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Gastrointestinal Neoplasms

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Tyrosine Kinase Inhibitors

Imatinib Mesylate

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Tyrosine

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

Infigratinib

BGJ398 With Imatinib Mesylate In the phase Ib portion of the study, patients will receive imatinib at 400 mg once daily and BGJ398 at the standard 3+3 escalation doses for 21 days on, 7 days off (treatment schedule A).Using treatment schedule A, if dose level 1 to -2 is identified as the MTD and concern exists regarding therapeutic activity of BGJ398 at this dose level, expansions with higher dose levels (1 to 3) may be considered at the MSKCC PI's discretion, with modification of the treatment schedule. In this setting BGJ398 will be administered daily for one week followed by 3 weeks off and imatinib will be taken daily throughout the 4 week cycle period (treatment schedule B). In the phase II portion of the study, patients will receive imatinib at 400 mg once daily (standard of care first line imatinib dose) and BGJ398 at the RP2D and treatment schedule identified in the phase Ib portion of the study. One cycle is 28 days.

BGJ398

William Tap, MD

The goal of a phase Ib clinical trial is to find the doses of drugs that are safe. Although BGJ398 has been given to patients safely on its own, it has never been given together with imatinib mesylate. In this study, we will test the safety of taking BGJ398 with imatinib mesylate. The investigators will learn this by closely checking for side effects that the patient may experience. Side effects can be seen in laboratory studies, on physical examination, or by asking the patient.Once a dose has been determined to be safe, a larger Phase II study will be done in patients with advanced GIST who have never received any prior treatments.

BGJ398 in Combination With Imatinib Mesylate in Patients With Untreated Advanced Gastrointestinal Stromal Tumor (GIST)

A Phase Ib/II Study of BGJ398 in Combination With Imatinib Mesylate in Patients With Untreated Advanced Gastrointestinal Stromal Tumor (GIST)

The phase Ib will be pursued in standard 3+3 format, based on toxicities encountered during the first cycle of therapy.

(CR+PR, RECIST 1.1) and by CHOI criteria

PHASE 1b PARTICIPANTS ONLY

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

defined by RECIST 1.1 criteria and by CHOI criteria,and by EORTC criteria

PHASE 1b PARTICIPANTS ONLY

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Efficiency of Imatinib Treatment After 10 Years of Treatment in Patients With Gastrointestinal Stromal Tumours (GIST) (Gist-Ten)	NCT05009927	Metastatic Gast... C-KIT Mutation Advanced Gastro...	Imatinib tablet...	18 Years -	Centre Leon Berard
BGJ398 in Combination With Imatinib Mesylate in Patients With Untreated Advanced Gastrointestinal Stromal Tumor (GIST)	NCT02257541	Advanced Gastro...	BGJ398 Imatinib Mesyla...	18 Years -	Memorial Sloan Kettering Cancer Center

Spots Global Cancer Trial Database for advanced gastrointestinal stromal tumor (gist)