The GALLOP-11 Study

Study Overview
=================
Brief Summary
-----------------
An observational, multicenter study will be performed. Regular 3-12 monthly follow-up by CT-scan will be compared to results of ctDNA analysis. Blood for analysis of mutation in ctDNA will be collected at the same moment a CT-scan is performed. All samples will be analyzed at the reference Pathology laboratory at the UMCG. A part of the samples will also be analyzed in other institutions to implement the ddPCR. Primary endpoint is concordance between CT-scan and ctDNA analysis results, from which the negative predictive value (NPV) of our ddPCR assay will be calculated.

Detailed Description
-----------------
This is an observational, non-interventional, multicenter study. The study will be performed within the Dutch GIST consortium (NKI-AvL, Erasmus MC, Radboud UMC, LUMC and UMCG). Patients diagnosed with GIST with a KIT exon 11 mutations that can be detected by our ddPCR assay are eligible. In this way we will study a homogenous patient population with GIST that (usually) responds very well to initial TKI treatment. Therefore, the KIT mutation status must be known. Patients can enter the study at any time point of their disease trajectory. Patients included in GALLOP-11 will have follow-up as described in the European Society of Medical Oncology and Dutch guidelines but with blood draws for ctDNA assessment at similar time points. The primary objective is the negative predictive value (NPV) of the ddPCR assay result in relation to the results of the CT-scan and/or MRI scan (according to RECIST 1.1) at the same time point. Concordance of these results will be determined, from which the negative predictive value (NPV) of our ddPCR assay will be calculated. This is considered the most important value, as the most harmful scenario would be to miss progressive disease because not seen on ctDNA while it could have been seen on CT (and/or MRI). That would mean that ctDNA analysis is not reliable enough to replace CT-scan (and/or MRI) follow-up in the future. To determine the negative predictive value, at least 250 patients need to have an evaluable follow-up strategy. To pursue a solid follow-up period within an achievable timeline, patients with at least four ctDNA measurements, accompanied by a CT-scan (and/or MRI scan), will be considered evaluable for the NPV analysis. Patients who have progression within four scans are always evaluable, since a positive outcome outweighs negative outcomes because it is known that ctDNA should have had measured change once it is seen on CT-scans (and/or MRI scans).

Official Title
-----------------
Validation of Mutation Analysis in Circulating Tumor DNA With a ddPCR Assay as Diagnostic and Follow-up Tool for Patients With a KIT Exon 11 Mutated GIST: GALLOP-11

Conditions
-----------------
Gastro-intestinal Stromal Tumors

Intervention / Treatment
-----------------
* Other: vena punction


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with GIST with a biopsy confirmed primary KIT exon 11 mutation covered by our KIT exon 11 ddPCR assay (mutation/deletion within target sequence of c.1665_1736); Patients with an indication for at least 4 CT-scans concomitant with regular laboratory examination in a neoadjuvant, adjuvant and/or palliative care trajectory within the time frame of the study; Age ≥18 years; Written informed consent provided. Exclusion Criteria: 1. Patients who are unable to comply with study procedures and follow up.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| GALLOP-11<br>Patients with a proven KIT exon 11 mutated GIST covered by our in-house designed ddPCR assay. | Other: vena punction<br>* Regular 3-12 monthly follow-up by CT-scan will be compared to results of ctDNA analysis. Blood for analysis of mutation in ctDNA will be collected at the same moment a CT-scan is performed<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The negative predictive value of the ddPCR assay with regard to KIT exon 11 circulating tumour mutation | The negative predictive value of the ddPCR assay with regard to KIT exon 11 circulating tumour mutation digital droplet PCR (ddPCR) assay in relation to CT-scans. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The sensitivity and specificity of the designed KIT exon 11 mutation | To establish the sensitivity and specificity of the designed KIT exon 11 mutation ddPCR assay | 3 years | 
| Technical validity of the ddPCR assay | The detection of ctDNA expressed in copies/mL and fractional abundance, assessed by the designed KIT exon 11 circulating tumour mutation digital droplet PCR (ddPCR) assay, in different laboratories, and by Agena Bioscience, will be assessed. | 3 years | 
| Clinical validity of the ddPCR assay | The first detection of increase in the level of the primary KIT exon 11 mutation in ctDNA determined in time to progression seen on standard radiological evaluation by CT-scan based on RECIST 1.1 | 3 years | 
| Development of new assays to detect secondary mutations | Based on mutation analysis of tumor biopsies of patients with progressive disease, ctDNA assays will be designed and tested | 3 years | 
| Determination of time between first detection of secondary mutations and progression | Based on progression of disease on CT, we will analyze ctDNA of patients to determine wether secondary mutations could be found before radiologic progression | 3 years |