Protocol Title

Phase III, randomised, intergroup, international trial assessing the clinical activity of Imatinib at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) expressing the kit receptor tyrosine kinase (CD117).

Publication Reference

1. Casali PG, Zalcberg J, Le Cesne A, Reichardt P, Blay JY, Lindner LH, Judson IR, Schoffski P, Leyvraz S, Italiano A, Grunwald V, Pousa AL, Kotasek D, Sleijfer S, Kerst JM, Rutkowski P, Fumagalli E, Hogendoorn P, Litiere S, Marreaud S, van der Graaf W, Gronchi A, Verweij J. Ten-year progression-free and overall survival in patients with unresectable or metastatic GI stromal tumors: long-term analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group intergroup phase III randomized trial on imatinib at two dose levels. Journal of Clinical Oncology. Published online 1 Apr 2017.
2. Lee CK, Goldstein D, Gibbs E, Joensuu H, Zalcberg J, Verweij J, Casali PG, Maki RG, Cioffi A, McArthur G, Lord SJ, Yip D, Kanjanapan Y, Rutkowski P. Development and validation of prognostic nomograms for metastatic gastrointestinal stromal tumour treated with imatinib. European Journal of Cancer 2015; 51(7): 852-860.
3. Hohenberger P, Bonvalot S, Litiere S, Rutkowski P, van Coevorden F, Meeus P, Marréaud S, Raventos VA, Kotasek D, Padbury R, Van der Graaf W, Gronchi A. Surgical resection of metastatic GIST on imatinib delays recurrence and death: results of a cross-match comparison in the EORTC intergroup study 62005, aimed at assessing the clinical activity of imatinib at two dose levels in patients with unresectable or metastatic GIST Connective Tissue Oncology Society; 15–18 Oct 2014; Berlin.
4. MetaGIST: Gastrointestinal Stromal Tumor Meta-Analysis Group, Verweij J, Blay J, Debiec-Rychter M, Demetri G, Heinrich M, Borden E, Blanke C, Crowley J, Rankin C, Casali P, Von Mehren M, Fletcher C, Fletcher J, Owzar K, Zalcberg J, Simes J, Bramwell V. Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1640 patients. Journal of Clinical Oncology 2010; 28(7): 1247–1253.
5. Le Cesne A, Van Glabbeke M, Verweij J, Casali PG, Findlay M, Reichardt P, Issels R, Judson I, Schoffski P, Leyvraz S, Bui B, Hogendoorn PC, Sciot R, Blay JY. Absence of progression as assessed by response evaluation criteria in solid tumors predicts survival in advanced GI stromal tumors treated with imatinib mesylate: the Intergroup EORTC-ISG-AGITG phase III trial. Journal of Clinical Oncology 2009;27(24): 3969–3974.
6. Romeo S, Debiec-Rychter M, Van Glabbeke M, Van Paassen H, Comite P, Van Eijk R, Oosting J, Verweij J, Terrier P, Schneider U, Sciot R, Blay J, Hogendoorn P, on behalf of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Cell cycle/apoptosis molecule expression correlates with imatinib response in patients with advanced gastrointestinal stromal tumors. Clinical Cancer Research 2009; 15(12): 4191-4198.
7. Sciot R, Debiec-Rychter M, Daugaard S, Fisher C, Collin F, Van Glabbeke M, Verweij J, Blay J-Y, Hogendoorn, PCW; on behalf of the EORTC Soft Tissue and Bone Sarcoma Group, the Italian Sarcoma Group and the Australian Trials Group. Distribution and prognostic value of histopathologic data and immunohistochemical markers in gastrointestinal stromal tumors. An analysis of the EORTC phase III trial of treatment of metastatic GISTs with imatinib mesylate. European Journal of Cancer 2008; 44; 1855–1860.
8. Verweij J, Casali PG, Kotasek D, LeCesne A, Reichard P, Judson IR, Issels R, Van Oosterom AT, Van Glabbeke M, Blay J-Y. Imatinib does not induce cardiac left ventricular failure in gastrointestinal stromal tumours patients: analysis of EORTC-ISG-AGITG study 62005. European Journal of Cancer 2007; 43: 974–978.
9. Debiec-Rychter M, Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT, Blay JY, Leyvraz S, Stul M, Casali PG, Zalcberg J, Verweij J, Van Glabbeke M, Hagemeijer A, Judson I; On behalf of the EORTC Soft Tissue and Bone Sarcoma Group, The Italian Sarcoma Group and the Australasian Gastro-Intestinal Trials Group. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. European Journal of Cancer 2006; 42(8): 1093–103.
10. Tamborini E, Bonadiman L, Greco A, Albertini V, Negri T, Gronchi A, Bertulli R, Colecchia M, Casali P, Pierotti M, Pilotti S. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 2004; 127(1): 294–299.
11. Van Glabbeke M, Verweij J, Casali PG, Simes J, Cesne AL, Reichardt P, Issels R, Judson IR, van Oosterom AT, Blay JY. Predicting toxicities for patients with advanced gastrointestinal stromal tumours treated with imatinib: a study of the European Organisation for Research and Treatment of Cancer, the Italian Sarcoma Group, and the Australasian Gastro-Intestinal Trials Group (EORTC- IS G-AGITG). European Journal of Cancer 2006; 42(14): 2277–2285.
12. 12   Goldstein D, Tan B, Rossleigh M, Haindl W, Walker B, Dixon J. Gastrointestinal stromal tumours: correlation of F-18-FDG gamma camera-based coincidence positron emission tomography with CT for the assessment of treatment respons–an AGITG study. Oncology 2005; 69(4): 326-332.
13. Van Glabbeke M, Verweij J, Casali P, Le Cesne A, Hohenberger P, Ray-Coquard I, Schlemmer M, van Oosterom A, Goldstein D, Sciot R, Hogendoorn P, Brown M, Bertulli R, Judson I. Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group–Australasian Gastro-Intestinal Trials Group Study. Journal of Clinical Oncology 2005; 23(24): 5795-5804.
14. Zalcberg J, Verweij J, Casali P, Le Cesne A, Reichardt P, Blay J, Schlemmer M, Van Glabbeke M, Brown M, Judson I, EORTC Soft Tissue and Bone Sarcoma Group tISGAG-ITG. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. European Journal of Cancer 2005; 41(12): 1751-1757.
15. Verweij J, Casali P, Zalcberg J, Le Cesne A, Reichardt P, Blay J-Y, Issels R, van Oosterom A, Hogendoorn P, van Glabbeke M, Judson I, Bertulli R, Judson I, for the EORTC Soft Tissue and Bone Sarcoma Group, the Italian Sarcoma Group and the Australian Gastro-intestinal trials group: Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004; 364: 1127–1134.

