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Efficiency of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST) (ImadGist)

This study is currently recruiting participants.
See Contacts and Locations
Verified August 2017 by Centre Leon Berard
Sponsor:
Information provided by (Responsible Party):
Centre Leon Berard
ClinicalTrials.gov Identifier:
NCT02260505
First received: July 30, 2014
Last updated: August 4, 2017
Last verified: August 2017
  Purpose

This is a 2 arms study concerning patients with primary GIST who followed an Imatinib adjuvant treatment for 3 years after surgery and who have a high risk of recurrence.

In the first arm, patients will continue Imatinib treatment for 3 more years, allowing to determine if the continuation of this treatment is efficient for disease control, in terms of Disease Free Survival improvement.

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


Condition Intervention Phase
Gastrointestinal Stromal Tumors Resected Gastrointestinal Stromal Tumors Non-metastatic High Risk of Recurrence KIT Gene Mutation Drug: Imatinib maintenance Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Randomized Multicenter Phase III Trial Evaluating the Interest of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST)

Resource links provided by NLM:


Further study details as provided by Centre Leon Berard:

Primary Outcome Measures:
  • Disease Free Survival (DFS) [ Time Frame: 6 years (i.e. at the the time of last patient last visit) ]
    Time from the date of randomisation to the first documented relapse or death due to any cause. Patients with no event at the time of analysis will be censored at the date of the last adequate tumour assessment. The results will be analyzed according to the study arm and randomization strata to wich patients were assigned.


Secondary Outcome Measures:
  • Overall Survival (OS) [ Time Frame: 6 years (i.e. at the the time of last patient last visit) ]
    Time from the date of randomization until the date of death due to any cause and censored at the date of last contact for patients alive at last contact. The results will be analyzed according to the study arm and randomization strata to wich patients were assigned.

  • Time to Secondary Resistance (TSR) [ Time Frame: 6 years (i.e. at the the time of last patient last visit) ]
    Time from the date of randomization until the date of first relapse under Imatinib treatment (i.e first relapse in the "Imatinib maintenance arm" and relapse after reintroduction of Imatinib in the "Interruption of Imatinib arm"). The results will be analyzed according to the study arm and randomization strata to wich patients were assigned.

  • Percentage of patients in Complete Response (%CR) in interruption arm after reintroduction of Imatinib [ Time Frame: 6 years (i.e. at the the time of last patient last visit) ]
    Percentage of patients in Complete Response (CR) after reintroduction of Imatinib treatment for patients assigned to the interruption arm and who experience GIST recurrence. CR is assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria

  • Frequency of Adverse Events (AE) [ Time Frame: 6 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 4 grade. AE will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). Descriptive statistics will be provided for characterizing and assessing patient tolerance to treatment. Patients with at least either one serious AE, or one grade 3-4, or one AE requiring the interruption of study treatment, will be described by study arm and compared using a Pearson's Chi2 test or a Fisher's exact test, if adequate. Patients will be analyzed according the duration of exposure to imatinib

  • Patient's Quality of Life (QoL) [ Time Frame: 6 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). Descriptive statistics (e.g. means and medians) will be used to summarize the scored scales at it scheduled assessment time point of the questionnaire. The distribution of time to definitive health-related QoL deterioration by study arms will be estimated using the Kaplan-Meier method. The time to definitive deterioration is defined as the time from the date of randomization to the date of event, wich is defined as > 10 points decrease from baseline of QLQ-C30 global score (items 29 and 30) or death due to any cause. If patient has not had an event, time to QoL deterioration will be censored at the date of last adequate evaluation.


Estimated Enrollment: 256
Actual Study Start Date: December 24, 2014
Estimated Study Completion Date: December 2020
Estimated Primary Completion Date: December 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Imatinib maintenance
Maintenance of Imatinib at the last dose routinely taken by the patient in the 3 years period prior to randomization (either 300 or 400 mg/day). Increase dose up to 800 mg/day if relapse according to RECIST 1.1 criteria. Any relapse/progressive disease at 800 mg/day will lead to Imatinib permanent discontinuation and study discontinuation. In case of toxicity, Imatinib dose will be interrupted or adjusted in accordance with Imatinib Specific Product Characteristics (SPC).
Drug: Imatinib maintenance
Either 300 or 400 mg/day in accordance with the last dose routinely taken by the patient in the 3-year period before randomization. The treatment will be orally taken at time of meal with a large glass of water
Other Names:
  • Glivec
  • Imatinib mésilate
No Intervention: Imatinib Interruption
Treatment corresponding to standard practice : interruption of Imatinib from the day of randomization. Reintroduction of Imatinib at 400 mg/day after first relapse according to RECIST 1.1 criteria; Then increase dose to 800 mg/day after 2d relapse. Any relapse/progressive disease at 800 mg/day will lead to Imatinib permanent discontinuation and study discontinuation. In case of toxicity, Imatinib dose will be interrupted or adjusted in accordance with Imatinib SPC.

Detailed Description:

Gastrointestinal stromal tumours (GISTs) are rare mesenchymal neoplasms, mostly diagnosed between 55 and 60 years of age, which account for 5% of all sarcomas. Worldwide annual incidence is approximately 12 cases per million people, corresponding to approximately 800 new cases per year in France.

A large majority of GISTs 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. First results from prospective trials conducted with imatinib in GIST patients have demonstrated a 300% increase in median overall survival, and a likely 100% increase in 5 and 10-year survival as compared to cytotoxic chemotherapy.

The successful use of imatinib in the treatment of advanced GISTs and the significant risk of recurrence of advanced GISTs have prompted the investigation of the clinical benefit of imatinib as a post-operative adjuvant therapy. Two prospective randomized Phase III trials have demonstrated that adjuvant imatinib treatment significantly prolong overall survival (OS) and recurrence-free survival (RFS) when given for 3 years. To date, imatinib is also indicated in the adjuvant setting after complete resection of primary, localized, KIT-positive GIST at high risk of recurrence. However, the optimal treatment duration remains unclear and it should be determined whether

  1. prolonged use of adjuvant imatinib beyond 3 years may enable to reduce the risk of GIST recurrence and to improve overall survival, and
  2. imatinib rechallenge is efficient for treating recurrence after completion of 3-year adjuvant imatinib therapy.

This trial is an open-label, randomized, multicenter phase III study aiming to determine the clinical impact of maintaining imatinib treatment beyond 3 years in the adjuvant setting for patients with resected GISTs at high risk of recurrence according to the National Comprehensive Cancer Network Task Force on GIST (NCCN) risk classification.

  Eligibility

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

Inclusion Criteria:

  • Age ≥ 18 years at the day of consenting to the study
  • Patients must have histologically confirmed diagnosis of localized GIST with documented KIT (CD117) positivity (by polyclonal DAKO antibody staining)
  • Documented macroscopically complete surgical R0 or R1 resection of primary GIST lesion with no evidence of residual lesions or metastases on the baseline CT-scan or MRI performed no more than 4 weeks before randomization.
  • Risk of tumor recurrence ≥ 35% according to National Comprehensive Cancer Network Task Force on GIST (NCCN) risk classification (Demetri et al., 2010) (See Appendix 1)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
  • Patients must be under imatinib treatment (at 300 or 400 mg/day) initiated immediately after resection and maintained for 3 years (i.e. 36 months ± 3 months at the time of randomization) with no more than 3 consecutive months or 6 months in total of interruption during these past 3 years.
  • Patients must have normal organ and bone marrow function at baseline as defined below:

    • absolute neutrophil count (ANC) ≥ 1.5 G/L, platelet count ≥ 100 G/L, and haemoglobin of ≥ 9 g/dL).
    • Serum total bilirubin ≤ 1.5 (upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN (or 5 x ULN in case of hepatic metastases at time of reintroduction)
    • Adequate renal function assessed by at least one of the following:

      • 1) Serum creatinine ≤ 1.5 x ULN or
      • 2) creatinine clearance estimate ≥ 50 mL/min (as calculated according to Cockcroft-Gault formula or MDRD formula for patients > 65 years).
  • Recovered from prior anti-neoplasia treatment-related toxicity (persistent treatment-related toxicity < Grade 2 as per Common Toxicity Criteria for Adverse Effects (CTCAE) v4 are accepted)
  • Women of childbearing potential are required to have a negative serum pregnancy test within 72 hours prior to randomization. A positive urine test must be confirmed by a serum pregnancy test
  • Patient must use effective contraception at least 4 weeks prior to study entry, during the study participation and for at least 30 days post-treatment (not applicable for women of non-childbearing potential)
  • Ability to understand and willingness for follow-up visits.
  • Covered by a medical 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:

  • Pregnant or breastfeeding women
  • Patient concurrently using other approved or investigational antineoplastic agents
  • Any contra-indication to imatinib treatment as per Glivec® SPC
  • 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 with Grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e., congestive heart failure, myocardial infarction within 6 months of study)
  • Patient has a known diagnosis of human immunodeficiency virus (HIV) infection.
  • Major surgery within 2 weeks prior to study entry
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02260505

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

Locations
France
Institut Paoli-Calmettes Not yet recruiting
Marseille, Bouches du Rhône, France, 13273
Contact: François BERTUCCI, Pr    +33 4 91 22 35 37    bertuccif@ipc.unicancer.fr   
Principal Investigator: François BERTUCCI, Pr         
Sub-Investigator: Slimane DERMERCHE, Dr         
Sub-Investigator: Delphine PERROT, Dr         
Sub-Investigator: Magali PROVANSAL, Dr         
Centre Hospitalier Universitaire La Timone Recruiting
Marseille, Bouches du Rhône, France, 13386
Contact: Florence DUFFAUD, Pr    +33 4 91 38 57 08    florence.duffaud@ap-hm.fr   
Principal Investigator: Florence DUFFAUD, Pr         
Sub-Investigator: Sébastien SALAS, Dr         
CHRU de Besançon - Hôpital Minjoz Recruiting
Besançon, Doubs, France, 25030
Contact: Elsa KALBACHER, Doctor    + 33 3 81 66 81 66    ekalbacher@chu-besancon.fr   
Sub-Investigator: Loïc CHAIGNEAU, Doctor         
Principal Investigator: Elsa KALBACHER, Doctor         
Institut Bergonié Recruiting
Bordeaux, Gironde, France, 33076
Contact: Antoine ITALIANO, Dr    +33 5 24 07 19 47    a.italiano@bordeaux.unicancer.fr   
Principal Investigator: Antoine ITALIANO, Dr         
Sub-Investigator: Sophie COUSIN, Dr         
Sub-Investigator: Maud TOULMONDE, Dr         
Centre Hospitalier Universitaire Toulouse Purpan Not yet recruiting
Toulouse, Haute-Garonne, France, 31059
Contact: Rosine GUIMBAUD, Pr    +33 5 61 77 96 49    Guimbaud.r@chu-toulouse.fr   
Principal Investigator: Rosine GUIMBAUD, Pr         
Centre Régional de Lutte contre le Cancer de Montpellier Not yet recruiting
Montpellier, Hérault, France, 34298
Contact: Didier CUPISSOL, Dr    +33 4 67 61 31 83    didier.cupissol@icm.unicancer.fr   
Principal Investigator: Didier CUPISSOL, Dr         
Sub-Investigator: Nelly FIRMIN, Dr         
AP-HP Hôpital Européen Georges Pompidou Recruiting
