GIST: Assessment of Tumor Mutations and TKI Plasma Exposure

Last updated: May 12, 2025
Sponsor: University Medical Center Groningen
Overall Status: Completed

Phase

N/A

Condition

Solid Tumors

Abdominal Cancer

Digestive System Neoplasms

Treatment

Vena puncture for blood collection

Tumor biopsy

Clinical Study ID

NCT02331914
19082014
  • Ages 18-90
  • All Genders

Study Summary

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.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  • Patients diagnosed with a GIST with an indication to be treated with a TKI of whom ahistological biopsy before start treatment is available.

  • Informed consent is given

Exclusion

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 tumorprogression (for example anti-coagulants that cannot be interrupted).

Study Design

Total Participants: 740
Treatment Group(s): 2
Primary Treatment: Vena puncture for blood collection
Phase:
Study Start date:
December 08, 2014
Estimated Completion Date:
January 31, 2024

Study Description

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.

Connect with a study center

  • Antoni van Leeuwenhoek Hospital

    Amsterdam,
    Netherlands

    Site Not Available

  • University Medical Center Groningen

    Groningen, 9713 GZ
    Netherlands

    Site Not Available

  • Leiden University Medical Center

    Leiden,
    Netherlands

    Site Not Available

  • University Medical Center St. Radboud

    Nijmegen,
    Netherlands

    Site Not Available

  • Erasmus MC

    Rotterdam,
    Netherlands

    Site Not Available

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