GIST: A Phase 2 Trial of Ponatinib in Participants With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor

• Sponsor: Ariad Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01874665
• Collaborator: (none)
• Enrollment: 45
• Locations: 4
• Arms: 2
• Actual Duration (Months): 37.8
• Patients Per Site: 11.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
GIST	Drug: Ponatinib	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Trial of Ponatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor Following Failure of Prior Tyrosine Kinase Inhibitor Therapy
• Actual Study Start Date: Jun 5, 2013
• Actual Primary Completion Date: Feb 28, 2015
• Actual Study Completion Date: Jul 31, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A Participants with KIT exon 11-mutant GIST.	Drug: Ponatinib; Ponatinib 45 mg, tablets, orally, once-daily.; Other Names: AP24534 Iclusig
Experimental: Cohort B Participants with GIST that lack KIT exon 11 mutations (Cohort B).	Drug: Ponatinib; Ponatinib 45 mg, tablets, orally, once-daily.; Other Names: AP24534 Iclusig

Outcome Measures

Primary Outcome Measures

1. Clinical Benefit Rate (CBR) in Cohort A [16 weeks after first dose]

   To assess clinical benefit rate in participants with KIT exon 11-mutant GIST.It is defined as the composite of complete response(CR),partial response(PR),and stable disease(SD) lasting >=16 weeks per modified Response Evaluation Criteria In Solid Tumors(RECIST) 1.1 as a measure of disease control.CR is complete disappearance of all target lesions and non-target disease, with the exception of nodal disease.All nodes, both target and non-target, must decrease to normal (short axis <10millimeter [mm]).No new lesions.PR is >=30% decrease under baseline of the sum of diameters of all target lesions.The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions.No unequivocal progression of non-target disease.No new lesions.SD is not qualifying for CR,PR,Progressive Disease(PD).PD is >=20% increase from the smallest prior sum of the longest diameter(SLD)and with >=5mm absolute increase, or appearance of a new lesion.

Secondary Outcome Measures

1. Clinical Benefit Rate (CBR) in Cohort B [16 weeks after first dose]

   To assess clinical benefit rate in participants with GIST that lacks KIT exon 11 mutations (Cohort B) and in the total participant population. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 millimeter [mm]). No new lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. SD was defined as not qualifying for CR, PR, PD.

2. Progression-free Survival (PFS) [From date of enrollment until the end of the study or disease progression or death due to any cause, whichever came first, assessed up to 3 years]

   PFS is defined as the duration of time from start of study drug administration to time of objective disease progression or death due to any cause, whichever may come first. To assess PFS in each cohort and in the total participant population.

3. Percentage of Participants With Objective Response Rate (ORR) [From date of enrollment until discontinuation or the end of the study, whichever came first, assessed up to 3 years]

   ORR is defined as the composite of CR and PR per Response Evaluation Criteria in RECIST 1.1, assessed for each cohort and in the total participant population. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions.

4. Overall Survival (OS) [From first dose of drug until the end of the study or death, whichever came first, assessed up to 3 years]

   OS is defined as the time interval between the first dose of study drug to death due to any cause. Overall survival was analyzed using the Kaplan-Meier method.

5. Number of Participants With Physical Examination [From date of enrollment until the End-of-Treatment, assessed up to 3 years]

6. Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Vital Sign Measurements [From date of enrollment until the End-of-Treatment, assessed up to 3 years]

7. Number of Participants With Worst Shift From Baseline Values to Post-baseline Values in Laboratory Parameters [From date of enrollment until the End-of-Treatment, assessed up to 3 years]

8. Number of Participants With TEAEs Related to Electrocardiogram (ECG) Findings [From date of enrollment until the End-of-Treatment, assessed up to 3 years]

9. Number of Participants With TEAEs Related to Echocardiography Parameter [From date of enrollment until the End-of-Treatment, assessed up to 3 years]

10. Number of Participants Reporting One or More TEAEs and Serious Adverse Event (SAE) [From date of enrollment until the End-of-Treatment, assessed up to 3 years]

11. Cmax, SS: Maximum Observed Plasma Concentration at Steady State for Ponatinib [Pre-dose and at multiple timepoints (up to 1 month) post-dose]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

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

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

3. 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.

4. 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).

5. 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.

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

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

8. Total serum bilirubin less than or equal to (<=) 1.5*Upper Limit of Normal (ULN), unless due to Gilbert's syndrome.

9. ALT <=2.5ULN or <=5.0ULN if liver metastases are present.

10. AST <=2.5ULN or <=5.0ULN if liver metastases are present.

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

1. Serum creatinine <1.5*ULN.

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

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

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

2. 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.

3. Provision of written informed consent.

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

5. 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:

7. Any history of myocardial infarction (MI).

8. Any history of unstable angina.

9. 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.

10. History of clinically significant (as determined by the treating physician) atrial arrhythmia.

11. Any history of ventricular arrhythmia.

12. Any history of cerebrovascular accident or transient ischemic attack (TIA).

13. Any history of peripheral vascular infarction, including visceral infarction; or any revascularization procedure of any vasculature, including the placement of a stent.

14. Venous thromboembolism including deep venous thrombosis (DVT) or pulmonary embolism within 6 months prior to enrollment.

15. 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.

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

17. 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.

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

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

20. Pregnant or breastfeeding.

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

22. 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.

23. 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.

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital, Site #047	Boston	Massachusetts	United States	02114
2	Dana-Farber Cancer Institute, Site #008	Boston	Massachusetts	United States	02215
3	Oregon Health & Sciences University, Site #048	Portland	Oregon	United States	97239
4	Fox Chase Cancer Center, Site #012	Philadelphia	Pennsylvania	United States	19111

Sponsors and Collaborators

• Ariad Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ariad Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01874665
• Other Study ID Numbers: AP24534-12-202
• First Posted: Jun 11, 2013
• Last Update Posted: May 18, 2018
• Last Verified: Apr 1, 2018

• Keywords provided by Ariad Pharmaceuticals: Gastrointestinal Neoplasms; Gastrointestinal stromal tumor; mesenchymal tumor
• Additional relevant MeSH terms: Gastrointestinal Stromal Tumors; Ponatinib

Study Results

Participant Flow

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Participants with KIT exon 11-mutant GIST ponatinib: 45 milligram (mg), taken orally once-daily.	Participants with gastrointestinal stromal tumors (GIST) that lack KIT exon 11 mutations (Cohort B) ponatinib: 45 mg, taken orally once-daily.
Period Title: Overall Study
STARTED	30	15
COMPLETED	0	0
NOT COMPLETED	30	15

Baseline Characteristics

Arm/Group Title	Cohort A	Cohort B	Total
Arm/Group Description	Participants with KIT exon 11-mutant GIST ponatinib: 45 mg, taken orally once-daily.	Participants with GIST that lack KIT exon 11 mutations (Cohort B) ponatinib: 45 mg, taken orally once-daily.	Total of all reporting groups
Overall Participants	30	15	45
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.3 (10.37)	53.9 (16.06)	57.5 (12.63)
Sex: Female, Male (Count of Participants)
Female	11 36.7%	8 53.3%	19 42.2%
Male	19 63.3%	7 46.7%	26 57.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 3.3%	0 0%	1 2.2%
Not Hispanic or Latino	29 96.7%	15 100%	44 97.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	29 96.7%	15 100%	44 97.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 3.3%	0 0%	1 2.2%
Region of Enrollment (Count of Participants)
United States	30 100%	15 100%	45 100%
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	80.12 (20.699)	75.10 (13.917)	78.45 (18.702)
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	171.20 (7.839)	171.28 (7.149)	171.23 (7.534)

Outcome Measures

1. Primary Outcome

Title	Clinical Benefit Rate (CBR) in Cohort A
Description	To assess clinical benefit rate in participants with KIT exon 11-mutant GIST.It is defined as the composite of complete response(CR),partial response(PR),and stable disease(SD) lasting >=16 weeks per modified Response Evaluation Criteria In Solid Tumors(RECIST) 1.1 as a measure of disease control.CR is complete disappearance of all target lesions and non-target disease, with the exception of nodal disease.All nodes, both target and non-target, must decrease to normal (short axis <10millimeter [mm]).No new lesions.PR is >=30% decrease under baseline of the sum of diameters of all target lesions.The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions.No unequivocal progression of non-target disease.No new lesions.SD is not qualifying for CR,PR,Progressive Disease(PD).PD is >=20% increase from the smallest prior sum of the longest diameter(SLD)and with >=5mm absolute increase, or appearance of a new lesion.
Time Frame	16 weeks after first dose

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who received any dose of ponatinib in the study. The ITT population where data at specified time points was available.

Arm/Group Title	Cohort A
Arm/Group Description	Participants with KIT exon 11-mutant GIST ponatinib: 45 mg, taken orally once-daily.
Measure Participants	28
Number (95% Confidence Interval) [percentage (%) of participants]	35.7 119%

2. Secondary Outcome

Title	Clinical Benefit Rate (CBR) in Cohort B
Description	To assess clinical benefit rate in participants with GIST that lacks KIT exon 11 mutations (Cohort B) and in the total participant population. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 millimeter [mm]). No new lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. SD was defined as not qualifying for CR, PR, PD.
Time Frame	16 weeks after first dose

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who received any dose of ponatinib in the study.

Arm/Group Title	Cohort B
Arm/Group Description	Participants with GIST that lack KIT exon 11 mutations (Cohort B) ponatinib: 45 mg, taken orally once-daily.
Measure Participants	15
Number (95% Confidence Interval) [percentage (%) of participants]	20.0 66.7%

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS is defined as the duration of time from start of study drug administration to time of objective disease progression or death due to any cause, whichever may come first. To assess PFS in each cohort and in the total participant population.
Time Frame	From date of enrollment until the end of the study or disease progression or death due to any cause, whichever came first, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who received any dose of ponatinib in the study.

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Participants with KIT exon 11-mutant GIST ponatinib: 45 mg, taken orally once-daily.	Participants with GIST that lack KIT exon 11 mutations (Cohort B) ponatinib: 45 mg, taken orally once-daily.
Measure Participants	30	15
Median (95% Confidence Interval) [days]	112.0	57.0

4. Secondary Outcome

Title	Percentage of Participants With Objective Response Rate (ORR)
Description	ORR is defined as the composite of CR and PR per Response Evaluation Criteria in RECIST 1.1, assessed for each cohort and in the total participant population. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions.
Time Frame	From date of enrollment until discontinuation or the end of the study, whichever came first, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who received any dose of ponatinib in the study. The ITT population where data at specified time points was available.

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Participants with KIT exon 11-mutant GIST ponatinib: 45 mg, taken orally once-daily.	Participants with GIST that lack KIT exon 11 mutations (Cohort B) ponatinib: 45 mg, taken orally once-daily.
Measure Participants	28	15
Number (95% Confidence Interval) [percentage of participants]	7.1 23.7%	0.0 0%

5. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time interval between the first dose of study drug to death due to any cause. Overall survival was analyzed using the Kaplan-Meier method.
Time Frame	From first dose of drug until the end of the study or death, whichever came first, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who received any dose of ponatinib in the study.

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Participants with KIT exon 11-mutant GIST ponatinib: 45 mg, taken orally once-daily.	Participants with GIST that lack KIT exon 11 mutations (Cohort B) ponatinib: 45 mg, taken orally once-daily.
Measure Participants	30	15
Median (95% Confidence Interval) [days]	411.0	399.0

6. Secondary Outcome

Title	Number of Participants With Physical Examination
Time Frame	From date of enrollment until the End-of-Treatment, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who received any dose of ponatinib in the study.

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Participants with KIT exon 11-mutant GIST ponatinib: 45 mg, taken orally once-daily.	Participants with GIST that lack KIT exon 11 mutations (Cohort B) ponatinib: 45 mg, taken orally once-daily.
Measure Participants	30	15
Count of Participants [Participants]	6 20%	1 6.7%

7. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Vital Sign Measurements
Time Frame	From date of enrollment until the End-of-Treatment, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who received any dose of ponatinib in the study.

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Participants with KIT exon 11-mutant GIST ponatinib: 45 mg, taken orally once-daily.	Participants with GIST that lack KIT exon 11 mutations (Cohort B) ponatinib: 45 mg, taken orally once-daily.
Measure Participants	30	15
Hypertension	15 50%	2 13.3%
Procedural hypotension	1 3.3%	0 0%
Pyrexia	7 23.3%	3 20%
Chills	3 10%	1 6.7%
Feeling of body temperature change	1 3.3%	0 0%

8. Secondary Outcome

Title	Number of Participants With Worst Shift From Baseline Values to Post-baseline Values in Laboratory Parameters
Time Frame	From date of enrollment until the End-of-Treatment, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who received any dose of ponatinib in the study.

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Participants with KIT exon 11-mutant GIST ponatinib: 45 mg, taken orally once-daily.	Participants with GIST that lack KIT exon 11 mutations (Cohort B) ponatinib: 45 mg, taken orally once-daily.
Measure Participants	30	15
Albumin decreased	13 43.3%	4 26.7%
Alkaline phosphatase increased	12 40%	8 53.3%
Alanine aminotransferase (ALT) increased	11 36.7%	7 46.7%
Amylase	3 10%	5 33.3%
Absolute neutrophil count (ANC) decreased	2 6.7%	0 0%
Aspartate aminotransferase (AST) increased	11 36.7%	8 53.3%
Bicarbonate decreased	1 3.3%	1 6.7%
Bilirubin	4 13.3%	2 13.3%
Calcium decreased	5 16.7%	4 26.7%
Calcium increased	5 16.7%	1 6.7%
Creatinine increased	3 10%	3 20%
Glucose decreased	1 3.3%	3 20%
Glucose increased	19 63.3%	9 60%
Hemoglobin decreased	10 33.3%	5 33.3%
Lipase increased	6 20%	7 46.7%
Lymphocytes (ALC)/ lymphopenia	5 16.7%	4 26.7%
Phosphorus decreased	5 16.7%	1 6.7%
Platelets decreased	2 6.7%	0 0%
Potassium decreased	5 16.7%	2 13.3%
Potassium increased	8 26.7%	3 20%
Sodium decreased	8 26.7%	1 6.7%
Sodium increased	7 23.3%	2 13.3%
Triglycerides increased	2 6.7%	0 0%
White blood cells (WBC) decreased	2 6.7%	0 0%

9. Secondary Outcome

Title	Number of Participants With TEAEs Related to Electrocardiogram (ECG) Findings
Time Frame	From date of enrollment until the End-of-Treatment, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who received any dose of ponatinib in the study.

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Participants with KIT exon 11-mutant GIST ponatinib: 45 mg, taken orally once-daily.	Participants with GIST that lack KIT exon 11 mutations (Cohort B) ponatinib: 45 mg, taken orally once-daily.
Measure Participants	30	15
Ejection Fraction Decreased	1 3.3%	2 13.3%
Atrial Fibrillation	1 3.3%	2 13.3%
Sinus Tachycardia	1 3.3%	1 6.7%
Cardiac Failure Congestive	1 3.3%	0 0%
Myocardial Ischaemia	1 3.3%	0 0%
Pericardial Effusion	0 0%	1 6.7%
Right Ventricular Dysfunction	1 3.3%	0 0%
Sinus Bradycardia	1 3.3%	0 0%

10. Secondary Outcome

Title	Number of Participants With TEAEs Related to Echocardiography Parameter
Time Frame	From date of enrollment until the End-of-Treatment, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who received any dose of ponatinib in the study.

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Participants with KIT exon 11-mutant GIST ponatinib: 45 mg, taken orally once-daily.	Participants with GIST that lack KIT exon 11 mutations (Cohort B) ponatinib: 45 mg, taken orally once-daily.
Measure Participants	30	15
Congestive Cardiac Failure	1 3.3%	0 0%
Right Ventricular Dysfunction	1 3.3%	0 0%
Decreased Ejection Fraction	1 3.3%	2 13.3%
Pulmonary Oedema	0 0%	1 6.7%

11. Secondary Outcome

Title	Number of Participants Reporting One or More TEAEs and Serious Adverse Event (SAE)
Time Frame	From date of enrollment until the End-of-Treatment, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who received any dose of ponatinib in the study.

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Participants with KIT exon 11-mutant GIST ponatinib: 45 mg, taken orally once-daily.	Participants with GIST that lack KIT exon 11 mutations (Cohort B) ponatinib: 45 mg, taken orally once-daily.
Measure Participants	30	15
TEAE	30 100%	15 100%
SAE	20 66.7%	6 40%

12. Secondary Outcome

Title	Cmax, SS: Maximum Observed Plasma Concentration at Steady State for Ponatinib
Time Frame	Pre-dose and at multiple timepoints (up to 1 month) post-dose

Outcome Measure Data

Analysis Population Description

Data was not collected for Cmax,ss, since outcome measure was not planned to be analyzed.

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Participants with KIT exon 11-mutant GIST ponatinib: 45 mg, taken orally once-daily.	Participants with GIST that lack KIT exon 11 mutations (Cohort B) ponatinib: 45 mg, taken orally once-daily.
Measure Participants	0	0