Paris, Ile de France, France, 75908
Contact: Bruno LANDI, Dr    +33 1 56 09 35 55    bruno.landi@aphp.fr   
Principal Investigator: Bruno LANDI, Dr         
Sub-Investigator: Anne-Laure POINTET, Dr         
Institut de Cancérologie de l'Ouest Recruiting
Saint-Herblain, Loire Atlantique, France, 44805
Contact: Elisabeth BOMPAS, Dr    +33 2 40 67 99 39    emmanuelle.bompas@ico.unicancer.fr   
Principal Investigator: Elisabeth BOMPAS, Dr         
Sub-Investigator: Frédéric ROLLAND, Dr         
Sub-Investigator: Damien VANSTEENE, Dr         
Sub-Investigator: Marie ROBERT, Dr         
Sub-Investigator: Akila BENINE DANDEC, Dr         
Sub-Investigator: Mathilde COLOMBIE, Dr         
Sub-Investigator: Carole GOURMELON, Dr         
Sub-Investigator: Audrey ROLLOT, Dr         
Institut de cancérologie LUCIEN NEUWIRTH Recruiting
Saint-priest-en-jarez, Loire, France, 42270
Contact: Olivier COLLARD, Dr    00 334 77 91 70 34    olivier.collard@icloire.fr   
Principal Investigator: Olivier COLLARD, Dr         
Sub-Investigator: Cecile VASSAL, Dr         
Centre Hospitalier universitaire Robert Debré Recruiting
Reims, Marne, France, 51092
Contact: Olivier BOUCHE, Pr    +33 3 26 78 71 72    obouche@chu-reims.fr   
Principal Investigator: Olivier BOUCHE, Pr         
Sub-Investigator: Julien VOLET, Dr         
Institut de Cancérologie de Lorraine Recruiting
Vandoeuvre-les-Nancy, Meurthe et Moselle, France, 54519
Contact: Maria RIOS, Dr    +33 3 83 59 85 66    m.rios@nancy.unicancer.fr   
Principal Investigator: Maria RIOS, Dr         
Centre Oscar Lambret Recruiting
Lille, Nord, France, 59020
Contact: Nicolas PENEL, Pr    +33 3 20 29 59 20    n-penel@o-lambret.fr   
Sub-Investigator: Farid EL HAJBI, Dr         
Principal Investigator: Nicolas PENEL, Dr         
Sub-Investigator: Charlotte PEUGNIEZ, Dr         
Centre Léon Bérard Recruiting
Lyon, Rhône, France, 69008
Contact: Jean-Yves BLAY, Pr    +33 4 78 78 27 57    jean-yves.blay@lyon.unicancer.fr   
Principal Investigator: Jean-Yves BLAY, Pr         
Sub-Investigator: Olivia BALLY, Dr         
Sub-Investigator: Philippe CASSIER, Dr         
Sub-Investigator: Isabelle RAY-COQUART, Dr         
Sub-Investigator: Nathalie MARQUES, Dr         
Sub-Investigator: Matthieu SARABI, Dr         
Institut de Cancérologie Gustave Roussy Recruiting
Villejuif, Val de Marne, France, 94805
Contact: Axel LE CESNE, Dr    +33 1 42 11 43 16    axel.lecesne@gustaveroussy.fr   
Principal Investigator: Axel LE CESNE, Dr         
Sub-Investigator: Julien DOMONT, Dr         
Sub-Investigator: Sarah DUMONT, Dr         
Sub-Investigator: Olivier MIR, Dr         
AP-HP Hôpital Saint-Antoine Not yet recruiting
Paris, France, 75571
Contact: Isabelle TROUILLOUD, Dr    +33 1 48 29 23 29    isabelle.trouilloud@aphp.fr   
Sub-Investigator: Pauline AFCHAIN, Dr         
Sub-Investigator: Thierry ANDRE, Dr         
Sub-Investigator: Marie-Line GARCIA, Dr         
Sub-Investigator: Daniel LOPEZ-TRABADA-ATAZ, Dr         
CHRU Strasbourg - Hôpital Hautepierre Not yet recruiting
Strasbourg, France, 67098
Contact: Jean-Emmanuel KURTZ, Pr    +33 3 88 12 78 82    emmanuel.kurtz@chru-strasbourg.fr   
Sub-Investigator: Laure DE COCK, Dr         
Sub-Investigator: Laure PIERARD, Dr         
Sponsors and Collaborators
Centre Leon Berard
Investigators
Principal Investigator: Jean-Yves Blay, Pr Centre Léon Bérard, Lyon
  More Information

