In this study, patients who have been diagnosed with gastrointestinal stromal tumor (GIST) will be randomly allocated in a 1:1 ratio to receive imatinib (Gleevec) either for 12 or for 36 months following surgery. The study participants are required to have a histologically verified GIST with high to very high risk of GIST recurrence despite complete removal of all macroscopic GIST tissue at surgery. The high/very high risk of recurrence is defined as one of the following: 1) the largest tumor diameter is over 10 cm; 2) the mitosis count is high (over 10 mitoses per 50 high power microscope fields, HPFs); 3) the largest tumor diameter over 5 cm and the mitosis count is over 5/50 HPFs; 4) tumor spillage has taken place into the abdominal cavity at the time of surgery or following spontaneous tumor rupture; 5) intra-abdominal metastases are present but they could all be removed along with the primary surgery. All study participants will receive imatinib 400 mg/day orally, but the duration of imatinib administration will be determined randomly (either for 12 or for 36 months). The study participants will be followed up using blood tests and computed tomography (or MRI) of the abdomen. The computed tomography examinations will be performed at 6 month intervals for a median of 5 years. A total of 240 patients will be entered into the study. The study hypothesis is that adjuvant imatinib may prevent some of the GIST recurrences, and that there may be a difference in the rate of GIST recurrence between the two groups.

Condition	Intervention	Phase
Sarcoma Gastrointestinal Stromal Tumor	Drug: imatinib mesylate	Phase III

Further Study Details: 

Primary Outcomes: Recurrence-free survival
Secondary Outcomes: Adverse effects; Survival; GIST-specific survival
Expected Total Enrollment:  240

This is an open-label, randomized, prospective, phase III, multicenter study carried out in the Nordic countries and in Germany. Following macroscopically complete surgery, the study participants will be allocated to receive imatinib either for 12 or for 36 months. At randomization, the patients are stratified into 2 strata: 1) local disease (1 GIST tumor); 2) intra-abdominal implants or resectable intra-abdominal/hepatic metastases, or intra-abdominal spillage is present, or R1 surgery has been carried out (microscopic disease has been left behind). The imatinib dose is 400 mg/day administered with food. Imatinib dose adjustments are made as per protocol.

Medical history, current medication, weight, height, and ECOG performance status are recorded prior to study entry. Physical examination, blood cell counts, blood biochemistry, pregnancy test, chest X-ray or CT, and CT or MRI of the abdomen and pelvis are carried out/measured prior to study entry. FDG-PET is an optional staging examination. Research serum samples are collected for banking prior to initiating imatinib and at 6-month intervals during the study. Tumor tissue is reviewed centrally to confirm the histological diagnosis of GIST, and KIT and PDGFRA gene mutation analyses will be performed from stored GIST tissue.

The study participants are monitored during adjuvant treatment and following adjuvant treatment. Physical examination, weight and ECOG performance status are assessed at 4- to 26-week intervals. Adverse events are collected using structured forms at the times of the evaluation visits. Blood cell counts and blood biochemistry are measured at 2- to 6-week intervals during imatinib therapy, and at 6-month intervals following completion of adjuvant therapy. CT or MRI examinations of the abdomen and pelvis are performed at 6-month intervals during the study.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• Age 18 or older
• Histologically documented diagnosis of GIST
• Resectable GIST
• GIST removed at open surgery
• Immunohistochemical documentation of GIST (immunostaining for KIT/CD117)
• High risk of tumor recurrence as defined as one of the following: 1) the largest tumor diameter greater than 10.0 cm (measured by a pathologist, with any mitotic count); 2) mitotic count over 10 mitoses per 50 high power fields (HPFs) (with any tumor size); the largest tumor diameter larger than 5.0 cm and the mitotic count is over 5/50 HPFs; 4) tumor spillage into the abdominal cavity at surgery (or tumor rupture); abdominal or liver metastases that can be completely removed along with the primary tumor at surgery. No residual tumors must be present at laparotomy, or in postoperative CT or MRI examinations. The primary tumor and the abdominal implants need all be resected with macroscopically clear margins, but patients who have microscopically infiltrated margins (or suspected microscopical infiltration, R1) are also allowed to enter study.
• Performance status 0, 1, or 2 (ECOG)
• Adequate organ function, defined as follows: 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, ANC (neutrophil count) >1.5 x 10^9/L, platelets >100 x 10^9/L.
• Negative pregnancy test (females with childbearing potential)
• Written, voluntary informed consent

Exclusion Criteria:

• Inoperable or metastatic GIST, where metastases cannot be removed completely at surgery
• Metastatic disease outside of the abdomen
• Less than 1 week or more than 12 weeks has elapsed from surgery
• Recurrent GIST
• Patient has received any investigational agents within 28 days as calculated from the first day of the study drug dosing
• Patient is less than 5 years free from another primary malignancy
• Patient with grade III/IV cardiac problems as defined by the New York Heart Association Criteria
• Female patients who are pregnant or breast-feeding
• Patient has severe or uncontrolled medical disease (i.e. uncontrolled diabetes, severe chronic renal disease, or active uncontrolled infection). Concurrent use of warfarin or acetaminophen are not allowed with imatinib.
• Chronic liver disease
• Known diagnosis of human immunodeficiency virus (HIV) infection
• Patient has received chemotherapy for GIST
• Patient has received neoadjuvant imatinib therapy prior to randomization
• Radiotherapy to 25% or more of the bone marrow
• Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent

Please refer to this study by ClinicalTrials.gov identifier  NCT00116935

Heikki Joensuu, M.D.      +358-9-471 73208    heikki.joensuu@hus.fi
Thor Alvegård, M.D.      +46-46-177550    thor.alvegard@cancerepid.lu.se

Sweden
      Scandinavian Sarcoma Group, Southern Swedish Regional Tumour Registry, Lund University Hospital, Lund,  SE-221 85,  Sweden; Recruiting

Study chairs or principal investigators

Heikki Joensuu, M.D.,  Principal Investigator,  Department of Oncology, Helsinki University Central Hospital   

Study ID Numbers:  SSGXVIII/AIO
Record last reviewed:  June 2005
Last Updated:  June 30, 2005
Record first received:  June 30, 2005
ClinicalTrials.gov Identifier:  NCT00116935
Health Authority: Finland: National Agency for Medicines
ClinicalTrials.gov processed this record on 2005-07-05