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

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ClinicalTrials.gov Identifier: NCT05009927
Recruitment Status : Recruiting
First Posted : August 18, 2021
Last Update Posted : September 1, 2023
Sponsor:
Information provided by (Responsible Party):
Centre Leon Berard

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Metastatic Gastrointestinal Stromal Tumor (GIST) C-KIT Mutation Advanced Gastrointestinal Stromal Tumor (GIST) Drug: Imatinib tablets Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : January 3, 2022
Estimated Primary Completion Date : January 2025
Estimated Study Completion Date : January 2027


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 Name: 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.



Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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.

  3. 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

  4. 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. 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.

  6. 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

  7. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05009927


Contacts
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Contact: Jean-Yves BLAY, Pr +33 4 78 78 27 57 jean-yves.blay@lyon.unicancer.fr

Locations
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France
CHU Besançon Recruiting
Besançon, France, 25000
Contact: Elsa KALBACHER, MD    03.70.63.24.03    ekalbacher@chu-besancon.fr   
Principal Investigator: Elsa KALBACHER, MD         
Sub-Investigator: Loïc CHAIGNEAU, MD         
Sub-Investigator: Guillaume MEYNARD, MD         
Institut Bergonié Recruiting
Bordeaux, France, 33076
Contact: Antoine ITALIANO       A.Italiano@bordeaux.unicancer.fr   
Principal Investigator: Antoine ITALIANO         
Sub-Investigator: Maud TOULMONDE         
Sub-Investigator: Kevin BOURCIER         
Sub-Investigator: Sophie COUSIN         
CHU Dupuytren Recruiting
Limoges, France, 87042
Contact: Valérie LE BRUN LY, MD       valerie.lebrunly@chu-limoges.fr   
Centre Léon Bérard Recruiting
Lyon, France, 69373
Contact: Jean-Yves BLAY, PhD         
Contact    04 78 78 27 57    jean-yves.blay@lyon.unicancer.fr   
Principal Investigator: Jean-Yves BLAY, PhD         
Sub-Investigator: Mehdi BRAHMI         
Sub-Investigator: Armelle DUFRESNE         
Sub-Investigator: Isabelle RAY-COQUARD         
Institut Paoli Calmettes Not yet recruiting
Marseille, France, 13273
Contact: François BERTUCCI, PhD       bertuccif@ipc.unicancer.fr   
Principal Investigator: François BERTUCCI, PhD         
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         
Institut Curie Not yet recruiting
Paris, France, 75005
Contact: Sophie PIPERNO NEUMANN       sophie.piperno-neumann@curie.fr   
Principal Investigator: Sophie PIPERNO NEUMANN         
CHU de Reims Recruiting
Reims, France, 51100
Contact: Olivier BOUCHE, PhD         
Principal Investigator: Olivier BOUCHE, PhD         
Sub-Investigator: Mathilde BRASSEUR, MD         
Sub-Investigator: Damien BOTSEN, MD         
Centre Eugène Marquis Not yet recruiting
Rennes, France, 35042
Sub-Investigator: Christophe PERRIN, MD         
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         
Institut de Cancérologie de l'Ouest - Site Réné Gauducheau Not yet recruiting
Saint-Herblain, France, 44805
Contact: Emanuelle BOMPAS         
Principal Investigator: Emanuelle BOMPAS         
Sub-Investigator: Fréderic ROLLAND         
Sub-Investigator: Damien VANSTEENE         
Institut de Cancérologie Lucien NEUWIRTH Not yet recruiting
Saint-Paul-en-Jarez, France, 42270
Contact: Olivier COLLARD, MD       Olivier.COLLARD@icloire.fr   
Principal Investigator: Olivier COLLARD, MD         
Sub-Investigator: Cécile VASSAL, MD         
Institut Claudius Regaud Not yet recruiting
Toulouse, France, 31059
Contact: Valentin THIBAUD       valentin.Thibaud@iuct-oncopole.fr   
Principal Investigator: Valentin THIBAUD         
Sub-Investigator: Iphigénie KORAKIS         
Sub-Investigator: Christine CHEVREAU         
Institut de Cancérologie de Lorraine Not yet recruiting
Vandœuvre-lès-Nancy, France, 54519
Contact: Maria RIOS, MD         
Principal Investigator: Maria RIOS, MD         
Institut Goustave Roussy Recruiting
Villejuif, France, 94805
Contact: Axel LE CESNE, PhD    01 42 11 43 16    axel.lecesne@gustaveroussy.fr   
Principal Investigator: Axel LE CESNE, PhD         
Sub-Investigator: Rastislav BAHLEDA, MD         
Sub-Investigator: Olivier MIR, MD         
Sub-Investigator: Benjamin VERRET, MD         
Sponsors and Collaborators
Centre Leon Berard
Investigators
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Principal Investigator: Jean-Yves BLAY, Pr Centre Léon Bérard, Lyon
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Responsible Party: Centre Leon Berard
ClinicalTrials.gov Identifier: NCT05009927    
Other Study ID Numbers: GIST-TEN
First Posted: August 18, 2021    Key Record Dates
Last Update Posted: September 1, 2023
Last Verified: August 2023

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Centre Leon Berard:
Gastrointestinal Stromal Tumors (GIST)
Tyrosine kinase inhibitor
Maintenance therapy
Bayesian design
KIT +
Imatinib
Randomisation study
Additional relevant MeSH terms:
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Neoplasms
Gastrointestinal Stromal Tumors
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Imatinib Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action