Adverse Events

Time Frame	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)
Adverse Event Reporting Description	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.
Arm/Group Title	Cohort A		Cohort B
Arm/Group Description	Participants with KIT exon 11-mutant GIST ponatinib: 45 mg, taken orally once-daily.		Participants with GIST that lack KIT exon 11 mutations (Cohort B) ponatinib: 45 mg, taken orally once-daily.
All Cause Mortality
	Cohort A		Cohort B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/30 (13.3%)		2/15 (13.3%)
Serious Adverse Events
	Cohort A		Cohort B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/30 (66.7%)		6/15 (40%)
Blood and lymphatic system disorders
ANAEMIA	1/30 (3.3%)		0/15 (0%)
Cardiac disorders
ATRIAL FIBRILLATION	1/30 (3.3%)		0/15 (0%)
MYOCARDIAL ISCHAEMIA	1/30 (3.3%)		0/15 (0%)
RIGHT VENTRICULAR DYSFUNCTION	1/30 (3.3%)		0/15 (0%)
CARDIAC FAILURE CONGESTIVE	1/30 (3.3%)		0/15 (0%)
Gastrointestinal disorders
ABDOMINAL PAIN	3/30 (10%)		1/15 (6.7%)
DUODENAL STENOSIS	1/30 (3.3%)		0/15 (0%)
NAUSEA	2/30 (6.7%)		0/15 (0%)
OBSTRUCTION GASTRIC	1/30 (3.3%)		0/15 (0%)
SMALL INTESTINAL OBSTRUCTION	3/30 (10%)		0/15 (0%)
SMALL INTESTINAL ULCER PERFORATION	1/30 (3.3%)		0/15 (0%)
UPPER GASTROINTESTINAL HAEMORRHAGE	0/30 (0%)		1/15 (6.7%)
VOMITING	2/30 (6.7%)		0/15 (0%)
General disorders
FATIGUE	1/30 (3.3%)		1/15 (6.7%)
Hepatobiliary disorders
HEPATIC FAILURE	1/30 (3.3%)		0/15 (0%)
Infections and infestations
COLONIC ABSCESS	1/30 (3.3%)		0/15 (0%)
PNEUMONIA	3/30 (10%)		0/15 (0%)
SEPSIS	0/30 (0%)		1/15 (6.7%)
URINARY TRACT INFECTION	1/30 (3.3%)		0/15 (0%)
Injury, poisoning and procedural complications
HIP FRACTURE	0/30 (0%)		1/15 (6.7%)
Metabolism and nutrition disorders
DEHYDRATION	1/30 (3.3%)		0/15 (0%)
HYPERCALCAEMIA	1/30 (3.3%)		0/15 (0%)
Musculoskeletal and connective tissue disorders
MUSCULAR WEAKNESS	1/30 (3.3%)		0/15 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
NEOPLASM PROGRESSION	3/30 (10%)		0/15 (0%)
TUMOUR HAEMORRHAGE	1/30 (3.3%)		0/15 (0%)
Nervous system disorders
CEREBROVASCULAR ACCIDENT	1/30 (3.3%)		0/15 (0%)
SYNCOPE	0/30 (0%)		1/15 (6.7%)
SPINAL CORD COMPRESSION	1/30 (3.3%)		0/15 (0%)
Respiratory, thoracic and mediastinal disorders
ACUTE RESPIRATORY FAILURE	0/30 (0%)		1/15 (6.7%)
DYSPNOEA	0/30 (0%)		1/15 (6.7%)
HYPOXIA	0/30 (0%)		1/15 (6.7%)
PULMONARY EMBOLISM	1/30 (3.3%)		1/15 (6.7%)
RESPIRATORY FAILURE	0/30 (0%)		1/15 (6.7%)
Vascular disorders
DEEP VEIN THROMBOSIS	0/30 (0%)		1/15 (6.7%)
PERIPHERAL ARTERY STENOSIS	1/30 (3.3%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Cohort A		Cohort B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/30 (100%)		15/15 (100%)
Blood and lymphatic system disorders
ANAEMIA	1/30 (3.3%)		5/15 (33.3%)
LEUKOCYTOSIS	2/30 (6.7%)		0/15 (0%)
IRON DEFICIENCY ANAEMIA	0/30 (0%)		1/15 (6.7%)
