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Clinical Trial 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).


Clinical Trial 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 Design


Related Conditions & MeSH terms


NCT number NCT03171389
Study type Interventional
Source Universität Duisburg-Essen
Contact Johanna Falkenhorst
Phone +49 201 723 84150
Email johanna.falkenhorst@uk-essen.de
Status Recruiting
Phase Phase 2
Start date March 22, 2017
Completion date September 22, 2020

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