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

August 31, 2023 updated by: Centre Leon Berard

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)

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

50

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • France
      • Besançon, France, 25000
        • Recruiting
        • CHU Besançon
        • Principal Investigator:
          • Elsa KALBACHER, MD
        • Contact:
        • Sub-Investigator:
          • Loïc CHAIGNEAU, MD
        • Sub-Investigator:
          • Guillaume MEYNARD, MD
      • Bordeaux, France, 33076
        • Recruiting
        • Institut Bergonie
        • Contact:
        • Principal Investigator:
          • Antoine Italiano
        • Sub-Investigator:
          • Maud TOULMONDE
        • Sub-Investigator:
          • Kevin BOURCIER
        • Sub-Investigator:
          • Sophie COUSIN
      • Limoges, France, 87042
      • Lyon, France, 69373
        • Recruiting
        • Centre LEON BERARD
        • Contact:
          • Jean-Yves BLAY, PhD
        • Contact:
        • Sub-Investigator:
          • Mehdi BRAHMI
        • Sub-Investigator:
          • Armelle DUFRESNE
        • Sub-Investigator:
          • Isabelle RAY-COQUARD
        • Principal Investigator:
          • Jean-Yves BLAY, PhD
      • Marseille, France, 13273
        • Not yet recruiting
        • Institut Paoli Calmettes
        • Sub-Investigator:
          • Audrey MONNEUR
        • Sub-Investigator:
          • Elika LOIR
        • Sub-Investigator:
          • Simon LAUNAY
        • Sub-Investigator:
          • Frédéric VIRET
        • Sub-Investigator:
          • Brice CHANEZ
        • Sub-Investigator:
          • Delphine LOUVEL PERROT
        • Contact:
        • Principal Investigator:
          • François BERTUCCI, PhD
      • Paris, France, 75005
      • Reims, France, 51100
        • Recruiting
        • CHU de Reims
        • Contact:
          • Olivier BOUCHE, PhD
        • Principal Investigator:
          • Olivier BOUCHE, PhD
        • Sub-Investigator:
          • Mathilde BRASSEUR, MD
        • Sub-Investigator:
          • Damien BOTSEN, MD
      • Rennes, France, 35042
        • Not yet recruiting
        • Centre Eugene Marquis
        • Principal Investigator:
          • Marc PRACHT, MD
        • Sub-Investigator:
          • Angélique BRUNOT, MD
        • Sub-Investigator:
          • Astrid LIEVRE, PhD
        • Sub-Investigator:
          • Eugénie RIGAULT, MD
        • Sub-Investigator:
          • Thomas GRAINVILLE, MD
        • Sub-Investigator:
          • Anne-Sophie MOUSSADDAQ, MD
        • Sub-Investigator:
          • Christophe PERRIN, MD
      • Saint-Herblain, France, 44805
        • Not yet recruiting
        • Institut de Cancérologie de l'Ouest - Site René Gauducheau
        • Contact:
          • Emanuelle BOMPAS
        • Principal Investigator:
          • Emanuelle BOMPAS
        • Sub-Investigator:
          • Frédéric ROLLAND
        • Sub-Investigator:
          • Damien VANSTEENE
      • Saint-Paul-en-Jarez, France, 42270
        • Not yet recruiting
        • Institut de Cancérologie Lucien Neuwirth
        • Contact:
        • Principal Investigator:
          • Olivier COLLARD, MD
        • Sub-Investigator:
          • Cécile Vassal, MD
      • Toulouse, France, 31059
        • Not yet recruiting
        • Institut Claudius Regaud
        • Contact:
        • Principal Investigator:
          • Valentin THIBAUD
        • Sub-Investigator:
          • Iphigénie KORAKIS
        • Sub-Investigator:
          • Christine CHEVREAU
      • Vandœuvre-lès-Nancy, France, 54519
        • Not yet recruiting
        • Institut de Cancérologie de Lorraine
        • Contact:
          • Maria RIOS, MD
        • Principal Investigator:
          • Maria RIOS, MD
      • Villejuif, France, 94805
        • Recruiting
        • Institut Goustave Roussy
        • Principal Investigator:
          • Axel LE CESNE, PhD
        • Contact:
        • Sub-Investigator:
          • Rastislav BAHLEDA, MD
        • Sub-Investigator:
          • Olivier MIR, MD
        • Sub-Investigator:
          • Benjamin VERRET, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients ≥18 years of age;
  • Histologically documented diagnosis of malignant advanced/metastatic GIST with immunohistochemical documentation of c-kit (CD117) expression either by the primary tumor or metastases;
  • Eastern Cooperative Oncology Group (ECOG) - Performance status (PS) 0 to 2 evaluated within 7 days prior to the date of inclusion.
  • Patient must be under imatinib treatment (at 300 or 400mg/day) maintained for 10 years or over with no more than 12 months in total or 3 consecutive months of interruption during the treatment period;
  • Patient with controlled disease (without any progression under imatinib);
  • Willingness and ability to comply with scheduled visits, treatment plans , laboratory tests, and other study procedures;
  • Covered by a medical/health insurance;
  • Signed and dated informed consent document indicating that the patient has been informed of all aspects of the trial prior to enrolment.

Exclusion Criteria:

  • Patient concurrently using other approved or investigational antineoplastic agents;
  • Patient with GIST harboring the mutation D842V in PDGFRA;
  • Major concurrent disease affecting cardiovascular system, liver, kidneys, haematopoietic system or else considered as clinically important by the investigator and that could be incompatible with patient's participation in this trial or would likely interfere with study procedures or results;
  • Prior history of other malignancies other than study disease (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) unless the patient has been free of the disease for at least 3 years;
  • Patient receiving concurrent treatment with warfarin (acceptable alternative: low-molecular weight heparin) or any prohibited concomitant and/or concurrent medications
  • Patient has a known diagnosis of human immunodeficiency virus (HIV) infection;
  • Major surgery within 2 weeks prior to study entry.
  • Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
  • Pregnant or breastfeeding woman
  • Patient requiring tutorship or curatorship or patient deprivied of liberty.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Imatinib interruption
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.
Drug: Imatinib tablets
Imatinib interruption
Other Names:
  • Glivec
No Intervention: Imatinib maintenancce
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-free-rate at 6 months (PFR 6m)
Time Frame: 6 months after randomization
Defined as the rate of patients with a non-progressive disease 6 months after randomization
6 months after randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-free-survival (PFS)
Time Frame: 5 years (i.e. at the the time of last patient last visit)
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
5 years (i.e. at the the time of last patient last visit)
Overall Survival (OS)
Time Frame: 5 years (i.e. at the the time of last patient last visit)
the time from the date of randomization to the date of death due to any cause.
5 years (i.e. at the the time of last patient last visit)
Safety profile
Time Frame: 5 years (i.e. at the the time of last patient last visit)
The assessment of safety will be based mainly on the frequency of AE based on the Common Toxicity Criteria version 5
5 years (i.e. at the the time of last patient last visit)
Quality of Life (QoL)
Time Frame: 5 years (i.e. at the the time of last patient last visit)
QoL will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of life Questionnaire (QLQ-C30).
5 years (i.e. at the the time of last patient last visit)
Progression-free survival rechallenge
Time Frame: 5 years (i.e. at the the time of last patient last visit)
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.
5 years (i.e. at the the time of last patient last visit)
Objective Response Rate (ORR) after imatinib reintroduction
Time Frame: 5 years (i.e. at the the time of last patient last visit)
Defined as the proportion of patients with a best overall response of Partial Response (PR) or Complete Response (CR) after imatinib reintroduction
5 years (i.e. at the the time of last patient last visit)
Duration of response (DOR)
Time Frame: 5 years (i.e. at the the time of last patient last visit)
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.
5 years (i.e. at the the time of last patient last visit)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centre Leon Berard

Investigators

  • Principal Investigator: Jean-Yves Blay, Pr, Centre Léon Bérard, Lyon

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 3, 2022

Primary Completion (Estimated)

January 1, 2025

Study Completion (Estimated)

January 1, 2027

Study Registration Dates

First Submitted

August 2, 2021

First Submitted That Met QC Criteria

August 10, 2021

First Posted (Actual)

August 18, 2021

Study Record Updates

Last Update Posted (Actual)

September 1, 2023

Last Update Submitted That Met QC Criteria

August 31, 2023

Last Verified

August 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GIST-TEN

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on C-KIT Mutation

Clinical Trials on Imatinib tablets

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Belarus

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe