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GIST: Assessment of Tumor Mutations and TKI Plasma Exposure

This study is currently recruiting participants.
Verified April 2017 by A.K.L. Reyners, University Medical Center Groningen
Sponsor:
ClinicalTrials.gov Identifier:
NCT02331914
First Posted: January 6, 2015
Last Update Posted: April 21, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Dutch Cancer Society
Information provided by (Responsible Party):
A.K.L. Reyners, University Medical Center Groningen
  Purpose
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.

Condition Intervention
Gastro-intestinal Stromal Tumor Procedure: Vena puncture for blood collection Procedure: Tumor biopsy

Study Type: Observational
Study Design: Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Gastrointestinal Stromal Tumors: Assessment of Mutations in Tumors and in Circulating Tumor DNA and Measurement of TKI Plasma Exposure to Optimize Treatment

Resource links provided by NLM:


Further study details as provided by A.K.L. Reyners, University Medical Center Groningen:

Primary Outcome Measures:
  • Secondary GIST mutations in circulating tumor DNA of patients with progressive disease on TKI treatment [ Time Frame: 2 years ]
    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


Secondary Outcome Measures:
  • Secondary mutations in circulating tumor DNA before progressive disease according RECIST [ Time Frame: 2 years ]
    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

  • Secondary mutations in circulating tumor DNA related to pharmacokinetics of TKI [ Time Frame: 2 years ]
    To assess whether the occurence of secondary mutations in circulating tumor DNA is related to TKI trough levels


Biospecimen Retention:   Samples With DNA
Tumor biopsy after disease progression

Estimated Enrollment: 300
Study Start Date: November 2014
Estimated Study Completion Date: January 2019
Estimated Primary Completion Date: January 2019 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Gastro-intestinal stromal tumors

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
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.
Procedure: Tumor biopsy
Tumor biopsy after disease progression

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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Patients with locally advanced or metastatic gastrointestinal stromal tumors treated with tyrosine kinase inhibitors.
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).
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02331914


Contacts
Contact: A. K. Reyners, MD, PhD +31 50 361 2821 a.k.l.reyners@umcg.nl

Locations
Netherlands
Antoni van Leeuwenhoek Hospital Not yet recruiting
Amsterdam, Netherlands
Contact: N. Steeghs, MD, PhD       n.steeghs@nki.nl   
Principal Investigator: N. Steeghs, MD, PhD         
University Medical Center Groningen Recruiting
Groningen, Netherlands, 9713 GZ
Contact: A. K. Reyners, MD, PhD    +31 50 361 2821    a.k.l.reyners@umcg.nl   
Principal Investigator: A. K. Reyners, MD, PhD         
Leiden University Medical Center Not yet recruiting
Leiden, Netherlands
Contact: A. J. Gelderblom, MD, PhD       A.J.Gelderblom@lumc.nl   
Principal Investigator: A. J. Gelderblom, MD, PhD         
University Medical Center St. Radboud Not yet recruiting
Nijmegen, Netherlands
Contact: W. T. van der Graaf, MD, PhD       Winette.vanderGraaf@radboudumc.nl   
Principal Investigator: W. T. van der Graaf, MD, PhD         
Erasmus MC Not yet recruiting
Rotterdam, Netherlands
Contact: R. H. Mathijssen, MD, PhD       a.mathijssen@erasmusmc.nl   
Principal Investigator: R. H. Mathijssen, MD, PhD         
Sponsors and Collaborators
University Medical Center Groningen
Dutch Cancer Society
Investigators
Principal Investigator: A. K. Reyners, MD, PhD University Medical Center Groningen
  More Information

Responsible Party: A.K.L. Reyners, Principal investigator, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT02331914     History of Changes
Other Study ID Numbers: 19082014
First Submitted: December 29, 2014
First Posted: January 6, 2015
Last Update Posted: April 21, 2017
Last Verified: April 2017

Keywords provided by A.K.L. Reyners, University Medical Center Groningen:
GIST
Bio-databank

Additional relevant MeSH terms:
Gastrointestinal Stromal Tumors
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases