Three versus five years of adjuvant imatinib as treatment of patients with operable GIST with a high risk ofr recurrence: A randomised phase III study

1. Age >= 18 years.
2. 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).
3. Macroscopically complete surgical resection of GIST (either R0 or R1
resection).
4. Mutation analysis of KIT and PDGFR genes has been carried out.
5. A high risk of GIST recurrence, either
1) gastric GIST with mitotic count >10/50 HPFs, or >10/5mm2, or
2) non-gastric GIST with mitotic count >5/50 HPFs, or >5/5mm2, or
3) non gastric GIST with neoadjuvant imatinib and initially larger than 10 cm
4) tumour rupture
Tumour rupture (spillage of the tumour contents into the abdominal cavity) may
have occurred either 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 form
fewer than 50 HPF's to approximate the counts obtained from 50 HPFs in surgical
biopsies, or to multiply the count obtained form 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 form a core needle biopsy (from 5
or fewer HPFs, or only 1 mitosis can be indentified), multiplication should not
be attemted and is not considered acceptable.
6. ECOG performance status <= 2.
7. 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.
8. 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. For
females, a highly effective method for birth control must be used, which means
that the method can achieve a failure rate of less than 1% per year when used
consistently and correctly. All females of child-bearing potential must be
informed of such methods, and must also, if sexually active, accept a monthly
pregnancy test during treatment if randomized to prolonged imatinib use.
9. Patient willing to be followed up at the study site regardless of the result
of randomisation.
10. Patient has provided a written, voluntary informed consent prior to
study-specific screening procedures

1. Presence of distant metastases or local recurrence of GIST.
2. Not willing to donate tumour tissue and/or blood samples for the study
molecular studies.
3. Presence of a substitution mutation at PDGFRA codon D842 (usually D842V).
4. Administration of adjuvant imatinib longer than for 3 years is planned
regardless of the result of randomisation, or *life long* imatinib
administration is planned.
5. 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.
6. Neoadjuvant imatinib for a duration that exceeds 12 months.
7. Longer than 4-week break during adjuvant imatinib administration.
8. 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.
9. Patient has received any investigational anti-cancer agents during adjuvant
imatinib or between completion of adjuvant imatinib and the date of
randomisation.
10. 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 (2cm 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.
11. 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).
12. Female patients who are pregnant or breast-feeding.
13. Severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes,
severe chronic renal disease, or active uncontrolled infection).
14. Known diagnosis of human immunodeficiency virus (HIV) infection.
15. Patient with a significant history of non-compliance to medical regimens or
with inability to grant reliable informed consent
16. Inability of difficulty in swallowing tablets
17. Patients with chronic or active hepatitis B