POETIG Trial - POnatinib After rEsisTance to Imatinib in GIST

NCT03171389 | Unknown Phase 2 FDA Drug

• 1 other identifier: POETIG
• Study Type: interventional
• Target: 81
• Locations: 1 country
• Sites: 1

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).

Conditions

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

Keywords

GIST; KIT secondary mutation; ponatinib

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Progression-free survival (PFS)

  through study completion, an average of 3.5 years

• Objective response rate (ORR)

  16 weeks

• Overall survival (OS)

  through study completion, an average of 3.5 years

• Assessment of treatment-related adverse events

  3.5 years

• Quality of life assessment

  approx. 3.5 years (duration of study + 2 years follow-up period)

Study Arms (3)

Cohort A

EXPERIMENTAL

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

Cohort B

EXPERIMENTAL

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

Cohort C

EXPERIMENTAL

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

Interventions

Ponatinib 30 MG DRUG

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.

Also known as: Iclusiq

Cohort A; Cohort B; Cohort C

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sebastian Bauer: lead
• Hannover Medical School: collaborator
• Helios Klinikum Berlin-Buch: collaborator
• University Hospital Tuebingen: collaborator
• Universitätsmedizin Mannheim: collaborator
• University Hospital, Aachen: collaborator
• Helios Klinikum Bad Saarow: collaborator
• WiSP GmbH: collaborator

Study Sites (1)

West German Cancer Center

Essen, North Rhine-Westphalia, 45122, Germany

RECRUITING

Related Publications (4)

• 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.

  PMID: 23190221 BACKGROUND

• 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.

  PMID: 24180494 BACKGROUND

• 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.

  PMID: 25239608 BACKGROUND

• 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.

  PMID: 35091442 DERIVED

Related Links

• Iclusiq (ponatinib) prescribing information

MeSH Terms

Conditions

Gastrointestinal Stromal Tumors

Interventions

ponatinib

Condition Hierarchy (Ancestors)

Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases

Study Officials

• Sebastian Bauer, Prof. Dr.

  University Hospital, Essen

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Johanna Falkenhorst

CONTACT

+49 201 723 84150; johanna.falkenhorst@uk-essen.de

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr. med.

Study Record Dates

• First Submitted: April 25, 2017
• First Posted: May 31, 2017
• Study Start: March 22, 2017
• Primary Completion: September 22, 2018
• Study Completion: September 22, 2020
• Last Updated: May 31, 2017

Record last verified: 2017-05

Locations

DE (1)