Clinical Research of Drug Holiday Based on MRD Detection in GIST Patients at High Risk of Recurrence

Study Overview
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Brief Summary
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This study is aimed: to evaluate the dynamic monitoring value of MRD detection for postoperative recurrence in high-risk GIST patients; to evaluate the effect of drug holiday mode based on MRD detection on progression-free Survival (PFS) and/or overall survival (OS) after drug withdrawal for high-risk GIST patients who have achieved disease control after long-term use of imatinib; ③ to investigate the response rate of imatinib re-use in patients who developed disease progression after drug withdrawal; ④ to explore whether the drug holiday treatment mode based on MRD detection could delay the occurrence of secondary imatinib resistance mutations for high-risk GIST patients with long-term use of imatinib after surgery.

Detailed Description
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Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, and surgery is the preferred treatment method for primary resectable GIST. The guidelines recommend that patients at high risk of recurrence should be treated with tyrosine kinase inhibitors (TKI) such as imatinib for at least 3 years after surgery. However, in actual clinical practice, some patients face the situation of early withdrawal or prolonged medication, so the timing of drug withdrawal needs to be further studied. Recent studies have reported that some GIST patients who have achieved disease control through long-term use of imatinib can still achieve a long progression-free survival after drug withdrawal, and those who relapse after drug withdrawal can still achieve disease control after re-use of imatinib. This suggests that for some selected patients, a drug holiday treatment mode could be possible, in which drugs are discontinued when appropriate and restarted if necessary. How to select patients suitable for this mode of treatment needs further exploration. Liquid biopsy of peripheral blood circulating tumor DNA (ctDNA) to detect minimal residual disease (MRD) can be used for the diagnosis, efficacy evaluation, recurrence and drug resistance monitoring of a variety of malignant tumors. Existing studies have explored the drug holiday treatment mode based on MRD detection assisting patients with advanced non-small cell lung cancer to use TKI. Therefore, this one-arm prospective observational clinical study will assist some high-risk GIST patients who have been treated with imatinib for 3 years after surgery and have achieved disease control to adopt the treatment mode of drug holiday based MRD detection, aiming to evaluate the value of MRD detection in monitoring postoperative recurrence of high-risk GIST, investigate the effect of drug holiday treatment mode based on MRD detection on disease recurrence and patient survival, and to explore whether it can delay the occurrence of drug-resistant mutations.

Official Title
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Clinical Research of Drug Holiday Based on MRD Detection in Gastrointestinal Stromal Tumor Patients at High Risk of Recurrence

Conditions
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Gastrointestinal Stromal Tumors

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ① Age: ≥18 years and ≤75 years; ② The primary lesion (and metastatic lesion) underwent R0 or R1 surgical resection, and patients were clinically diagnosed with high recurrence risk GIST combined with postoperative pathological results; ③ The patient have received imatinib adjuvant therapy for 3 years after surgery, and no gross lesions were detected by imaging examination, and the possibility of drug withdrawal was considered based on the comprehensive judgment of the doctor in charge; ④ The liquid biopsy for baseline ctDNA is negative; ⑤ Primary Imatinib resistant mutations were not detected by genetic testing, such as SDH-deficient GIST, NF1-mutant GIST, BRAF-mutant GIST and GIST with NTRK3 rearrangement; ⑥ PS score is 0-1 and expected survival time is more than 4 months; ⑦ Patients are willing to stop drug use and observe, and patients and their families could understand the study protocol and voluntarily participate in this study, and signed informed consent. In the follow-up study, they could provide the clinical pathological data and imaging data needed for the study process, cooperate with the follow-up and collect the blood of the clinical efficacy evaluation, and agree to use the test data for the follow-up study and product development. Exclusion Criteria: ① Fresh or paraffin tissue of the surgical tumor is not available; ② Not receiving the assigned treatment or change therapy before disease progression; ③ Unable to cooperate with follow-up with the study according to defined clinical period; ④ Unable to take or provide defined imaging assessment examinations; ⑤ Other conditions that investigators consider inappropriate for enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| patients cohort<br>As an one-arm observational clinical trial, we have only one patients cohort. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progress-free Survival | Progression-free survival after patients first enter the drug holiday | From date when patients first enter the drug holiday until the date of imaging examinations confirmed disease progression up to 3 years | 
| Drug re-use rate | The proportion of patients who take drug re-use due to disease progression within 3 years after first entering drug holiday | 3 years from the time when patients first enter the drug holiday | 
| Drug retreatment response rate | Drug response rate among patients who take drug re-use due to disease progression within 3 years after first entering drug holiday | 3 years from the time when patients first enter the drug holiday | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival after patients first enter the drug holiday | From date when patients first enter the drug holiday until the date of death up to 3 years | 
| genetic mutation profiling of ctDNA-MRD | Results of genetic mutations in patients after the conversion of MRD from negative to positive, especially the detection of secondary imatinib resistance mutations | 3 years from the time when patients first enter the drug holiday | 
| MRD versus imaging examination | compare the time of MRD conversion and the time of disease progression assessed by imaging examination | 3 years from the time when patients first enter the drug holiday | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastrointestinal Stromal Tumors, Drug Holiday, Minimal Residual Disease, Circulating Tumor DNA