LYMPH NODE PAIN	1/30 (3.3%)		0/15 (0%)
Cardiac disorders
ATRIAL FIBRILLATION	1/30 (3.3%)		2/15 (13.3%)
SINUS TACHYCARDIA	1/30 (3.3%)		1/15 (6.7%)
PERICARDIAL EFFUSION	0/30 (0%)		1/15 (6.7%)
SINUS BRADYCARDIA	1/30 (3.3%)		0/15 (0%)
Ear and labyrinth disorders
EAR DISCOMFORT	1/30 (3.3%)		0/15 (0%)
EAR PAIN	1/30 (3.3%)		0/15 (0%)
HYPOACUSIS	1/30 (3.3%)		0/15 (0%)
Endocrine disorders
HYPOTHYROIDISM	3/30 (10%)		1/15 (6.7%)
Eye disorders
VISION BLURRED	1/30 (3.3%)		2/15 (13.3%)
DIPLOPIA	1/30 (3.3%)		0/15 (0%)
DRY EYE	1/30 (3.3%)		0/15 (0%)
EPISCLERITIS	0/30 (0%)		1/15 (6.7%)
EYELID PAIN	1/30 (3.3%)		0/15 (0%)
HYPERMETROPIA	1/30 (3.3%)		0/15 (0%)
PERIORBITAL OEDEMA	1/30 (3.3%)		0/15 (0%)
VISUAL ACUITY REDUCED	1/30 (3.3%)		2/15 (13.3%)
VISUAL IMPAIRMENT	1/30 (3.3%)		0/15 (0%)
VITREOUS DETACHMENT	1/30 (3.3%)		0/15 (0%)
Gastrointestinal disorders
ABDOMINAL PAIN	14/30 (46.7%)		6/15 (40%)
ASCITES	3/30 (10%)		1/15 (6.7%)
CONSTIPATION	14/30 (46.7%)		5/15 (33.3%)
DIARRHOEA	8/30 (26.7%)		2/15 (13.3%)
DRY MOUTH	3/30 (10%)		1/15 (6.7%)
DYSPEPSIA	4/30 (13.3%)		4/15 (26.7%)
NAUSEA	6/30 (20%)		3/15 (20%)
STOMATITIS	1/30 (3.3%)		2/15 (13.3%)
VOMITING	7/30 (23.3%)		2/15 (13.3%)
ABDOMINAL DISCOMFORT	2/30 (6.7%)		0/15 (0%)
ABDOMINAL DISTENSION	2/30 (6.7%)		0/15 (0%)
GASTROOESOPHAGEAL REFLUX DISEASE	2/30 (6.7%)		0/15 (0%)
ABDOMINAL TENDERNESS	1/30 (3.3%)		0/15 (0%)
COLITIS	1/30 (3.3%)		0/15 (0%)
DYSPHAGIA	1/30 (3.3%)		0/15 (0%)
ERUCTATION	0/30 (0%)		1/15 (6.7%)
GASTRIC ULCER	1/30 (3.3%)		0/15 (0%)
HAEMORRHOIDS	1/30 (3.3%)		0/15 (0%)
OBSTRUCTION GASTRIC	1/30 (3.3%)		0/15 (0%)
OESOPHAGEAL PAIN	1/30 (3.3%)		0/15 (0%)
PROCTALGIA	0/30 (0%)		1/15 (6.7%)
TOOTHACHE	0/30 (0%)		1/15 (6.7%)
UPPER GASTROINTESTINAL HAEMORRHAGE	0/30 (0%)		1/15 (6.7%)
General disorders
CHILLS	3/30 (10%)		1/15 (6.7%)
FATIGUE	15/30 (50%)		9/15 (60%)
NON-CARDIAC CHEST PAIN	3/30 (10%)		1/15 (6.7%)
OEDEMA PERIPHERAL	13/30 (43.3%)		3/15 (20%)
PAIN	2/30 (6.7%)		1/15 (6.7%)
PYREXIA	7/30 (23.3%)		3/15 (20%)
EARLY SATIETY	2/30 (6.7%)		1/15 (6.7%)
ASTHENIA	1/30 (3.3%)		0/15 (0%)
CHEST PAIN	1/30 (3.3%)		0/15 (0%)
FACE OEDEMA	1/30 (3.3%)		0/15 (0%)
FEELING OF BODY TEMPERATURE CHANGE	1/30 (3.3%)		0/15 (0%)
MALAISE	1/30 (3.3%)		0/15 (0%)
PERIPHERAL SWELLING	1/30 (3.3%)		0/15 (0%)
Infections and infestations
PNEUMONIA	0/30 (0%)		2/15 (13.3%)
URINARY TRACT INFECTION	1/30 (3.3%)		3/15 (20%)
CELLULITIS	1/30 (3.3%)		0/15 (0%)
CLOSTRIDIUM DIFFICILE INFECTION	0/30 (0%)		1/15 (6.7%)
CYSTITIS	1/30 (3.3%)		0/15 (0%)
DIVERTICULITIS	1/30 (3.3%)		0/15 (0%)
INFECTION	1/30 (3.3%)		0/15 (0%)
ORAL CANDIDIASIS	0/30 (0%)		1/15 (6.7%)
ORAL INFECTION	1/30 (3.3%)		0/15 (0%)
OTITIS MEDIA	1/30 (3.3%)		0/15 (0%)
POSTOPERATIVE WOUND INFECTION	0/30 (0%)		1/15 (6.7%)
PYURIA	0/30 (0%)		1/15 (6.7%)
SKIN INFECTION	0/30 (0%)		1/15 (6.7%)
TOOTH INFECTION	1/30 (3.3%)		0/15 (0%)
UPPER RESPIRATORY TRACT INFECTION	0/30 (0%)		1/15 (6.7%)
Injury, poisoning and procedural complications
FALL	2/30 (6.7%)		1/15 (6.7%)
HEAD INJURY	0/30 (0%)		1/15 (6.7%)
HIP FRACTURE	0/30 (0%)		1/15 (6.7%)
INCISION SITE HAEMATOMA	0/30 (0%)		1/15 (6.7%)
LOWER LIMB FRACTURE	0/30 (0%)		1/15 (6.7%)
POST PROCEDURAL HAEMORRHAGE	0/30 (0%)		1/15 (6.7%)
PROCEDURAL HYPOTENSION	1/30 (3.3%)		0/15 (0%)
PROCEDURAL PAIN	1/30 (3.3%)		0/15 (0%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	3/30 (10%)		5/15 (33.3%)
AMYLASE INCREASED	1/30 (3.3%)		2/15 (13.3%)
ASPARTATE AMINOTRANSFERASE INCREASED	5/30 (16.7%)		5/15 (33.3%)
BLOOD ALKALINE PHOSPHATASE INCREASED	7/30 (23.3%)		6/15 (40%)
EJECTION FRACTION DECREASED	1/30 (3.3%)		2/15 (13.3%)
LIPASE INCREASED	3/30 (10%)		4/15 (26.7%)
WEIGHT DECREASED	6/30 (20%)		1/15 (6.7%)
PLATELET COUNT DECREASED	1/30 (3.3%)		1/15 (6.7%)
BLOOD BILIRUBIN INCREASED	0/30 (0%)		1/15 (6.7%)
BLOOD CREATININE INCREASED	0/30 (0%)		1/15 (6.7%)
Metabolism and nutrition disorders
DECREASED APPETITE	11/30 (36.7%)		4/15 (26.7%)
DEHYDRATION	5/30 (16.7%)		1/15 (6.7%)
HYPERGLYCAEMIA	3/30 (10%)		3/15 (20%)
HYPOPHOSPHATAEMIA	2/30 (6.7%)		2/15 (13.3%)
HYPOGLYCAEMIA	0/30 (0%)		2/15 (13.3%)
HYPOKALAEMIA	2/30 (6.7%)		0/15 (0%)
HYPONATRAEMIA	2/30 (6.7%)		0/15 (0%)
HYPERKALAEMIA	1/30 (3.3%)		0/15 (0%)
HYPERNATRAEMIA	0/30 (0%)		1/15 (6.7%)
HYPERTRIGLYCERIDAEMIA	1/30 (3.3%)		0/15 (0%)
HYPOCALCAEMIA	1/30 (3.3%)		0/15 (0%)
HYPOMAGNESAEMIA	1/30 (3.3%)		0/15 (0%)
IRON DEFICIENCY	1/30 (3.3%)		0/15 (0%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	3/30 (10%)		4/15 (26.7%)
BACK PAIN	7/30 (23.3%)		0/15 (0%)
BONE PAIN	3/30 (10%)		0/15 (0%)
MUSCLE SPASMS	5/30 (16.7%)		2/15 (13.3%)
MYALGIA	15/30 (50%)		3/15 (20%)
NECK PAIN	3/30 (10%)		0/15 (0%)
PAIN IN EXTREMITY	4/30 (13.3%)		0/15 (0%)
FLANK PAIN	2/30 (6.7%)		0/15 (0%)
GROIN PAIN	1/30 (3.3%)		1/15 (6.7%)
LIMB DISCOMFORT	2/30 (6.7%)		0/15 (0%)
MUSCULOSKELETAL PAIN	1/30 (3.3%)		1/15 (6.7%)
MUSCULOSKELETAL CHEST PAIN	1/30 (3.3%)		0/15 (0%)
MUSCULOSKELETAL DISCOMFORT	1/30 (3.3%)		0/15 (0%)
NUCHAL RIGIDITY	1/30 (3.3%)		0/15 (0%)
OSTEOARTHRITIS	0/30 (0%)		1/15 (6.7%)
PAIN IN JAW	1/30 (3.3%)		0/15 (0%)
ROTATOR CUFF SYNDROME	0/30 (0%)		1/15 (6.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
TUMOUR HAEMORRHAGE	1/30 (3.3%)		1/15 (6.7%)
MALIGNANT PLEURAL EFFUSION	1/30 (3.3%)		0/15 (0%)
Nervous system disorders
DIZZINESS	3/30 (10%)		2/15 (13.3%)
HEADACHE	13/30 (43.3%)		7/15 (46.7%)
PERIPHERAL SENSORY NEUROPATHY	4/30 (13.3%)		0/15 (0%)
DYSGEUSIA	0/30 (0%)		2/15 (13.3%)
MEMORY IMPAIRMENT	2/30 (6.7%)		0/15 (0%)
TREMOR	0/30 (0%)		2/15 (13.3%)
CEREBROVASCULAR ACCIDENT	1/30 (3.3%)		0/15 (0%)
DIZZINESS POSTURAL	1/30 (3.3%)		0/15 (0%)
DYSAESTHESIA	1/30 (3.3%)		0/15 (0%)
HYPERAESTHESIA	1/30 (3.3%)		0/15 (0%)
