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Trial record 14 of 38 for:    ponatinib

POETIG Trial - POnatinib After rEsisTance to Imatinib in GIST (POETIG)

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ClinicalTrials.gov Identifier: NCT03171389
Recruitment Status : Recruiting
First Posted : May 31, 2017
Last Update Posted : May 31, 2017
Sponsor:
Collaborators:
Hannover Medical School
Helios Klinikum Berlin
University Hospital Tuebingen
Universitätsmedizin Mannheim
University Hospital, Aachen
Helios Klinikum Bad Saarow
WiSP GmbH
Information provided by (Responsible Party):
Sebastian Bauer, Universität Duisburg-Essen

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
GIST, Malignant KIT Exon 13 Mutation KIT Gene Mutation Drug: Ponatinib 30 MG Phase 2

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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 81 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 (GIST) Following Failure or Intolerance of Prior Therapy With Imatinib
Actual Study Start Date : March 22, 2017
Estimated Primary Completion Date : September 22, 2018
Estimated Study Completion Date : September 22, 2020


Arm Intervention/treatment
Experimental: Cohort A
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
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.
Other Name: Iclusiq

Experimental: Cohort B
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
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.
Other Name: Iclusiq

Experimental: Cohort C

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
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.
Other Name: Iclusiq




Primary Outcome Measures :
  1. clinical benefit rate (CBR) [ Time Frame: 16 weeks ]
    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 :
  1. Progression-free survival (PFS) [ Time Frame: through study completion, an average of 3.5 years ]
    Assessment in each cohort and in the total patient population

  2. Objective response rate (ORR) [ Time Frame: 16 weeks ]
    Assessment in each cohort and in the total patient population

  3. Overall survival (OS) [ Time Frame: through study completion, an average of 3.5 years ]
    Assessment in each cohort and in the total patient population

  4. Assessment of treatment-related adverse events [ Time Frame: 3.5 years ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  5. Quality of life assessment [ Time Frame: approx. 3.5 years (duration of study + 2 years follow-up period) ]
    Quality of life questionnaire SQLQ (Supplementary Quality of life questionnaire)

  6. Fatigue assessment [ Time Frame: approx. 3.5 years (duration of study + 2 years follow-up period) ]
    Quality of life and fatigue questionnaire FACIT-F Version 4 (Functional Assessment of Chronic Illness Therapy-Fatigue)



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03171389


Contacts
Contact: Johanna Falkenhorst +49 201 723 84150 johanna.falkenhorst@uk-essen.de

Locations
Germany
West German Cancer Center Recruiting
Essen, NRW, Germany, 45122
Principal Investigator: Sebastian Bauer, Prof. Dr.         
Sponsors and Collaborators
Sebastian Bauer
Hannover Medical School
Helios Klinikum Berlin
University Hospital Tuebingen
Universitätsmedizin Mannheim
University Hospital, Aachen
Helios Klinikum Bad Saarow
WiSP GmbH
Investigators
Principal Investigator: Sebastian Bauer, Prof. Dr. University Hospital, Essen

Additional Information:
Publications:
Responsible Party: Sebastian Bauer, Prof. Dr. med., Universität Duisburg-Essen
ClinicalTrials.gov Identifier: NCT03171389     History of Changes
Other Study ID Numbers: POETIG
First Posted: May 31, 2017    Key Record Dates
Last Update Posted: May 31, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Sebastian Bauer, Universität Duisburg-Essen:
GIST
KIT secondary mutation
ponatinib

Additional relevant MeSH terms:
Ponatinib
Gastrointestinal Stromal Tumors
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Imatinib Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action