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

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.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

1. Patients 18 years of age or over.
2. Histologically documented diagnosis of malignant GIST.
3. Immunohistochemical documentation of c-kit (CD117) expression either by the primary tumor or metastases using the DAKO assay.
4. Performance status 0,1, 2, 3 (ECOG)
5. Adequate end organ function, defined as the following: total bilirubin \< 1.5 x ULN, SGOT and SGPT \< 2.5 x UNL (or \< 5 x ULN if hepatic metastases are present), creatinine \< 1.5 x ULN, ANC \> 1.0 x 109/L, platelets \> 100 x 109/L.
6. Female patients of child-bearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing. Post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 2 weeks (according to updated Invest. Brochure) following discontinuation of study drug.
7. Written, voluntary, informed consent.

Exclusion Criteria:

1. Patient has another malignant tumor in CR\<3 years (except if the other primary malignancy is inactive and not requiring active intervention). Previous basal cell skin cancer or a cervical carcinoma in situ are allowed.
2. Patient with Grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e., congestive heart failure, myocardial infarction within 6 months of study)
3. Female patients who are pregnant or breast-feeding.
4. Patient has a known diagnosis of human immunodeficiency virus (HIV) infection.
5. Patients received chemotherapy within 2 weeks prior to study entry, unless the disease is rapidly progressing
6. Patients had a major surgery within 2 weeks prior to entry study
7. Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.
8. Previous treatment with Glivec®

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• BACKGROUNDBlay JY, Le Cesne A, Ray-Coquard I, Bui B, Duffaud F, Delbaldo C, Adenis A, Viens P, Rios M, Bompas E, Cupissol D, Guillemet C, Kerbrat P, Fayette J, Chabaud S, Berthaud P, Perol D. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol. 2007 Mar 20;25(9):1107-13. doi: 10.1200/JCO.2006.09.0183. PMID 17369574
• BACKGROUNDPatrikidou A, Chabaud S, Ray-Coquard I, Bui BN, Adenis A, Rios M, Bertucci F, Duffaud F, Chevreau C, Cupissol D, Domont J, Perol D, Blay JY, Le Cesne A; French Sarcoma Group. Influence of imatinib interruption and rechallenge on the residual disease in patients with advanced GIST: results of the BFR14 prospective French Sarcoma Group randomised, phase III trial. Ann Oncol. 2013 Apr;24(4):1087-93. doi: 10.1093/annonc/mds587. Epub 2012 Nov 21. PMID 23175622
• BACKGROUNDBlesius A, Cassier PA, Bertucci F, Fayette J, Ray-Coquard I, Bui B, Adenis A, Rios M, Cupissol D, Perol D, Blay JY, Le Cesne A. Neoadjuvant imatinib in patients with locally advanced non metastatic GIST in the prospective BFR14 trial. BMC Cancer. 2011 Feb 15;11:72. doi: 10.1186/1471-2407-11-72. PMID 21324142
• BACKGROUNDBlay JY, Perol D, Le Cesne A. Imatinib rechallenge in patients with advanced gastrointestinal stromal tumors. Ann Oncol. 2012 Jul;23(7):1659-65. doi: 10.1093/annonc/mdr622. Epub 2012 Feb 21. PMID 22357253
• DERIVEDBlay JY, Devin Q, Duffaud F, Toulmonde M, Firmin N, Collard O, Bompas E, Verret B, Ray-Coquard I, Salas S, Henon C, Honore C, Brahmi M, Dufresne A, Pracht M, Hervieu A, Penel N, Bertucci F, Rios M, Saada-Bouzid E, Soibinet P, Perol D, Chabaud S, Italiano A, Cesne AL. Discontinuation versus continuation of imatinib in patients with advanced gastrointestinal stromal tumours (BFR14): exploratory long-term follow-up of an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2024 Sep;25(9):1163-1175. doi: 10.1016/S1470-2045(24)00318-8. Epub 2024 Aug 7.