POETIG Trial - POnatinib After rEsisTance to Imatinib in GIST

Study Overview
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Brief Summary
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This is a non-randomized, open-label, multicenter phase 2 study to evaluate the efficacy and safety of ponatinib in patients with metastatic and/or unresectable GIST after prior failure or intolerability of imatinib. Patients will be enrolled into 1 of 2 cohorts based on absence (Cohort A) or presence (Cohort B) of KIT exon 13 resistance mutations as measured by liquid biopsy. A third cohort (Cohort C) will include patients who have received all approved lines of TKI treatments (imatinib, sunitinib and regorafenib).

Detailed Description
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Primary Objective To assess clinical benefit of ponatinib in patients with KIT or PDGFRA mutant GIST defined as clinical benefit rate (CBR), which is the composite of complete response (CR), partial response (PR) and stable disease (SD) at ≥16 weeks after start of treatment per modified response evaluation criteria in solid tumors (modified RECIST 1.1 [Demetri et al., 2013]) as a measure of disease control Two cohorts for second-line patients will be used: Cohort A: patients with secondary resistance mutations in other exons or no resistance mutations (as measured by liquid biopsy in circulating DNA); Cohort B: patients with evidence of secondary resistance mutations in exon 13 as assessed on progressing lesions or in circulating DNA One additional Cohort (Cohort C) will include heavily pretreated patients (failure of at least all approved lines of therapy) regardless of secondary mutation Secondary Objectives To assess progression-free survival (PFS) in each cohort and in the total patient population To assess objective response rate (ORR) in each cohort and in the total patient population To assess overall survival (OS) in each cohort and in the total patient population To evaluate the safety and tolerability of ponatinib in the total patient population To assess Quality of Life (QoL) Exploratory Objectives To assess limited elements of pharmacokinetics (PK) in the total patient population To explore the relationship between GIST genotype and CBR with ponatinib To explore the feasibility of detecting mutations in KIT and possibly other cancer-related genes using circulating nucleic acids derived from blood samples To explore the usefulness of liquid biopsies to predict treatment response and development of resistance To assess duration of follow-up treatment Primary Endpoint CBR consisting of CR+PR+SD by modified RECIST 1.1 (Demetri et al., 2013) at 16 weeks in patients with imatinib-resistant GIST (KIT-mutant) with other or no resistance mutations (Cohort A) and secondary resistance mutation in exon 13 (Cohort B) Secondary Endpoints PFS in each cohort and in the total patient population ORR (CR + PR) in each cohort and in the total patient population OS in each cohort and in the total patient population Safety and tolerability of ponatinib QoL CBR of Cohort C Exploratory Endpoints Correlation of plasma levels of ponatinib and response Molecular genetic features of GIST at baseline and after treatment with ponatinib Correlation of tumor DNA from available paraffin tissue with genotypes of plasma sequencing (liquid biopsies) and correlation of plasma genotype with treatment response, resistance and duration of follow-up treatment

Official Title
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Phase 2 Trial of Ponatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor (GIST) Following Failure or Intolerance of Prior Therapy With Imatinib

Conditions
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GIST, Malignant, KIT Exon 13 Mutation, KIT Gene Mutation

Intervention / Treatment
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* Drug: Ponatinib 30 MG


Participation Criteria
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Eligibility Criteria
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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: Patients lacking primary mutations of KIT or PDGFRA (including Succinate-Dehydrogenase(SDH)-deficient GIST) 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 and /or drug abuse Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL) 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 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 Taking medications that are known to be associated with Torsades de Pointes (Appendix A) 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) Ongoing or active infection. This includes but is not limited to the requirement for intravenous antibiotics Known history of human immunodeficiency virus. 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 the study drug 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 patient safety or interfere with the evaluation of the drug History of apoplectic insult

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>patients with primary c-KIT mutations and with either no detectable or non-exon13-secondary mutations (as measured by plasma sequencing); failure of imatinib treatment (only) Treatment with oral ponatinib 30MG (milligram) daily until progression or intolerable side effects. | Drug: Ponatinib 30 MG<br>* Ponatinib: once-daily oral dose of 30mg. A cycle of treatment is defined as 28 days. Doses may be reduced to manage drug-related adverse events and may be re-escalated once events resolve.<br>* Other names: Iclusiq;|
| Experimental: Cohort B<br>GIST patients with primary c-KIT mutations and secondary c-KIT mutations in Exon 13; failure of imatinib treatment (only) Treatment with oral ponatinib 30MG daily until progression or intolerable side effects. | Drug: Ponatinib 30 MG<br>* Ponatinib: once-daily oral dose of 30mg. A cycle of treatment is defined as 28 days. Doses may be reduced to manage drug-related adverse events and may be re-escalated once events resolve.<br>* Other names: Iclusiq;|
| Experimental: Cohort C<br>GIST patients with KIT-mutations and treatment failure of imatinib, sunitinib and regorafenib. Treatment with oral ponatinib 30MG daily until progression or intolerable side effects. | Drug: Ponatinib 30 MG<br>* Ponatinib: once-daily oral dose of 30mg. A cycle of treatment is defined as 28 days. Doses may be reduced to manage drug-related adverse events and may be re-escalated once events resolve.<br>* Other names: Iclusiq;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| clinical benefit rate (CBR) | CBR consisting of CR+PR+SD by modified RECIST 1.1 (Demetri et al., 2013) at 16 weeks in patients with imatinib-resistant GIST (KIT-mutant) with other or no resistance mutations (Cohort A) and secondary resistance mutation in exon 13 (Cohort B) | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Assessment in each cohort and in the total patient population | through study completion, an average of 3.5 years | 
| Objective response rate (ORR) | Assessment in each cohort and in the total patient population | 16 weeks | 
| Overall survival (OS) | Assessment in each cohort and in the total patient population | through study completion, an average of 3.5 years | 
| Assessment of treatment-related adverse events | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | 3.5 years | 
| Quality of life assessment | Quality of life questionnaire SQLQ (Supplementary Quality of life questionnaire) | approx. 3.5 years (duration of study + 2 years follow-up period) | 
| Fatigue assessment | Quality of life and fatigue questionnaire FACIT-F Version 4 (Functional Assessment of Chronic Illness Therapy-Fatigue) | approx. 3.5 years (duration of study + 2 years follow-up period) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GIST, KIT secondary mutation, ponatinib