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    The EU Clinical Trials Register currently displays   44339   clinical trials with a EudraCT protocol, of which   7369   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2015-002285-23
    Sponsor's Protocol Code Number:POETIG
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-09-26
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2015-002285-23
    A.3Full title of the trial
    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 (POETIG trial – POnatinib after rEsisTance to Imatinib in GIST)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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 (POETIG trial – POnatinib after rEsisTance to Imatinib in GIST)
    A.3.2Name or abbreviated title of the trial where available
    POETIG
    A.4.1Sponsor's protocol code numberPOETIG
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversitaetsklinikum Essen
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportIncyte Biosciences UK Ltd.
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversitaetsklinikum Essen
    B.5.2Functional name of contact pointProf. Dr. med. Sebastian Bauer
    B.5.3 Address:
    B.5.3.1Street AddressHufelandstr. 55
    B.5.3.2Town/ cityEssen
    B.5.3.3Post code45122
    B.5.3.4CountryGermany
    B.5.4Telephone number00492017232112
    B.5.5Fax number00492017235996
    B.5.6E-mailsebastian.bauer@uk-essen.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Iclusig
    D.2.1.1.2Name of the Marketing Authorisation holderIncyte Biosciences UK Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    gastrointestinal stromal tumor (GIST)
    Gastrointestinale Stromatumore (GIST)
    E.1.1.1Medical condition in easily understood language
    Tumor of connective tissue in the digestive tract
    Bindegewebstumoren im Verdauungstrakt
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10051066
    E.1.2Term Gastrointestinal stromal tumour
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • 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
    E.2.2Secondary objectives of the trial
    • 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)
    • 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
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients ≥18 years old
    2. GIST with failure or intolerance to imatinib or failure / intolerance to all three approved TKIs defined as:
    a. 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
    b. Patients in Cohort A must have evidence of an activating resistance mutation in KIT exon 13 (by direct sequencing of progressing lesions or by liquid biopsy). Patients in Cohort B must have evidence of clinical resistance mutations in any other exon or no resistance mutation but evidence of progression by CT or MRI imaging
    3. 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
    4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
    5. Adequate hepatic function as defined by the following criteria:
    a. Total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert’s syndrome
    b. ALT ≤2.5×ULN or ≤5.0xULN if liver metastases are present
    c. AST ≤2.5×ULN or ≤5.0xULN 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 patients of childbearing potential, a negative pregnancy test must be documented prior to enrollment
    9. 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
    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 the study drug treatment
    E.4Principal exclusion criteria
    1. Patients lacking primary mutations of KIT or PDGFRA (including 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:
    a. Myocardial infarction within 6 months prior to enrollment
    b. Unstable angina within 6 months prior to enrollment
    c. 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
    d. History of clinically significant (as determined by the treating physician) atrial arrhythmia
    e. Any history of ventricular arrhythmia
    f. Cerebrovascular accident or transient ischemic attack within 6 months prior to enrollment
    g. Any history of peripheral arterial occlusive disease requiring revascularization
    h. 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
    E.5 End points
    E.5.1Primary end point(s)
    • 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)
    E.5.1.1Timepoint(s) of evaluation of this end point
    CBR of Cohort A and B at 16 weeks after start of treatment
    E.5.2Secondary end point(s)
    • 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
    • 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
    E.5.2.1Timepoint(s) of evaluation of this end point
    CBR of Cohort C at 16 weeks after start of treatment

    PFS and OS at 24 months from the time the last patient is enrolled or until patient contact discontinues

    During and at the end of the study.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA14
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 54
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 27
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state48
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 81
    F.4.2.2In the whole clinical trial 81
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-01-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-01-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-10-20
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