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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase 2 Trial of Ponatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor Following Failure of Prior Tyrosine Kinase Inhibitor Therapy

Conditions
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GIST

Intervention / Treatment
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* Drug: Ponatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants >=18 years old. GIST with failure of prior TKI therapy defined as: 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. 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). 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. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Adequate hepatic function as defined by the following criteria: Total serum bilirubin less than or equal to (<=) 1.5*Upper Limit of Normal (ULN), unless due to Gilbert's syndrome. ALT <=2.5*ULN or <=5.0*ULN if liver metastases are present. AST <=2.5*ULN or <=5.0*ULN if liver metastases are present. Adequate renal function as defined by the following criterion: a. Serum creatinine <1.5*ULN. Adequate pancreatic function as defined by the following criterion: a. Serum lipase and amylase <=1.5*ULN. For participants of childbearing potential, a negative pregnancy test must be documented prior to enrollment. 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. 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 study drug. Exclusion Criteria: Major surgery within 28 days prior to initiating therapy History of bleeding disorder History of acute pancreatitis within 1 year of study or history of chronic pancreatitis History of alcohol abuse Uncontrolled hypertriglyceridemia (triglycerides >450 milligram per deciliter [mg/dL]) Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: Any history of myocardial infarction (MI). Any history of unstable angina. 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. History of clinically significant (as determined by the treating physician) atrial arrhythmia. Any history of ventricular arrhythmia. Any history of cerebrovascular accident or transient ischemic attack (TIA). Any history of peripheral vascular infarction, including visceral infarction; or any revascularization procedure of any vasculature, including the placement of a stent. Venous thromboembolism including deep venous thrombosis (DVT) or pulmonary embolism within 6 months prior to enrollment. 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. Taking medications with a known risk of Torsades de Pointes. 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. Ongoing or active infection. This includes but is not limited to the requirement for intravenous antibiotics. Known history of human immunodeficiency virus (HIV). Testing is not required in the absence of prior documentation or known history. Pregnant or breastfeeding. Malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drugs. 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. 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. Any condition or illness that, in the opinion of the investigator, would compromise participant safety or interfere with the evaluation of the drug.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>Participants with KIT exon 11-mutant GIST. | Drug: Ponatinib<br>* Ponatinib 45 mg, tablets, orally, once-daily.<br>* Other names: Iclusig;|
| Experimental: Cohort B<br>Participants with GIST that lack KIT exon 11 mutations (Cohort B). | Drug: Ponatinib<br>* Ponatinib 45 mg, tablets, orally, once-daily.<br>* Other names: Iclusig;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (CBR) in Cohort A | 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. | 16 weeks after first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (CBR) in Cohort B | 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. | 16 weeks after first dose | 
| Progression-free Survival (PFS) | 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. | 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 | 
| Percentage of Participants With Objective Response Rate (ORR) | 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. | From date of enrollment until discontinuation or the end of the study, whichever came first, assessed up to 3 years | 
| Overall Survival (OS) | 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. | From first dose of drug until the end of the study or death, whichever came first, assessed up to 3 years | 
| Number of Participants With Physical Examination |  | From date of enrollment until the End-of-Treatment, assessed up to 3 years | 
| 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 | 
| 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 | 
| Number of Participants With TEAEs Related to Electrocardiogram (ECG) Findings |  | From date of enrollment until the End-of-Treatment, assessed up to 3 years | 
| Number of Participants With TEAEs Related to Echocardiography Parameter |  | From date of enrollment until the End-of-Treatment, assessed up to 3 years | 
| 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 | 
| Cmax, SS: Maximum Observed Plasma Concentration at Steady State for Ponatinib |  | Pre-dose and at multiple timepoints (up to 1 month) post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mesenchymal tumor, Gastrointestinal Neoplasms, Gastrointestinal stromal tumor