GIST: Assessment of Tumor Mutations and TKI Plasma Exposure

NCT02331914 | Completed

• 1 other identifier: 19082014
• Study Type: observational
• Target: 740
• Locations: 1 country
• Sites: 5

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.

Conditions

Gastro-intestinal Stromal Tumor

Keywords

GIST; Bio-databank

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Secondary mutations in circulating tumor DNA before progressive disease according RECIST

  2 years

• Secondary mutations in circulating tumor DNA related to pharmacokinetics of TKI

  2 years

Study Arms (1)

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; Procedure: Tumor biopsy

Interventions

Vena puncture for blood collection PROCEDURE

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.

Gastro-intestinal stromal tumors

Tumor biopsy PROCEDURE

Tumor biopsy after disease progression

Gastro-intestinal stromal tumors

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Patients with locally advanced or metastatic gastrointestinal stromal tumors treated with tyrosine kinase inhibitors.

You may qualify if:

• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• University Medical Center Groningen: lead
• Dutch Cancer Society: collaborator

Study Sites (5)

Antoni van Leeuwenhoek Hospital

Amsterdam, Netherlands

Location

University Medical Center Groningen

Groningen, 9713 GZ, Netherlands

Location

Leiden University Medical Center

Leiden, Netherlands

Location

University Medical Center St. Radboud

Nijmegen, Netherlands

Location

Erasmus MC

Rotterdam, Netherlands

Location

Biospecimen

Retention: SAMPLES WITH DNA

Tumor biopsy after disease progression

Study Officials

• A. K. Reyners, MD, PhD

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 29, 2014
• First Posted: January 6, 2015
• Study Start: December 8, 2014
• Primary Completion: January 31, 2024
• Study Completion: January 31, 2024
• Last Updated: May 13, 2025

Record last verified: 2025-05

Locations

NL (5)