Conference Presentation Reference

1. Hohenberger P, Bonvalot S, Litiere S, Rutkowski P, van Coevorden F, Meeus P, Marréaud S, Raventos VA, Kotasek D, Padbury R, Van der Graaf W, Gronchi A. Surgical resection of metastatic GIST on imatinib delays recurrence and death: results of a cross-match comparison in the EORTC intergroup study 62005, aimed at assessing the clinical activity of imatinib at two dose levels in patients with unresectable or metastatic GIST Connective Tissue Oncology Society; 15–18 Oct 2014; Berlin.
2. Casali PG, Zalcberg J, Le Cesne A, Reichardt P, Blay JY, Lindner L, Judson I, Fumagalli E, Hogendoorn P, Natukunda A, Marreaud S, Litiere S, van Der Graaf WTA. Long-term analysis of a phase III randomized, intergroup, international trial assessing the clinical activity of imatinib at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors. Connective Tissue Oncology Society 18th Annual Meeting; 30 Oct–2 Nov 2013; New York.
3. Lee CK, Joensuu H, McArthur G, Montemurro M, Yip D, Goldstein D, Bylina E, Andrzejuk J, Siedlecki JA, Rutkowski P. Development and validation of prognostic nomograms to predict survival outcomes in patients with locally advanced or metastatic gastrointestinal stromal tumor receiving first line imatinib therapy. Connective Tissue Oncology Society 18th Annual Meeting; 30 Oct–2 Nov 2013; New York.
4. Goldstein D, Lee C, Tracey E, Cook-Yarborough C, Lord S. Validating innovation: a population-based study of gastrointestinal stromal tumors (GIST) to estimate the survival benefit of imatinib. American Society of Clinical Oncology Annual Meeting; 4–8 Jun 2011; Chicago.
5. Van Glabbeke MM, Verweij J, Casali P, Zalcberg J, Le Cesne A, Reichardt P, Issels R, Judson I, Debiec-Rychter, Blay J. Type of progression in patients treated with imatinib for advanced gastrointestinal stromal tumor: a study based on the EORTC-ISG-AGITG trial 62005. Annual Meeting of the American Society of Clinical Oncology; 29 May–2 Jun 2009; Orlando. Journal of Clinical Oncology 2009; 27: 15s. Abstract 10536.
6. Romeo S, Van Paassen H, Van Glabbeke M, Comitel P, Oosting J, Nielsen OS, Verweij J, Sciot R, Debiec-Rychter M, Hogendoorn PCW. Pattern of expression of cell cycle/apoptosis regulators reflect location, mutation and progression free survival (PFS) of gastrointestinal stromal tumour (GIST) treated with imatinib from randomized phase III trial 62005 EORTC/STBSG. European Society of Pathology Annual Congress; 8-13 Sep 2007; Istanbul. Virchows Archive 2007; 451(2): 151.
7. Le Cesne A, Van Glabbeke M, Verweij J, Casali P, Zalcberg J, Reichardt P, Issels RD, Judson IR, Blay JY. Is a stable disease according to RECIST criteria a real stable disease in GIST patients treated with imatinib mesylate included in the intergroup EORTC/ISG/AGITG trial? 42nd Annual Meeting of the American Society of Clinical Oncology 2–6 Jun 2006; Atlanta. Journal of Clinical Oncology 2006; 24 (18S, Part 1): 9510.
8. Casali PG, Verweij J, Kotasek D, LeCesne A, Reichardt P, Blay JY, Issels R, Rychter MD, Van Glabbeke M, Judson I. Imatinib mesylate in advanced gastrointestinal stromal tumors: survival analysis of the intergroup EORTC/ISG/AGITG randomized trial in 946 patients. EJC Supplements 2005; 3(2): 201–202.
9. Zalcberg JR, Verweij J, Casali PG, Le Cesne A, Reichardt P, Blay JY, Schlemmer M, Van Glabbeke M, Brown M, Judson IR. Outcome of patients with advanced gastro-intestinal stromal tumors crossing over to a daily imatinib dose of 800 mg after progression on 400mg: an international, intergroup study of the EORTC, ISG and AGITG. 40th Annual Meeting of the American Society of Clinical Oncology; 5–8 Jun 2004; New Orleans. Journal of Clinical Oncology 2004; 22(14): 819S.
10. Van Glabbeke M, Verweij J, Casali P, Zalcberg J, Le Cesne A, Reichard P, Blay J, Schlemmer M, Donato Di Paola E, Judson I. Prognostic factors of toxicity and efficacy in patients with gastro-intestinal stromal tumors (GIST) treated with imatinib: a study of the EORTC-STBSG, ISG and AGITG. American Society of Clinical Oncology; 31 May–3 Jun 2003; Chicago.
11. Verweij J, Casali P, Zalcberg J, Le Cesne A, Reichard P, Blay J, Issels R, Van Glabbeke M, Donato Di Paola E, Judson I. Early efficacy comparison of two doses of imatinib for the treatment of advanced gastrointestinal stromal tumors: Interim results of a randomized phase III trial from the EORTC-STBSG, ISG and AGITG. American Society of Clinical Oncology; 31 May–3 Jun 2003; Chicago.
12. Zalcberg J, Verweij J, Casali P, Le Cesne A, Reichardt P, Blay J, Issels R, Van Glabbeke M, Donato di Paola E, Judson I, Dhillon H, Kotasek D, Findlay M, Goldstein D. Early efficacy comparison of two doses of imatinib for the treatment of advanced gastro-intestinal stromal tumors: interim results of a randomized phase II trial from EORTC-STBSG, ISG & AGITG. Clinical Oncological Society of Australia 30th Annual Scientific Meeting; 25–28 Nov 2003; Perth.
13. Casali PG, Verweij J, Zalcberg J, Le Cesne A, Reichardt P, Ray-Coquard I, Wendtner C, Judson I, Di Paola ED, Van Glabbeke M, Bertulli R, Dhillon H, Nielsen OS. Imatinib (Glivec) 400 vs 800 mg daily in patients with gastrointestinal stromal tumors: a randomized phase III trial from the EORTC Soft Tissue and Bone Sarcoma Group, the Italian Sarcoma Group (ISG), and the Australasian Gastro-Intestinal Trials Group (AGITG). A toxicity report. American Society of Clinical Oncology Annual Meeting; 18–21 May 2002; Orlando.

