A Randomized Phase III Study of Adjuvant Imatinib for Recurrence-Free Survival in High-Risk Operable Gastrointestinal Stromal Tumor Patients

Trial ID: 2024-512243-23-00
Sponsor: Region Skane

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Diseases & Conditions

Gastrointestinal stromal tumour

Objectives

The primary objective of this study is to **calculate the recurrence-free survival (RFS)** after randomisation in patients with operable gastrointestinal stromal tumor (GIST) who are at high risk for recurrence. This is clinically relevant as it aims to determine the efficacy of extending adjuvant imatinib treatment from three to five years, potentially improving patient outcomes by reducing the likelihood of tumor recurrence.

Secondary objectives include:

Calculate the overall survival, providing insights into the long-term benefits of extended treatment.
Calculate the GIST-specific survival, which focuses on survival directly related to the disease.
Assess the toxicity in patients treated with **imatinib**, evaluating the safety profile of prolonged therapy.
Assess the quality of life in patients treated with imatinib, determining the impact of extended treatment on patient well-being.

Participants

The clinical trial involves a total of **95 participants** diagnosed with **gastrointestinal stromal tumor** (GIST). The study population includes both male and female subjects, aged 18 years and older, who have undergone macroscopically complete surgical resection of GIST. Participants were selected based on specific criteria, including morphological and immunohistological documentation of GIST, a high risk of tumor recurrence, and adequate organ function. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, ensuring they are in a relatively stable health condition. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to effective birth control methods if of reproductive potential. The trial population is not limited to a specific gender, and both vulnerable and non-vulnerable populations are included. The selection process ensures that participants have provided informed consent and are willing to comply with follow-up requirements at the study site.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of extending adjuvant **imatinib** treatment from three to five years in patients with operable **gastrointestinal stromal tumor** (GIST) at high risk for recurrence. This is a randomized, phase III study with a double-blind, controlled design. The trial aims to calculate the recurrence-free survival (RFS) after randomization, with primary endpoints including the time interval between the date of randomization and the first detection of GIST recurrence or death. Secondary endpoints include overall survival, GIST-specific survival, safety, and quality of life. The trial is expected to conclude by December 31, 2030, with recruitment having started on December 1, 2014.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented GIST, and adequate organ function. Following randomization, participants will have follow-up visits at six-month intervals during the first five years, with CT/MRI scans to monitor for recurrence. An end-of-study visit will occur at the conclusion of the participant's involvement in the trial. The expected length of participant involvement is up to five years, with conditions for early termination including significant adverse events or withdrawal of consent.

Participants must meet specific inclusion criteria, such as being 18 years or older, having a high risk of tumor recurrence, and having undergone macroscopically complete surgical resection of GIST. Exclusion criteria are not specified in the provided data. The study drug, Glivec 100 mg film-coated tablets, is administered orally, with a maximum daily dose of 400 mg. The trial is not classified as low intervention and is conducted under the sponsorship of Novartis Europharm Limited. The study is not intended for pediatric populations, and participants must agree to effective birth control measures if of reproductive potential.

Treatment

The clinical trial involves the administration of **Glivec 100 mg film-coated tablets**, which contain the active substance **imatinib**. Imatinib is a chemical compound used in the treatment of patients with operable gastrointestinal stromal tumors (GIST) at high risk for recurrence. The pharmaceutical form of the medication is a film-coated tablet, designed for **oral use**. The maximum daily dose of imatinib administered in this trial is 400 mg, with a total maximum dose of 292,000 mg over the course of the study. The treatment period is set for a maximum of 24 months. The medication is manufactured by Novartis Europharm Limited and is not a pediatric formulation.

