Clinical trial NCT00103168: Imatinib Mesylate or Observation Only in Treating Patients Who Have Undergone Surgery for Localized Gastrointestinal Stromal Tumor
Official title: Intermediate and High Risk Localized, Completely Resected, Gastrointestinal Stromal Tumors (GIST) Expressing KIT Receptor: A Controlled Randomized Trial on Adjuvant Imatinib Mesylate (Glivec) Versus No Further Therapy After Complete Surgery
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Gastrointestinal Stromal Tumor
Keywords: gastrointestinal stromal tumor
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
Collaborators: name: Italian Sarcoma Group
name: UNICANCER
name: Grupo Espanol de Investigacion en Sarcomas
First posted: 2005-02-08
Enrollment: 908
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Imatinib mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving imatinib mesylate after surgery may kill any remaining tumor cells. It is not yet known whether imatinib mesylate is more effective than observation only in treating gastrointestinal stromal tumor.

PURPOSE: This randomized phase III trial is studying imatinib mesylate to see how well it works compared to observation only in treating patients who have undergone surgery for localized gastrointestinal stromal tumor.

Detailed description: OBJECTIVES:

Primary

* Assess whether there is a difference in overall survival between intermediate and high-risk localized GIST patients undergoing complete surgery alone and those undergoing complete surgery plus adjuvant imatinib mesylate 400 mg daily for two years Secondary
* Assess whether there is a difference in relapse-free survival and relapse-free interval between GIST undergoing complete surgery alone and those undergoing surgery + adjuvant Imatinib mesylate 400 mg daily for two years.
* Determine the safety of this drug in these patients.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to participating center, risk category (high vs intermediate), tumor site (gastric vs other), and resection level (R0 vs R1).

* Arm I: Patients receive adjuvant oral imatinib mesylate once daily for 2 years in the absence of disease progression or unacceptable toxicity.
* Arm II: Patients are observed (without receiving further antitumoral therapy) every 3 months for 2 years.

After completion of study treatment, patients in arm I are followed every 3 months for 2 years. All patients are then followed every 4 months for 3 years and at least annually thereafter.

PROJECTED ACCRUAL: A total of 900 patients will be accrued for this study within 3.5 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed gastrointestinal stromal tumor

  * Localized disease
* Meets 1 of the following criteria:

  * At high-risk of relapse, defined by 1 of the following criteria:

    * Tumor size \> 10 cm
    * Mitotic rate \> 10/50 high-power field (HPF)
    * Tumor size \> 5 cm AND mitotic rate \> 5/50 HPF
  * At intermediate-risk of relapse, defined by 1 of the following criteria:

    * Tumor size \< 5 cm AND mitotic rate 6-10/50 HPF
    * Tumor size 5-10 cm AND mitotic rate \< 5/50 HPF
* Tumor must stain positive for Kit (CD117) by polyclonal DAKO antibody staining
* Must have undergone complete resection of the primary tumor at least 2 weeks, but no more than 3 months, before study entry

  * Meets criteria for 1 of the following resection levels:

    * R0 (clear margins)
    * R1, defined by 1 of the following criteria:

      * Margins of resection are contaminated by tumor, but no macroscopic tumor is left behind
      * Intraoperative tumor rupture
      * Shelling-out procedure
      * Endoscopic maneuver
  * No residual macroscopic disease after surgery

    * Regional positive lymph nodes allowed provided they have been macroscopically excised
* No distant metastases\*, including any of the following:

  * Peritoneal lesion not contiguous to the primary tumor
  * Liver metastases
  * Hemoperitoneal metastases NOTE: \*Even if a complete resection (R0) was performed

PATIENT CHARACTERISTICS:

Age

* 18 and over

Performance status

* WHO 0-2

Life expectancy

* Not specified

Hematopoietic

* Absolute neutrophil count ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Hemoglobin ≥ 9 g/dL (transfusions allowed)

Hepatic

* Bilirubin ≤ 1.5 times upper limit of normal (ULN)
* AST or ALT ≤ 2.5 times ULN
* No uncontrolled liver disease
* No chronic viral hepatitis at risk of reactivation

