)

          7. Clinically significant, uncontrolled, or active cardiovascular disease, or other
             arterial or venous vascular occlusion diseases specifically including, but not
             restricted to: Myocardial infarction within 6 months prior to enrollment Unstable
             angina within 6 months prior to enrollment Congestive heart failure within 6 months
             prior to enrollment, or left ventricular ejection fraction (LVEF) less than lower
             limit of normal per local institutional standards History of clinically significant
             (as determined by the treating physician) atrial arrhythmia Any history of ventricular
             arrhythmia Cerebrovascular accident or transient ischemic attack within 6 months prior
             to enrollment Any history of peripheral arterial occlusive disease requiring
             revascularization Venous thromboembolism including deep venous thrombosis or pulmonary
             embolism within 6 months prior to enrollment

          8. Uncontrolled hypertension (diastolic blood pressure >90 mm Hg; systolic >140 mm Hg).
             Patients with hypertension should be under treatment on study entry to effect blood
             pressure control

          9. Taking medications that are known to be associated with Torsades de Pointes (Appendix
             A)

         10. Taking any medications or herbal supplements that are known to be strong inhibitors of
             CYP3A4 within at least 14 days before the first dose of ponatinib (Appendix B)

         11. Ongoing or active infection. This includes but is not limited to the requirement for
             intravenous antibiotics

         12. Known history of human immunodeficiency virus. Testing is not required in the absence
             of prior documentation or known history

         13. Pregnant or breastfeeding

         14. Malabsorption syndrome or other gastrointestinal illness that could affect oral
             absorption of the study drug

         15. Individuals with a history of a different malignancy, other than cervical cancer in
             situ, basal cell or squamous cell carcinoma of the skin, are ineligible, except if
             they have been disease-free for at least 5 years, and are deemed by the investigator
             to be at low risk for recurrence of that malignancy OR if the other primary malignancy
             is neither currently clinically significant nor requiring active intervention.

         16. Use of any approved TKIs or investigational agents within 2 weeks or 6 half-lives of
             the agent, whichever is longer, prior to receiving study drug

         17. Any condition or illness that, in the opinion of the investigator, would compromise
             patient safety or interfere with the evaluation of the drug

         18. History of apoplectic insult