Clinical trial NCT02331914: GIST: Assessment of Tumor Mutations and TKI Plasma Exposure
Official title: Gastrointestinal Stromal Tumors: Assessment of Mutations in Tumors and in Circulating Tumor DNA and Measurement of TKI Plasma Exposure to Optimize Treatment
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Gastro-intestinal Stromal Tumor
Keywords: GIST
Bio-databank
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: Dutch Cancer Society
First posted: 2015-01-06
Enrollment: 740
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients with locally advanced or metastatic gastrointestinal stromal tumors treated with tyrosine kinase inhibitors.

Brief 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.

Detailed 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Secondary GIST mutations in circulating tumor DNA of patients with progressive disease on TKI treatment
timeFrame: 2 years
Secondary outcomes:
measure: Secondary mutations in circulating tumor DNA before progressive disease according RECIST
timeFrame: 2 years
measure: Secondary mutations in circulating tumor DNA related to pharmacokinetics of TKI
timeFrame: 2 years
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek Hospital
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Nijmegen
country: Netherlands
facility: University Medical Center St. Radboud
city: Rotterdam
country: Netherlands
facility: Erasmus MC
Study officials:
affiliation: University Medical Center Groningen
name: A. K. Reyners, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: