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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.

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.

Ponatinib 30 MG

Johanna Falkenhorst

Sebastian Bauer, Prof. Dr.

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).

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

POETIG Trial - POnatinib After rEsisTance to Imatinib in GIST

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

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)

Assessment in each cohort and in the total patient population

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Quality of life questionnaire SQLQ (Supplementary Quality of life questionnaire)

Quality of life and fatigue questionnaire FACIT-F Version 4 (Functional Assessment of Chronic Illness Therapy-Fatigue)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
POETIG Trial - POnatinib After rEsisTance to Imatinib in GIST	NCT03171389	GIST, Malignant KIT Exon 13 Mut... KIT Gene Mutati...	Ponatinib 30 MG	18 Years -	Universität Duisburg-Essen
POETIG Trial - POnatinib After rEsisTance to Imatinib in GIST	NCT03171389	GIST, Malignant KIT Exon 13 Mut... KIT Gene Mutati...	Ponatinib 30 MG	18 Years -	Universität Duisburg-Essen

Spots Global Cancer Trial Database for kit exon 13 mutation