Trial Information

A Prospective Multicentric Randomized Study of Glivec® in Patients With Advanced Gastrointestinal Stromal Tumors Expressing C-kit Comparing Treatment Interruption After 5 Years vs Treatment Maintenance

Gastrointestinal stromal tumors (GISTs) are associated with a dismal prognosis in localized
and advanced phase with a major resistance to conventional chemotherapy agents. GIST cells
are positive for KIT (CD117) and CD34 in 100% and 70% of cases, respectively. Virtually all
malignant GISTs actually harbor activating mutations of the kit pathway in the tumor cells,
leading to ligand-independent activation of KIT tyrosine kinase activity and tumor growth in
vitro. Glivec® inhibits KIT activity at an IC50 of approximately 100 nM which is similar to
that required for inhibiting the tyrosine kinase associated with Bcr-abl and the PDGF
receptor. Experiments on cell lines containing an activating juxtamembrane mutation (similar
to that found in GISTs) and cell lines containing transfected wild type KIT protein, showed
that these cells appear to be strongly dependent upon the activity of the mutant receptor to
prevent apoptosis, thus providing further scientific justification for the development of
Glivec® as an antineoplastic agent with specific activity against GIST as a KIT-driven
malignancy.

Since the first single patient with metastatic GIST treated by Glivec® in March 2000 (16),
more than 2000 patients have been included in prospective trials testing activity and
tolerance of Glivec® in patients with advanced/metastatic GIST. High response rates have
been documented, only a limited percentage of patients progressed after achieving objective
response, and median survival has not been reached in all studies. There has been no clear
demonstration of a dose-response relationship. About 15% of patients experienced a rapid
disease progression under treatment but the mechanisms of resistance remain unknown. Some
patients progressing at 400 mg/day further responded to higher doses of Glivec®. Toxicities
were infrequent, mainly mild to moderate and their incidence seems to be related to the
total daily dose administered.

The optimal duration of treatment with Glivec® remains unknown. In addition the impact of
surgical procedures of tumoral residual masses is not yet evaluated on progression free and
overall survival. The objective of this study is to determine the feasibility of Glivec®
treatment interruption with reintroduction at progression in GIST patients.

Primary objective

- To compare progression-free overall survival beyond 1 year in patients treated by Glivec®
achieving a CR, PR or SD at 5 years. Patients will be randomized between 1) interruption of
Glivec® until progression w/ RECIST criteria and then re-start (group 1) vs 2) maintenance
of Glivec® (group 2).

Secondary objectives

- To compare overall survival in the two groups of randomized patients.

- To determine progression free survival beyond 1 year in patients in CR, PR or SD at 5
years who refused randomization and 1) selected Glivec® interruption or 2) chose
Glivec® maintenance.

- To determine CR, PR and SD rates after re-start of Glivec® in group 1.

- To assess the number of patients who completed radical surgery on tumour residual
masses after an objective response.

- To assess resource utilisation by evaluating direct and indirect cost.

- To evaluate the correlation between the serum rates of Glivec® and the response to the
treatment w/ RECIST criteria, in patients with the diagnosis of GIST and treated by
Glivec® 400mg /day, and this until progression, stop treatment or study exit.

- To follow immune modifications induced by Glivec® administration potentially related to
clinical response and toxicity.

- To realize if possible the sequencing with aiming diagnoses KIT, in order to evaluate
the correlations existing between the response/or the absence of response to Glivec®
and the type of mutation of KIT.

Overall study design : This is an open label clinical trial of oral Glivec® 400 mg/day in a
population of patients with metastatic and/or unresectable malignant GIST in relapse. 564
patients will be enrolled in ten years in 20-30 French Cooperative Centers.

Treatment : Patients will receive Glivec® 400 mg /day for an exposure period of 60 months.
At the end of a 5 years period, patients with non progressive disease will be proposed for
randomization between 1) interruption of Glivec® until progression w/ RECIST criteria and
then re-start vs 2) maintenance of Glivec®. Patient who refuse randomization will be
proposed either solution and followed according to the same schedule. During treatment with
Glivec® 400mg/day, Glivec® may be increased to 600 mg/day or 800 mg/day if the patient is
progressing. In case of re-progression, the patient will be excluded of this study.

Signed informed consent for the study, including the possible randomization, will be
obtained.