LETHARGY	1/30 (3.3%)		0/15 (0%)
PERIPHERAL MOTOR NEUROPATHY	1/30 (3.3%)		0/15 (0%)
RESTLESS LEGS SYNDROME	1/30 (3.3%)		0/15 (0%)
SOMNOLENCE	1/30 (3.3%)		0/15 (0%)
Psychiatric disorders
INSOMNIA	4/30 (13.3%)		1/15 (6.7%)
ANXIETY	1/30 (3.3%)		0/15 (0%)
CONFUSIONAL STATE	1/30 (3.3%)		0/15 (0%)
DEPRESSION	1/30 (3.3%)		0/15 (0%)
Renal and urinary disorders
URINARY RETENTION	1/30 (3.3%)		2/15 (13.3%)
POLLAKIURIA	1/30 (3.3%)		2/15 (13.3%)
ACUTE KIDNEY INJURY	2/30 (6.7%)		0/15 (0%)
DYSURIA	0/30 (0%)		2/15 (13.3%)
MICTURITION URGENCY	1/30 (3.3%)		1/15 (6.7%)
HAEMATURIA	0/30 (0%)		1/15 (6.7%)
NOCTURIA	1/30 (3.3%)		0/15 (0%)
URINARY TRACT OBSTRUCTION	1/30 (3.3%)		0/15 (0%)
URINARY TRACT PAIN	0/30 (0%)		1/15 (6.7%)
Reproductive system and breast disorders
ERECTILE DYSFUNCTION	3/30 (10%)		0/15 (0%)
GYNAECOMASTIA	1/30 (3.3%)		0/15 (0%)
TESTICULAR PAIN	1/30 (3.3%)		0/15 (0%)
Respiratory, thoracic and mediastinal disorders
COUGH	8/30 (26.7%)		4/15 (26.7%)
DYSPHONIA	3/30 (10%)		4/15 (26.7%)
DYSPNOEA	4/30 (13.3%)		0/15 (0%)
NASAL CONGESTION	3/30 (10%)		1/15 (6.7%)
PLEURAL EFFUSION	2/30 (6.7%)		2/15 (13.3%)
DYSPNOEA EXERTIONAL	2/30 (6.7%)		0/15 (0%)
WHEEZING	2/30 (6.7%)		0/15 (0%)
EPISTAXIS	0/30 (0%)		1/15 (6.7%)
HYPOXIA	0/30 (0%)		1/15 (6.7%)
OROPHARYNGEAL PAIN	0/30 (0%)		1/15 (6.7%)
PLEURITIC PAIN	1/30 (3.3%)		0/15 (0%)
PULMONARY OEDEMA	0/30 (0%)		1/15 (6.7%)
THROAT IRRITATION	1/30 (3.3%)		0/15 (0%)
UPPER-AIRWAY COUGH SYNDROME	1/30 (3.3%)		0/15 (0%)
Skin and subcutaneous tissue disorders
ALOPECIA	2/30 (6.7%)		2/15 (13.3%)
DRY SKIN	11/30 (36.7%)		4/15 (26.7%)
HYPERHIDROSIS	0/30 (0%)		3/15 (20%)
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME	2/30 (6.7%)		1/15 (6.7%)
PRURITUS	1/30 (3.3%)		3/15 (20%)
RASH	15/30 (50%)		12/15 (80%)
DERMATITIS ACNEIFORM	2/30 (6.7%)		0/15 (0%)
EXFOLIATIVE RASH	1/30 (3.3%)		0/15 (0%)
NIGHT SWEATS	1/30 (3.3%)		0/15 (0%)
PAIN OF SKIN	1/30 (3.3%)		0/15 (0%)
PITYRIASIS RUBRA PILARIS	1/30 (3.3%)		0/15 (0%)
PRURITUS GENERALISED	1/30 (3.3%)		0/15 (0%)
RASH FOLLICULAR	1/30 (3.3%)		0/15 (0%)
RASH PRURITIC	1/30 (3.3%)		0/15 (0%)
SKIN REACTION	1/30 (3.3%)		0/15 (0%)
Vascular disorders
HYPERTENSION	15/30 (50%)		2/15 (13.3%)
FLUSHING	1/30 (3.3%)		1/15 (6.7%)
HOT FLUSH	1/30 (3.3%)		0/15 (0%)
PERIPHERAL ARTERY STENOSIS	1/30 (3.3%)		0/15 (0%)

Limitations/Caveats

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

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor can review results communications prior to public release and can embargo communications regarding trial results for up to 1 year (to first generate a multicenter publication) and a period that is 60 to 120 days from the time submitted to the sponsor for review. The sponsor can require changes to the communication to delete confidential information, excluding the results of the Study.