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

Information source: Centre Leon Berard
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Gastrointestinal Stromal Tumors; KIT +; Resected Gastrointestinal Stromal Tumors; Non-metastatic; High Risk of Recurrence

Intervention: Imatinib maintenance (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Centre Leon Berard

Official(s) and/or principal investigator(s):
Jean-Yves Blay, Pr, Principal Investigator, Affiliation: Centre Léon Bérard, Lyon

Overall contact:
Jean-Yves Blay, Pr, Phone: +33 4 78 78 27 57, Email: jean-yves.blay@lyon.unicancer.fr

Summary

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.

Clinical Details

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)

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Primary outcome: Disease Free Survival (DFS)

Secondary outcome:

Overall Survival (OS)

Time to Secondary Resistance (TSR)

Percentage of patients in Complete Response (%CR) in interruption arm after reintroduction of Imatinib

Frequency of Adverse Events (AE)

Patient's Quality of Life (QoL)

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

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

Locations and Contacts

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

Centre Hospitalier Universitaire La Timone, Marseille, Bouches du Rhône 13386, France; Active, not recruiting

Institut Paoli-Calmettes, Marseille, Bouches du Rhône 13273, France; Active, not recruiting

CHRU de Besançon - Hôpital Minjoz, Besançon, Doubs 25030, France; Not yet recruiting
Elsa KALBACHER, Doctor, Phone: + 33 3 81 66 81 66, Email: ekalbacher@chu-besancon.fr
Loïc CHAIGNAAU, Doctor, Sub-Investigator
Elsa KALBACHER, Doctor, Principal Investigator

Institut Bergonié, Bordeaux, Gironde 33076, France; Not yet recruiting
Binh BUI NGUYEN, Dr, Phone: +33 5 56 33 32 44, Email: B.Bui@bordeaux.unicancer.fr
Binh BUI NGUYEN, Dr, Principal Investigator
Antoine ITALIANO, Dr, Sub-Investigator

Institut Claudius Regaud, Toulouse, Haute Garonne 31059, France; Not yet recruiting
Christine CHEVREAU, Dr, Phone: +33 5 61 42 41 74, Email: chevreau.christine@iuct-oncopole.fr
Christine CHEVREAU, Dr, Principal Investigator

Centre Hospitalier Universitaire Toulouse Purpan, Toulouse, Haute-Garonne 31059, France; Not yet recruiting
Rosine GUIMBAUD, Pr, Phone: +33 5 61 77 96 49, Email: Guimbaud.r@chu-toulouse.fr
Rosine GUIMBAUD, Pr, Principal Investigator

Centre Régional de Lutte contre le Cancer de Montpellier, Montpellier, Hérault 34298, France; Not yet recruiting
Didier CUPISSOL, Dr, Phone: +33 4 67 61 31 83, Email: didier.cupissol@icm.unicancer.fr
Didier CUPISSOL, Dr, Principal Investigator

Institut de cancérologie LUCIEN NEUWIRTH, Saint-priest-en-jarez, Loire 42270, France; Recruiting
Olivier COLLARD, Dr, Phone: 00 334 77 91 70 34, Email: olivier.collard@icloire.fr
Olivier COLLARD, Dr, Principal Investigator
Cecile VASSAL, Dr, Sub-Investigator

Institut de Cancérologie de l'Ouest, Saint-Herblain, Loire Atlantique 44805, France; Recruiting
Elisabeth BOMPAS, Dr, Phone: +33 2 40 67 99 39, Email: emmanuelle.bompas@ico.unicancer.fr
Elisabeth BOMPAS, Dr, Principal Investigator
Frédéric ROLLAND, Dr, Sub-Investigator
Damien VANSTEENE, Dr, Sub-Investigator

Centre Hospitalier universitaire Robert Debré, Reims, Marne 51092, France; Recruiting
Olivier BOUCHE, Pr, Phone: +33 3 26 78 71 72, Email: obouche@chu-reims.fr
Olivier BOUCHE, Pr, Principal Investigator
Julien VOLET, Dr, Sub-Investigator

Centre Alexis Vautrin, Vandoeuvre-les-Nancy, Meurthe et Moselle 54519, France; Recruiting
Maria RIOS, Dr, Phone: +33 3 83 59 85 66, Email: m.rios@nancy.unicancer.fr
Maria RIOS, Dr, Principal Investigator

Centre Oscar Lambret, Lille, Nord 59020, France; Recruiting
Antoine ADENIS, Pr, Phone: +33 3 20 29 59 42, Email: a-adenis@o-lambret.fr
Antoine ADENIS, Pr, Principal Investigator
Farid EL HAJBI, Dr, Sub-Investigator
Nicolas PENEL, Dr, Sub-Investigator
Charlotte PEUGNIEZ, Dr, Sub-Investigator

Centre Léon Bérard, Lyon, Rhône 69008, France; Active, not recruiting

Institut de Cancérologie Gustave Roussy, Villejuif, Val de Marne 94805, France; Recruiting
Axel LE CESNE, Dr, Phone: +33 1 42 11 43 16, Email: axel.lecesne@gustaveroussy.fr
Axel LE CESNE, Dr, Principal Investigator
Julien DOMONT, Dr, Sub-Investigator
Sarah DUMONT, Dr, Sub-Investigator
Olivier MIR, Dr, Sub-Investigator

Additional Information

Related publications:

Blackstein ME, Blay JY, Corless C, Driman DK, Riddell R, Soulières D, Swallow CJ, Verma S; Canadian Advisory Committee on GIST. Gastrointestinal stromal tumours: consensus statement on diagnosis and treatment. Can J Gastroenterol. 2006 Mar;20(3):157-63.

Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA, Corless CL, Fletcher CD, Roberts PJ, Heinz D, Wehre E, Nikolova Z, Joensuu H. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008 Feb 1;26(4):620-5. doi: 10.1200/JCO.2007.13.4403.

Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, Raymond AK, Bramwell VH, Baker LH, Maki RG, Tanaka M, Hecht JR, Heinrich MC, Fletcher CD, Crowley JJ, Borden EC. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008 Feb 1;26(4):626-32. doi: 10.1200/JCO.2007.13.4452.

Blay JY, von Mehren M, Blackstein ME. Perspective on updated treatment guidelines for patients with gastrointestinal stromal tumors. Cancer. 2010 Nov 15;116(22):5126-37. doi: 10.1002/cncr.25267. Review.

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Casali PG, Jost L, Reichardt P, Schlemmer M, Blay JY; ESMO Guidelines Working Group. Gastrointestinal stromal tumors: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008 May;19 Suppl 2:ii35-8. doi: 10.1093/annonc/mdn080.

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Starting date: December 2014
Last updated: June 8, 2015

Page last updated: August 23, 2015

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