Aim

To compare the outcome of patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) expressing KIT (CD117) treated with low dose imatinib versus high dose imatinib.   Secondary objectives are to assess the response rates of patients treated with these two doses of imatinib and to assess the toxicities of patients in the two treatment groups.

Background

Gastrointestinal stromal tumours are rare cancers that are highly resistant to standard therapies, including surgery, chemotherapy and radiation. When the cancer has metastasised, it cannot be surgically removed and is not curable with any current treatment.

Imatinib is a tyrosine kinase inhibitor that has been found to shrink tumours and has the potential to increase survival outcomes in patients with advanced gastrointestinal stromal tumours.

The Advanced GIST/EORTC 62005 trial is an international collaboration between AGITG and the European Organisation for Research and Treatment of Cancer. The study compares higher and lower doses of imatinib to see which one is more effective. The trial aims to investigate whether there is an association between the dose of imatinib and its activity and subsequent impact on disease progression.

Updated analyses indicated that there was no significant difference in progression-free survival or overall survival between patients who were treated with Imatinib dose of 400mg twice a day and patients who were treated with Imatinib 400mg once a day.

As of December 2016, the trial is now closed.

CLINICAL TRIAL DESIGN

Eligible participants are patients with inoperable or metastatic gastrointestinal stromal tumours (GIST) expression the KIT receptor tyrosine kinase (CD117).

Patients were randomly allocated to receive one of two doses – 400mg or 800mg – of Imatinib. They continued taking the study drug until disease progression or unacceptable toxicity.

Blood and tissue samples were also obtained before and following treatment with imatinib for future studies. Patients were monitored for overall survival, objective response to treatment and toxicity profile.

Contact Email

Principal Investigator

Professor John Zalcberg (School of Public Health & Preventative Medicine, Monash University, Melbourne VIC)

More Information

Available online at the Australian New Zealand Clinical Trial Registry (ANZCTR) here.

Funding

Novartis Australia
European Organisation for Research and Treatment of Cancer (EORTC)