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

Gastrointestinal Stromal Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05867901
• Other study ID #: 2023-076
• Status: Recruiting
• Start date: June 1, 2023
• Est. completion date: June 30, 2027

Study information

• Verified date: May 2023
• Source: Peking University People's Hospital
• Contact: Zhidong Gao, MD
• Phone: 010-88326600
• Email: gaozhidong[@]pkuph.edu.cn
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: June 30, 2027
• Est. primary completion date: June 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• ? Age: =18 years and =75 years;

• ? 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;

• ? 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;

• ? The liquid biopsy for baseline ctDNA is negative;

• ? 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;

• ? PS score is 0-1 and expected survival time is more than 4 months;

• ? 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:

• ? Fresh or paraffin tissue of the surgical tumor is not available;

• ? Not receiving the assigned treatment or change therapy before disease progression;

• ? Unable to cooperate with follow-up with the study according to defined clinical period;

• ? Unable to take or provide defined imaging assessment examinations;

• ? Other conditions that investigators consider inappropriate for enrollment.

Related Conditions & MeSH terms

• Gastrointestinal Stromal Tumors
• Recurrence

Locations

Country	Name	City	State
China	Peking University People's Hospital	Beijing	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
Peking University People's Hospital

Country where clinical trial is conducted

China, 

References & Publications (13)

Begum FA, Rahman MA, Rabbi H, Mostofa G, Chowdhury Q. Primary Jejunal Gastrointestinal Stromal Tumor: Diagnosis Delay of 3 Years but Successful Management in Early Stage (II) by Surgery and Adjuvant Therapy. Gastrointest Tumors. 2019 Aug;6(1-2):36-42. doi — View Citation

Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Hogarty MD, Holdhoff M, Hon — View Citation

Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, Dunning MJ, Gale D, Forshew T, Mahler-Araujo B, Rajan S, Humphray S, Becq J, Halsall D, Wallis M, Bentley D, Caldas C, Rosenfeld N. Analysis of circulating tumor DNA to monitor metastatic breast c — View Citation

Howland RH. Medication holidays. J Psychosoc Nurs Ment Health Serv. 2009 Sep;47(9):15-8. doi: 10.3928/02793695-20090804-01. — View Citation

Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schutte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Sarlomo-Rikala M, Nilsson B, Sihto H, Monge OR, Bono P, Kallio R, Vehtari A, Leinonen M, Alvegard — View Citation

Joensuu H, Eriksson M, Sundby Hall K, Reichardt A, Hermes B, Schutte J, Cameron S, Hohenberger P, Jost PJ, Al-Batran SE, Lindner LH, Bauer S, Wardelmann E, Nilsson B, Kallio R, Jaakkola P, Junnila J, Alvegard T, Reichardt P. Survival Outcomes Associated W — View Citation

Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol. 2008 Oct;39(10):1411-9. doi: 10.1016/j.humpath.2008.06.025. — View Citation

Kang YK, Kim HD, Kim HJ, Park YS, Beck MY, Ryu MH. Interruption of imatinib in advanced gastrointestinal stromal tumor after prolonged imatinib maintenance in the absence of gross tumor lesions. Gastric Cancer. 2023 Mar 8. doi: 10.1007/s10120-023-01377-2. — View Citation

Mazur MT, Clark HB. Gastric stromal tumors. Reappraisal of histogenesis. Am J Surg Pathol. 1983 Sep;7(6):507-19. doi: 10.1097/00000478-198309000-00001. — View Citation

Mitchell SM, Ho T, Brown GS, Baker RT, Thomas ML, McEvoy A, Xu ZZ, Ross JP, Lockett TJ, Young GP, LaPointe LC, Pedersen SK, Molloy PL. Evaluation of Methylation Biomarkers for Detection of Circulating Tumor DNA and Application to Colorectal Cancer. Genes — View Citation

Mouliere F, Thierry AR. The importance of examining the proportion of circulating DNA originating from tumor, microenvironment and normal cells in colorectal cancer patients. Expert Opin Biol Ther. 2012 Jun;12 Suppl 1:S209-15. doi: 10.1517/14712598.2012.6 — View Citation

Pantel K, Alix-Panabieres C. Liquid biopsy and minimal residual disease - latest advances and implications for cure. Nat Rev Clin Oncol. 2019 Jul;16(7):409-424. doi: 10.1038/s41571-019-0187-3. — View Citation

Raut CP, Espat NJ, Maki RG, Araujo DM, Trent J, Williams TF, Purkayastha DD, DeMatteo RP. Efficacy and Tolerability of 5-Year Adjuvant Imatinib Treatment for Patients With Resected Intermediate- or High-Risk Primary Gastrointestinal Stromal Tumor: The PER — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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