GIST: Assessment of Tumor Mutations and TKI Plasma Exposure

Study Overview
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Brief Summary
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Gastrointestinal stromal tumors (GISTs) belong to the sarcoma group and are characterized by oncogenic mutations in the c-KIT, PDGFRA, BRAF and NF-1 genes that drive tumor growth. Since tyrosine kinase inhibitors (TKIs) have become available, the median survival of GIST patients increased from 9 months to over 5 years. Consequently, this rare disease has become a role model for other targeted therapies. However, response to TKIs is extremely heterogeneous:  15% of the patients experience no benefit from imatinib, whereas  17% of the patients enjoy stable disease for over 9 years. Treatment failure due to primary and secondary resistance is caused in part by mutations in oncogenic genes that cause change in drug sensitivity. A new technique, using circulating tumor DNA, has enabled us to assess mutations in a simple blood sample obtained from patients on treatment, and thus detect new mutations early in the course of the disease. Also, differences in pharmacokinetic drug behavior add to the observed heterogeneity, and may cause resistance due to drug underexposure and thereby proliferation of the least sensitive tumor cells. This offers the opportunity to optimize and personalize targeted treatment for individual GIST patients by timely treatment adaptation based on early detection of secondary TKIs resistance mutations. Achieving this urgently requires data on daily clinical practice, including prospective serial mutation analysis and serial drug plasma concentration measurement. At a fundamental level this will also help to unravel the driving factors behind primary and secondary TKIs resistance in this model disease.

Detailed Description
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The treatment of Dutch GIST patients is centralized: almost all patients are referred to one of the five collaborating centers forming the Dutch GIST consortium, UMCG, NKI-AvL, Radboud UMC, Erasmus MC and LUMC. To further optimize treatment for all patients, these centers have implemented a standard-of-care diagnostic and treatment plan that assures collection of homogenous phenotypic and treatment data for the bio-databank. The consortium is supported by and works in close collaboration with the Dutch sarcoma and GIST patient organizations. A prospective, longitudinal bio-databank will be set up. Data regarding multi-morbidity, drug pharmacokinetics and serial tumor genotypic data will be collected prospectively from all (new) GIST patients during TKI treatment. Our standard-of-care plan includes primary tumor mutation analysis, performed by pathology laboratories on site. At each follow up visit during treatment, blood will be collected to assess TKI plasma exposure and to perform mutation analysis on circulating tumor DNA. All patients will be followed for tumor RECIST 1.1 progression assessed by CT scans and asked to undergo a tumor biopsy at progression to detect secondary resistance mutations. The development of a model predicting secondary imatinib resistance based on patient phenotype and tumor genotype, will be achieved by analyzing GIST patients with progressive disease on imatinib (index patients; n=30) in our bio-databank. These patients will be matched 1:1 with non-progressive patients treated for the same duration as the index patients. Regarding the index patients, next-generation gene-targeted mutation analysis will be performed on archival tumor material and on a tumor biopsy at progression to identify patient's unique secondary mutations. The mutations that will be studied are: KIT exon 9, exon 11, exon 13, exon 14, exon 17 and exon 18; PDGFRA exon 12, exon 14 and exon 18 and BRAF exon 10 en exon 15. In-depth analysis regarding mutation analysis in circulating tumor DNA and imatinib drug concentration assessment will be performed for these 60 patients.

Official Title
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Gastrointestinal Stromal Tumors: Assessment of Mutations in Tumors and in Circulating Tumor DNA and Measurement of TKI Plasma Exposure to Optimize Treatment

Conditions
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Gastro-intestinal Stromal Tumor

Intervention / Treatment
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* Procedure: Vena puncture for blood collection
* Procedure: Tumor biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients diagnosed with a GIST with an indication to be treated with a TKI of whom a histological biopsy before start treatment is available. Informed consent is given Exclusion Criteria: Patients of whom no tumor is available before start of first line TKI Patients that refuse a tumor biopsy in case of tumor progression Patients in whom it will not be possible to perform a biopsy in case of tumor progression (for example anti-coagulants that cannot be interrupted).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Gastro-intestinal stromal tumors<br>A bio-databank consisting of TKI drug level and serum for analysis of mutations in circulating tumor DNA will be set up. This bio-databank will be used to study whether changes in the amount of the primary KIT mutation is an early predictor of treatment response and/of failure. Moreover, secondary TKI resistant mutations in circulating tumor DNA will be assessed. To be able to assess those mutations, a tumor biopsy will be performed at the time of radiologic progressive disease. Vena puncture for blood collection will be performed at routine out patient visits. | Procedure: Vena puncture for blood collection<br>* GIST patients will be asked to provide 40ml blood that will be collected in four Na-EDTA 10ml blood collection tubes at every routine outpatient visit.<br>Procedure: Tumor biopsy<br>* Tumor biopsy after disease progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary GIST mutations in circulating tumor DNA of patients with progressive disease on TKI treatment | To assess whether secondary GIST mutations can be found in circulating tumor DNA of patients with progressive disease on TKI treatment (according to RECIST 1.1 on computer tomography), whereas they are NOT present in the patients that have no progressive disease after the same time of TKI treatment | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary mutations in circulating tumor DNA before progressive disease according RECIST | To establish whether these secondary mutations can be detected some time (> 3 months) before progressive disease is assessed according to RECIST 1.1 on computer tomography | 2 years | 
| Secondary mutations in circulating tumor DNA related to pharmacokinetics of TKI | To assess whether the occurence of secondary mutations in circulating tumor DNA is related to TKI trough levels | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GIST, Bio-databank