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

Primary Purpose

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

Status
Unknown status
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Ponatinib 30 MG
Sponsored by
Sebastian Bauer
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for GIST, Malignant focused on measuring GIST, KIT secondary mutation, ponatinib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • West German Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Cohort A

Cohort B

Cohort C

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

Progression-free survival (PFS)
Assessment in each cohort and in the total patient population
Objective response rate (ORR)
Assessment in each cohort and in the total patient population
Overall survival (OS)
Assessment in each cohort and in the total patient population
Assessment of treatment-related adverse events
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Quality of life assessment
Quality of life questionnaire SQLQ (Supplementary Quality of life questionnaire)
Fatigue assessment
Quality of life and fatigue questionnaire FACIT-F Version 4 (Functional Assessment of Chronic Illness Therapy-Fatigue)

Full Information

First Posted
April 25, 2017
Last Updated
May 26, 2017
Sponsor
Sebastian Bauer
Collaborators
Hannover Medical School, Helios Klinikum Berlin-Buch, University Hospital Tuebingen, Universitätsmedizin Mannheim, University Hospital, Aachen, Helios Klinikum Bad Saarow, WiSP GmbH
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1. Study Identification

Unique Protocol Identification Number
NCT03171389
Brief Title
POETIG Trial - POnatinib After rEsisTance to Imatinib in GIST
Acronym
POETIG
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Unknown status
Study Start Date
March 22, 2017 (Actual)
Primary Completion Date
September 22, 2018 (Anticipated)
Study Completion Date
September 22, 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Sebastian Bauer
Collaborators
Hannover Medical School, Helios Klinikum Berlin-Buch, University Hospital Tuebingen, Universitätsmedizin Mannheim, University Hospital, Aachen, Helios Klinikum Bad Saarow, WiSP GmbH

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

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).
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
GIST, Malignant, KIT Exon 13 Mutation, KIT Gene Mutation
Keywords
GIST, KIT secondary mutation, ponatinib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
81 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort A
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort B
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort C
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Ponatinib 30 MG
Other Intervention Name(s)
Iclusiq
Intervention Description
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.
Primary Outcome Measure Information:
Title
clinical benefit rate (CBR)
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)
Time Frame
16 weeks
Secondary Outcome Measure Information:
Title
Progression-free survival (PFS)
Description
Assessment in each cohort and in the total patient population
Time Frame
through study completion, an average of 3.5 years
Title
Objective response rate (ORR)
Description
Assessment in each cohort and in the total patient population
Time Frame
16 weeks
Title
Overall survival (OS)
Description
Assessment in each cohort and in the total patient population
Time Frame
through study completion, an average of 3.5 years
Title
Assessment of treatment-related adverse events
Description
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame
3.5 years
Title
Quality of life assessment
Description
Quality of life questionnaire SQLQ (Supplementary Quality of life questionnaire)
Time Frame
approx. 3.5 years (duration of study + 2 years follow-up period)
Title
Fatigue assessment
Description
Quality of life and fatigue questionnaire FACIT-F Version 4 (Functional Assessment of Chronic Illness Therapy-Fatigue)
Time Frame
approx. 3.5 years (duration of study + 2 years follow-up period)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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: 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Johanna Falkenhorst
Phone
+49 201 723 84150
Email
johanna.falkenhorst@uk-essen.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sebastian Bauer, Prof. Dr.
Organizational Affiliation
University Hospital, Essen
Official's Role
Principal Investigator
Facility Information:
Facility Name
West German Cancer Center
City
Essen
State/Province
NRW
ZIP/Postal Code
45122
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sebastian Bauer, Prof. Dr.

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
23190221
Citation
Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O'Hare T, Hu S, Narasimhan NI, Rivera VM, Clackson T, Turner CD, Haluska FG, Druker BJ, Deininger MW, Talpaz M. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012 Nov 29;367(22):2075-88. doi: 10.1056/NEJMoa1205127.
Results Reference
background
PubMed Identifier
24180494
Citation
Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio J, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Muller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H; PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013 Nov 7;369(19):1783-96. doi: 10.1056/NEJMoa1306494. Epub 2013 Nov 1.
Results Reference
background
PubMed Identifier
25239608
Citation
Garner AP, Gozgit JM, Anjum R, Vodala S, Schrock A, Zhou T, Serrano C, Eilers G, Zhu M, Ketzer J, Wardwell S, Ning Y, Song Y, Kohlmann A, Wang F, Clackson T, Heinrich MC, Fletcher JA, Bauer S, Rivera VM. Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients. Clin Cancer Res. 2014 Nov 15;20(22):5745-5755. doi: 10.1158/1078-0432.CCR-14-1397. Epub 2014 Sep 19.
Results Reference
background
PubMed Identifier
35091442
Citation
George S, von Mehren M, Fletcher JA, Sun J, Zhang S, Pritchard JR, Hodgson JG, Kerstein D, Rivera VM, Haluska FG, Heinrich MC. Phase II Study of Ponatinib in Advanced Gastrointestinal Stromal Tumors: Efficacy, Safety, and Impact of Liquid Biopsy and Other Biomarkers. Clin Cancer Res. 2022 Apr 1;28(7):1268-1276. doi: 10.1158/1078-0432.CCR-21-2037.
Results Reference
derived
Links:
URL
http://www.iclusig.com/pi/
Description
Iclusiq (ponatinib) prescribing information

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POETIG Trial - POnatinib After rEsisTance to Imatinib in GIST

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