The purpose of this study is to evaluate the efficacy and safety of ponatinib in participants with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) following failure of prior tyrosine kinase inhibitor (TKI) therapy.

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

The primary objective is to assess clinical benefit in participants with KIT exon 11-mutant GIST (Cohort A) defined as clinical benefit rate (CBR), which is the composite of complete response (CR), partial response (PR) and stable disease (SD) lasting greater than or equal to (>=) 16 weeks per modified response evaluation criteria in solid tumors (RECIST 1.1) as a measure of disease control. The secondary objective is to assess clinical benefit in participants with GIST that lacks an activating KIT exon 11 mutation (Cohort B) and in the total participant population. The efficacy assessments are tumor response using RECIST Version 1.1, modified for GIST and assessment of progression-free survival (PFS) and overall survival (OS). The safety assessments include routine physical and laboratory evaluations, electrocardiograms (ECGs), echocardiograms (ECHOs), and adverse event (AE) monitoring. Other assessments include optional 18F fluorodeoxyglucose positron emission tomography (FDG-PET); optional pre- and post-treatment tumor biopsy for pharmacodynamic studies; and pharmacokinetics (PK). It is estimated that accrual will be complete within 1 year; the total estimated duration of the study is 3 years.

Inclusion Criteria:

1. Male or female participants >=18 years old.

2. GIST with failure of prior TKI therapy defined as:

   1. Histologically confirmed metastatic and/or unresectable GIST after experiencing failure of prior treatment with imatinib, sunitinib, and regorafenib. If prior TKI treatment was neoadjuvant therapy, then relapse must have occurred during the neoadjuvant therapy in order to consider it failed therapy.
   2. Participants in Cohort A must have evidence of activation mutations in exon 11 of KIT in their tumors. Demonstration of an exon 11 mutation may be based on prior assessment or on evaluation of a tumor sample after enrollment in this study. Participants in Cohort B must have GIST that lacks activating mutations in KIT exon 11, but may have evidence of another activating mutation such as in KIT exon 9 or in PDGFR-α. Participants may be enrolled in the study prior to determination of the appropriate cohort (as long as both cohorts are open for enrollment).

3. Measurable disease per modified RECIST 1.1. 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.

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

5. Adequate hepatic function as defined by the following criteria:

   1. Total serum bilirubin less than or equal to (<=) 1.5*Upper Limit of Normal (ULN), unless due to Gilbert's syndrome.
   2. ALT <=2.5*ULN or <=5.0*ULN if liver metastases are present.
   3. AST <=2.5*ULN or <=5.0*ULN if liver metastases are present.

6. Adequate renal function as defined by the following criterion:

   a. Serum creatinine <1.5*ULN.

7. Adequate pancreatic function as defined by the following criterion:

   a. Serum lipase and amylase <=1.5*ULN.

8. For participants of childbearing potential, a negative pregnancy test must be documented prior to enrollment.

9. Female and male participants 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.

10. Provision of written informed consent.

11. Willingness and ability to comply with scheduled visits and study procedures

12. Fully recovered (<= Grade 1 or returned to baseline or deemed irreversible) from the acute effects of prior cancer therapy before initiation of study drug.

Exclusion Criteria:

1. Major surgery within 28 days prior to initiating therapy

2. History of bleeding disorder

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

4. History of alcohol abuse

5. Uncontrolled hypertriglyceridemia (triglycerides >450 milligram per deciliter [mg/dL])

6. Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

   1. Any history of myocardial infarction (MI).
   2. Any history of unstable angina.
   3. 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 within 6 months prior to enrollment.
   4. History of clinically significant (as determined by the treating physician) atrial arrhythmia.
   5. Any history of ventricular arrhythmia.
   6. Any history of cerebrovascular accident or transient ischemic attack (TIA).
   7. Any history of peripheral vascular infarction, including visceral infarction; or any revascularization procedure of any vasculature, including the placement of a stent.
   8. Venous thromboembolism including deep venous thrombosis (DVT) or pulmonary embolism within 6 months prior to enrollment.

7. Uncontrolled hypertension (diastolic blood pressure greater than (>) 90 millimeter of mercury [mmHg]; systolic >150 mmHg). Participants with hypertension should be under treatment on study entry to effect blood pressure control.

8. Taking medications with a known risk of Torsades de Pointes.

9. Taking any medications or herbal supplements that are known to be strong inhibitors of cytochrome P3A4 (CYP3A4) within at least 14 days before the first dose of ponatinib.

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

11. Known history of human immunodeficiency virus (HIV). Testing is not required in the absence of prior documentation or known history.

12. Pregnant or breastfeeding.

13. Malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drugs.

14. 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.

15. 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.

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

The intention to treat (ITT) population included all participants who received any dose of ponatinib in the study.

Treatment-emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug and no more than 30 days after the last dose of study drug (up to 3 years)

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Study is ongoing. Uncontrolled Study. Small participant population. Non-randomized.