Clinical Trials /

POETIG Trial - POnatinib After rEsisTance to Imatinib in GIST

NCT03171389

Description:

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).

Related Conditions:
  • Gastrointestinal Stromal Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: POETIG Trial - POnatinib After rEsisTance to Imatinib in GIST
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: POETIG
  • NCT ID: NCT03171389

Conditions

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

Interventions

DrugSynonymsArms
Ponatinib 30 MGIclusiqCohort A

Purpose

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

      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
    

Trial Arms

NameTypeDescriptionInterventions
Cohort AExperimentalpatients 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.
  • Ponatinib 30 MG
Cohort BExperimentalGIST 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.
  • Ponatinib 30 MG
Cohort CExperimentalGIST patients with KIT-mutations and treatment failure of imatinib, sunitinib and regorafenib. Treatment with oral ponatinib 30MG daily until progression or intolerable side effects.
  • Ponatinib 30 MG

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:clinical benefit rate (CBR)
Time Frame:16 weeks
Safety Issue:
Description: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 Outcome Measures

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sebastian Bauer

Trial Keywords

  • GIST
  • KIT secondary mutation
  • ponatinib

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