Publications:
ClinicalTrials.gov. Imatinib mesilate or observation only in treating patients who have undergone surgery for localized gastrointestinal stromal tumor. NCT identifier: NCT00103168. 13-12-2009. Ref Type: Online Source
ClinicalTrials.gov. Five year adjuvant imatinib mesilate (Gleevec®) in gastrointestinal stromal tumor (GIST). NCT Identifier: NCT00867113. 24-8-2011. Ref Type: Online Source
H.Joensuu, M.Eriksson, J.Hatrmann, K.Sundby Hall, J.Schutte, A. Reichardt, M.Schlemmer, E. Wardelmann, G.Ramadori, S. E. Al-Batran B. E. Nilsson O. Monge R. Kallio, and M.Sarlomo-Rikala, P. Bono M. Leinonen P. Hohenberger T. Alvegard P. Reichardt. Three years of imatinib improves survival for high-risk gastrointestinal stromal tumours. ASCO 2011 . 2011. Ref Type: Abstract
Joensuu,H. and Ericksson,M.H.J. (2011). Twelve versus 36 monts of adjuvant imatinib as treatment of operable GIST with high risk of recurrence: Final results of a randomized trial (SSGXVIII/AIO). J. Clin. Oncol.
Le Cesne,A., Ray-Coquard,I.L., Bui Nguyen,B., Adenis,A., Rios,M., Bertucci,F., Duffaud,F., Cupissol,D., Chevreau,C., Bompas,E., Cioffi,A., Chabaud,S., Perol,D., and Blay,J. (2011). Time to secondary resistance (TSR) after interruption of imatinib (IM) in advanced GIST: Updated results of the prospective French Sarcoma Group randomized phase III trial on long-term survival. ASCO Meeting Abstracts 29, 10015.
Ray-Coquard,I.L., Bin Bui,N., Adenis,A., Rios,M., Bertucci,F., Chabaud,S., Perol,D., Blay,J., Le Cesne,A., and Groupe Sarcome Francais & Groupe d'Etude des Tumeurs Osseuses (GSF-GETO) (2010). Risk of relapse with imatinib (IM) discontinuation at 5 years in advanced GIST patients: Results of the prospective BFR14 randomized phase III study comparing interruption versus continuation of IM at 5 years of treatment: A French Sarcoma Group Study. ASCO Meeting Abstracts 28, 10032.

Responsible Party: Centre Leon Berard
ClinicalTrials.gov Identifier: NCT02260505     History of Changes
Other Study ID Numbers: IMADGIST
2013-001372-37 ( EudraCT Number )
Study First Received: July 30, 2014
Last Updated: August 4, 2017

Keywords provided by Centre Leon Berard:
Gastrointestinal Stromal Tumors
Non-metastatic
KIT +
Imatinib
Adjuvant treatment
High risk of recurrence
Tyrosine kinase inhibitor
Disease Free Survival
Overall survival
Time To Secondary Resistance
Safety profile
Quality of Life during treatment

Additional relevant MeSH terms:
Neoplasms
Gastrointestinal Stromal Tumors
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Gastrointestinal Neoplasms
Digestive System Neoplasms
Gastrointestinal Diseases
Recurrence
Disease Attributes
Pathologic Processes
Digestive System Diseases
Imatinib Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 20, 2017