In this randomized phase III study, the primary objective is to calculate the recurrence-free survival (RFS) after randomization. Participants will be monitored for compliance with the dosing schedule, which involves the regular oral administration of the medication as per the prescribed dosage. The study does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The trial is designed to assess the efficacy of imatinib in prolonging recurrence-free survival in the specified patient population.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the measurement of **recurrence-free survival (RFS)**. RFS is defined as the time interval between the date of randomization and the date of first detection of gastrointestinal stromal tumor (GIST) recurrence or death, whichever occurs first. To evaluate RFS, participants will undergo CT/MRI scans at 6-month intervals during the first 5 years of the study in each arm, followed by annual assessments. Secondary endpoints include overall survival, GIST-specific survival, safety, and quality of life. GIST-specific survival is measured as the time period between the date of randomization and the date of death attributed to GIST, with patients who die from other causes being censored on the date of death. These efficacy parameters will be collected and analyzed to determine the effectiveness of the treatment regimen in preventing recurrence and improving survival outcomes in patients with operable GIST at high risk for recurrence.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age ≥ 18 years.
Morphological and immunohistological documentation of GIST (immunostaining for KIT [CD117] and/or DOG-1 positive, or mutation of KIT or PDGFRA present in tumour tissue).
Macroscopically complete surgical resection of GIST (either R0 or R1 resection).
Mutation analysis of KIT and PDGFR genes has been carried out.
A high risk of tumour recurrence following surgery and 3 years of adjuvant imatinib defined as one of the following: 1) gastric GIST with mitotic count >10/50 HPFs HPF, high Power field of the microscope) or >10/5mm2, or 2) non-gastric GIST with mitotic count >5/50 HPFs or >5/5 HPFs mm2, or 3) non-gastric GIST treated with neoadjuvant imatinib and initially larger than 10 cm, or 4) tumour rupture Tumour rupture may have occurred before or at surgery. Tumour rupture is defined by spillage of the tumour contents into the abdominal cavity. A core needle biopsy from the tumour, or tumour bleed with no apparent spillage of the tumour contents, are not considered ruptures. If only a small amount of pretreatment tumour tissue is available from a core needle biopsy, it is acceptable to multiply the mitotic count obtained from fewer than 50 HPFs to approximate the counts obtained from 50 HPFs in surgical biopsies, or to multiply the count obtained from a tumour tissue area less than 5 mm2 to approximate the counts obtained from the 5 mm2 area. However, if only minimal amount of tumour tissue is available from a core needle biopsy (from 5 or fewer HPFs, or only 1 mitosis can be identified), multiplication should not be attempted and is not considered acceptable. For further explanation of this expanded high risk classification, please see section 3.2.3.
ECOG performance status ≤ 2.
Adequate organ function, defined as serum total bilirubin <1.5 x ULN (upper limit of normal), serum AST (SGOT) and ALT (SGPT) <2.5 x ULN, creatinine <1.5 x ULN; blood ANC (neutrophil count) ≥1.0 x 109/L, platelet count ≥100 x 109/L.
Female patients of childbearing potential must have a negative pregnancy test within 14 days before initiation of study drug dosing. Postmenopausal women must have amenorrhoea for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.
Patient willing to be followed up at the study site regardless of the result of randomisation.
Patient has provided a written, voluntary informed consent prior to study-specific screening procedures.

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Exclusion Criteria

Presence of distant metastases or local recurrence of GIST.
Not willing to donate tumour tissue and/or blood samples for the study molecular studies.
Presence of a substitution mutation at PDGFRA codon D842 (usually D842V).
Administration of adjuvant imatinib longer than for 3 years is planned regardless of the result of randomisation, or "life long" imatinib administration is planned.
Prior adjuvant (+ neoadjuvant) therapy with imatinib mesylate for at least 35 months has not been completed, or the total duration of prior adjuvant (+ neoadjuvant) imatinib administration exceeds the total duration of 38 months.
Neoadjuvant imatinib for a duration that exceeds 12 months.
Longer than 4-week break during adjuvant imatinib administration.
The dose of imatinib at completion of 3 years of adjuvant imatinib was 200 mg per day or less or greater than 800 mg per day.
Patient has received any investigational anti-cancer agents during adjuvant imatinib or between completion of adjuvant imatinib and the date of randomisation.
Patient has been free of another malignancy for less than 5 years except if the other malignancy is not currently clinically significant nor requiring active intervention, or if the other malignancy is one of the following: basal cell skin cancer, a cervical carcinoma in situ, a small (2 cm or less in diameter) node-negative breast cancer (pT1N0M0), a low Gleason score (<8) local (T1 or T2) prostate cancer. Recent existence of any other malignant disease is not allowed.
Patient with Grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., congestive heart failure, myocardial infarction within 6 months of study entry).
Female patients who are pregnant or breast-feeding.
Severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, severe chronic renal disease, or active uncontrolled infection).
Known diagnosis of human immunodeficiency virus (HIV) infection.
Patient with a significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	01 Dec 2014	20
Denmark	Not Recruiting	01 Dec 2014	10
Finland	Not Recruiting	01 Dec 2014	10
Germany	Not Recruiting	01 Dec 2014	50
The Netherlands	Not Recruiting	01 Dec 2014	—
Norway	Not Recruiting	01 Dec 2014	25
Spain	Not Recruiting	01 Dec 2014	50
Sweden	Not Recruiting	01 Dec 2014	20
Netherlands	—	—	20