Ignite Creation Date:
2024-05-05 @ 5:00 PM
Last Modification Date:
2024-10-26 @ 9:27 AM
Study NCT ID:
NCT00367861
Status:
COMPLETED
Last Update Posted:
2014-02-24
First Post:
2006-08-21
Brief Title:
Prospective Multicentric Randomized Study of Glivec in Advanced GIST Expressing C-kit Interruption After 5 Years vs Maintenance
Sponsor:
Centre Leon Berard
Organization:
Centre Leon Berard
Study Overview
Official Title:
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
Status:
COMPLETED
Status Verified Date:
2014-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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
Detailed Description:
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 advancedmetastatic 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 mgday 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 responseor 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 mgday in a population of patients with metastatic andor 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 400mgday Glivec may be increased to 600 mgday or 800 mgday 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
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 advancedmetastatic 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 mgday 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 responseor 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 mgday in a population of patients with metastatic andor 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 400mgday Glivec may be increased to 600 mgday or 800 mgday 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| ET2002-021 | None | None | None |