Phase II Multicenter Study on Imatinib Mesilate Maintenance vs. Interruption in Advanced/Metastatic Gastrointestinal Stromal Tumors After 10 Years of Treatment

The primary objective of this study is to compare the **6-month progression-free rate (PFR-6m)** between the interruption and maintenance of **imatinib** treatment in patients with advanced or metastatic **Gastrointestinal Stromal Tumors (GISTs)** who have been controlled after 10 years of imatinib treatment. This evaluation is clinically relevant as it aims to determine the optimal management strategy for long-term treatment in GIST patients, potentially impacting patient outcomes and quality of life.

Secondary objectives include:

• Comparing progression-free survival (PFS) between the two arms.
• Assessing overall survival (OS).
• Evaluating the safety profile of the treatment.
• Assessing the Quality of Life (QoL) of patients.
• In the interruption arm, determining the Progression-Free Survival rechallenge (PFS rechallenge) in patients who progressed.
• Evaluating the Objective Response Rate (ORR).
• Assessing the duration of response (DOR) after imatinib reintroduction.
• Translational objectives include identifying the genomic expression profile and immunologic characteristics of potentially cured patients.

The clinical trial involves participants diagnosed with **locally advanced or metastatic Gastrointestinal Stromal Tumors** (GIST). The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically documented diagnosis of malignant advanced/metastatic GIST with immunohistochemical documentation of c-kit (CD117) expression. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2, and must have been under imatinib treatment (at 300 or 400 mg/day) for 10 years or more, with controlled disease and no progression under imatinib. The sponsor has not provided the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. Participants must be covered by medical insurance and have the ability to understand and willingness for follow-up visits. The trial population was selected based on these criteria, ensuring that all participants have a stable health status conducive to the study's requirements.

The clinical trial is designed to evaluate the **interest of imatinib** treatment maintenance or interruption after at least 10 years of treatment in patients with locally advanced or metastatic **Gastrointestinal Stromal Tumors** (GISTs). This is a randomized, prospective, multicenter, open-label phase IV study. The primary objective is to compare the 6-month progression-free rate (PFR-6m) between the interruption and maintenance of imatinib treatment in patients with advanced/metastatic GIST controlled after 10 years of imatinib treatment. The trial is expected to run from December 22, 2021, to December 22, 2026.

Participants will be randomly assigned to either continue or interrupt imatinib treatment. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor disease progression and treatment safety, and an end-of-study visit to assess the final outcomes. The inclusion criteria require participants to be 18 years or older, have a histologically documented diagnosis of malignant advanced/metastatic GIST with c-kit (CD117) expression, and have been under imatinib treatment for at least 10 years with controlled disease. Participants must also have an ECOG Performance Status of 0, 1, or 2, and provide informed consent.

The expected length of participant involvement is up to 24 months, with conditions for early termination including disease progression, withdrawal of consent, or adverse events. The primary endpoint is the progression-free rate at 6 months, while secondary endpoints include progression-free survival (PFS), overall survival (OS), safety, quality of life (QoL), and response to imatinib reintroduction. Safety will be assessed through the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), with tolerance evaluated using the NCI-CTC AE v5 grading scale. The study aims to provide valuable insights into the long-term management of GISTs with imatinib therapy.

The clinical trial involves the use of **Imatinib Mesilate** as the experimental medication. Imatinib Mesilate is a chemical compound administered in the form of oral tablets. The pharmaceutical form is designated as PHF00082MIG. The maximum daily dose of Imatinib Mesilate is 800 mg, with a total maximum dose of 19,200 mg over the course of the treatment. The treatment period is capped at 24 months. The administration route is oral, and the medication is not formulated for pediatric use. The active substance, Imatinib Mesilate, is classified under the ATC code L01XE01, indicating its use as an antineoplastic agent. The trial aims to evaluate the maintenance or interruption of Imatinib treatment in patients with locally advanced or metastatic Gastrointestinal Stromal Tumors (GISTs) after at least 10 years of treatment.

In this study, there are no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments mentioned. The focus is solely on the administration of Imatinib Mesilate. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed to assess the progression-free rate at six months between the continuation and cessation of Imatinib treatment in the specified patient population.

Efficacy in this clinical trial will be assessed primarily through the **progression-free rate at 6 months (PFR-6m)**. This endpoint will be expressed as the rate of patients with non-progression of disease 6 months after randomization. Secondary efficacy endpoints include progression-free survival (PFS), overall survival (OS), and the objective response rate (ORR) after imatinib reintroduction. PFS will be measured from the date of randomization to the date of first documented progression or death from any cause, with patients without events being censored at the date of the last available tumor assessment. OS will be determined from the date of randomization to the date of death from any cause.

Additional secondary endpoints include the safety profile, assessed through the incidence of treatment-emergent adverse events (TEAE), serious adverse events (SAE), and death, with tolerance evaluated using the NCI-CTC AE v5 grading scale. Quality of life (QoL) will be measured using the EORTC QLQ-C30 questionnaire. PFS rechallenge will be defined as the time from the date of imatinib reintroduction in the experimental arm to the date of subsequent progression or death, with patients without events censored at the date of the last available tumor assessment. The duration of response to imatinib after reintroduction will be calculated from the date of first objective response following reintroduction to the date of first subsequent documented radiological progression or death, with censoring at the date of the last available tumor assessment.