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Tyrosine Kinase Inhibitors

Imatinib Mesylate

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Immediate interruption of imatinib until progressive disease. In case of 1st relapse, imatinib will be reintroduced at 400mg/d and further increased at 800mg/d in case of 2nd relapse after re-introduction.

Maintenance of imatinib at the last dose routinely taken by the patient in the 10-year period prior to randomization (either 300 or 400 mg once daily). In case of progressive disease imatinib will be increased up to 800mg/day.

Imatinib tablets

Jean-Yves BLAY, Pr

Elsa KALBACHER, MD

Loïc CHAIGNEAU, MD

Guillaume MEYNARD, MD

Antoine ITALIANO

Maud TOULMONDE

Kevin BOURCIER

Sophie COUSIN

Valérie LE BRUN LY, MD

Jean-Yves BLAY, PhD

Mehdi BRAHMI

Armelle DUFRESNE

Isabelle RAY-COQUARD

François BERTUCCI, PhD

Audrey MONNEUR

Elika LOIR

Simon LAUNAY

Frédéric VIRET

Brice CHANEZ

Delphine LOUVEL PERROT

Sophie PIPERNO NEUMANN

Olivier BOUCHE, PhD

Mathilde BRASSEUR, MD

Damien BOTSEN, MD

Christophe PERRIN, MD

Marc PRACHT, MD

Angélique BRUNOT, MD

Astrid LIEVRE, PhD

Eugénie RIGAULT, MD

Thomas GRAINVILLE, MD

Anne-Sophie MOUSSADDAQ, MD

Emanuelle BOMPAS

Fréderic ROLLAND

Damien VANSTEENE

Olivier COLLARD, MD

Cécile VASSAL, MD

Valentin THIBAUD

Iphigénie KORAKIS

Christine CHEVREAU

Maria RIOS, MD

Axel LE CESNE, PhD

Rastislav BAHLEDA, MD

Olivier MIR, MD

Benjamin VERRET, MD

This is a 2 arms study concerning patients under imatinib treatment for at least 10 years of treatment with locally advanced/metastatic GIST.

In the first arm, patients will discontinue Imatinib treatment. This arm will allow to determine if the re-introduction of Imatinib at relapse is still an efficient treatment for the control of disease.

In the second arm, patients will continue Imatinib treatment, allowing to determine if the continuation of this treatment is efficient for disease control, by the rate of non-progression disease.

Gastrointestinal stromal tumors (GISTs) arise from mesenchymal stem cells which also give rise to the interstitial cells of Cajal within the GI tract. A large majority of GIST tumors harbour activating mutations in the proto-oncogenes KIT and/or PDGFRA, both coding cell-surface cytokine receptors with tyrosine-protein kinase activity.

Imatinib mesilate (Glivec®, Novartis Pharma SAS) is a selective tyrosine kinase inhibitor, leading to inhibition of KIT and PDGFRA signalling pathways. The introduction of imatinib has revolutionised the therapeutic management of GIST patients and has provided an unprecedented demonstration of the clinical benefit of a targeted therapy for patients with advanced/metastatic solid tumors.

Several studies have investigated the optimal duration of imatinib treatment in the advanced phase. The BFR14 trial demonstrated that 31% of advanced GIST patients treated with continuous imatinib beyond 1 year had documented disease progression compared to 81% in the interrupted imatinib group (p\<0.0001). The authors concluded that treatment interruption resulted in rapid progression in most patients with advanced GIST and therefore should not be recommended in standard practice unless the patient experienced significant toxicity or disease progression. An update of the BFR14 trial at a median follow-up of 37 months showed that 91% of patients in the interrupted arm versus 62% in the continuous arm experienced progressive disease (p\<0.0001). Majority (92%) of patients in the interrupted arm achieved tumor control once they recommenced imatinib after first progression. Ray-Coquard et al. reported that stopping imatinib after 5 years resulted in a higher rate of disease progression than imatinib maintenance in patients with advanced GIST responding to or stabilised by imatinib.

However, whether lifelong imatinib treatment duration is mandatory in metastatic GIST patients remains unclear. It is not known whether a cytostatic treatment of 10 years or longer is sufficient to inhibit definitively GIST cancer cells proliferation even after the interruption of the kinase inhibitor. This question has broad implications for all targeted therapies.

The aim of the present study is to address this question rigorously in a randomized setting. The investigators therefore want to determine whether prolonged use of imatinib beyond 10 years is needed to reduce the risk of GIST recurrence and to improve overall survival. For patients with imatinib interruption after at least 10 years of treatment, the investigators want to determine if imatinib rechallenge is efficient for treating recurrence. Therefore, the investigators design an open-label, randomized, multicenter phase II study to determine the clinical impact of maintaining imatinib treatment beyond 10 years in patients with locally advanced/metastatic GIST.

Efficiency of Imatinib Treatment After 10 Years of Treatment in Patients With Gastrointestinal Stromal Tumours (GIST) (Gist-Ten)

Randomized, Multicentre, Phase II Study Evaluating the Interest of Imatinib Treatment Maintenance or Interruption After at Least 10 Years of Treatment in Patients With Locally Advanced/Metastatic Gastrointestinal Stromal Tumors (GISTs)

Defined as the rate of patients with a non-progressive disease 6 months after randomization

Time from the date of randomization to the date of the first documented progression, or date of death due to any cause. Patients with no event at the time of the analysis will be censored at the date of last available tumor assessment

the time from the date of randomization to the date of death due to any cause.

The assessment of safety will be based mainly on the frequency of AE based on the Common Toxicity Criteria version 5

QoL will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of life Questionnaire (QLQ-C30).

the time from the date of imatinib reintroduction in the experimental arm to the date of subsequent progression, or date of death due to any cause. Patients with no event at the time of the analysis will be censored at the the date of last available tumor assessment.

Defined as the proportion of patients with a best overall response of Partial Response (PR) or Complete Response (CR) after imatinib reintroduction

the time from the date of first objective response following the reintroduction of imatinib to the date of the first subsequent documented radiological progression or death and censored at the date of last available tumor assessment.

Centre Leon Berard

Spots Global Cancer Trial Database for randomisation study