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interruption of Glivec®

Jean Yves Blay, M.D., Ph.D

Axel Le Cesne, M.D.

Gastrointestinal stromal tumors (GISTs) are associated with a dismal prognosis in localized and advanced phase with a major resistance to conventional chemotherapy agents. 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 and exerts a major antitumor efficacy in vivo in patients with advanced GIST. Glivec® is generally pursued until progression or intolerance. The optimal duration of treatment with Glivec® remains unknown. The objective of this study is to determine the feasibility of Glivec® treatment interruption with reintroduction at progression in GIST patients.

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.

Prospective Multicentric Randomized Study of Glivec® in Advanced GIST Expressing C-kit: Interruption After 5 Years vs Maintenance

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

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

To compare overall survival beyond 2 years in the two groups of randomized patients.

Evaluation of toxicity during inclusion in the study

Gustave Roussy, Cancer Campus, Grand Paris

Centre Leon Berard

Spots Global Cancer Trial Database for interruption of glivec®