Renal

* Creatinine \< 1.5 times ULN
* No uncontrolled chronic renal disease

Cardiovascular

* No New York Heart Association class III-IV cardiac disease
* No congestive heart failure
* No myocardial infarction within the past 2 months

Other

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for up to 3 months after study participation
* No uncontrolled diabetes
* No uncontrolled active infection
* No HIV infection
* No psychological, familial, sociological, or geographical condition that would preclude study compliance or participation
* No other severe and/or uncontrolled medical disease
* No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy

* No other prior molecular targeted or biologic therapy
* No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF) to support blood counts
* No concurrent anticancer biologic agents

Chemotherapy

* No prior chemotherapy for gastrointestinal stromal tumors
* No concurrent anticancer chemotherapy

Endocrine therapy

* Not specified

Radiotherapy

* No prior radiotherapy
* No concurrent anticancer radiotherapy

Surgery

* See Disease Characteristics
* Prior non-curative surgery allowed (e.g., surgery with main diagnostic intent or emergency surgery with symptomatic intent)

Other

* No prior imatinib mesylate
* No prior randomization to this study
* No concurrent therapeutic anticoagulation with coumarin derivatives

  * Concurrent therapeutic low-molecular weight heparin or mini-dose coumarin derivatives (equivalent to oral warfarin 1 mg/day) allowed for prophylaxis of central venous catheter thrombosis
* No other concurrent antitumoral therapy
* No other concurrent anticancer agents
* No other concurrent investigational drugs

Primary outcomes:
measure: Overall survival
Secondary outcomes:
measure: Relapse-free survival
measure: Relapse-free interval
measure: Adverse events
Other outcomes:
Locations:
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Herlev
country: Denmark
facility: Herlev University Hospital
city: Abbeville
country: France
facility: Centre Hospitalier d'Abbeville
city: Angers
country: France
facility: Centre Paul Papin
city: Besancon
country: France
facility: Centre Hospitalier Regional de Besancon - Hopital Jean Minjoz
city: Bobigny
country: France
facility: Hopital Avicenne
city: Bordeaux
country: France
facility: Institut Bergonie
city: Boulogne Billancourt
country: France
facility: Hopital Ambroise Pare
city: Brest
country: France
facility: C.H.U. de Brest
city: Caen
country: France
facility: Centre Regional Francois Baclesse
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Colmar
country: France
facility: Hopital Louis Pasteur
city: Dijon
country: France
facility: Centre de Lutte Contre le Cancer Georges-Francois Leclerc
city: Dreux
country: France
facility: Centre Hospitalier de Dreux
city: Le Chesnay
country: France
facility: Hopital Andre Mignot
city: Le Mans
country: France
facility: C. H. Du Mans
city: Libourne
country: France
facility: Hopital Robert Boulin
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Leon Berard
city: Lyon
country: France
facility: Hopital Edouard Herriot - Lyon
city: Marseille
country: France
facility: Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes
city: Marseille
country: France
facility: CHU de la Timone
city: Mont-de-Marsan
country: France
facility: Centre Hospitalier General de Mont de Marsan
city: Montpellier
country: France
facility: Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
city: Nantes-Saint Herblain
country: France
facility: Centre Regional Rene Gauducheau
city: Nantes
country: France
facility: CHR Hotel Dieu
city: Orleans
country: France
facility: CHR D'Orleans - Hopital de la Source
city: Paris
country: France
facility: Hopital Europeen Georges Pompidou
city: Paris
country: France
facility: Hopital Bichat - Claude Bernard
city: Paris
country: France
facility: Hopital Saint Antoine
city: Paris
country: France
facility: Hopital Cochin
city: Paris
country: France
facility: Hopital Tenon
city: Pau
country: France
facility: Centre Hospitalier - Pau
city: Reims
country: France
facility: CHU - Robert Debre
city: Rennes
country: France
facility: Centre Hospitalier Universitaire de Rennes
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Rouen
country: France
facility: Hopital Charles Nicolle
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint Cloud
country: France
facility: Centre Rene Huguenin
city: Saint Priest en Jarez
country: France
facility: Institut de Cancerologie de la Loire
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Strasbourg
country: France
facility: Hopital Universitaire Hautepierre
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Vandoeuvre-les-Nancy
country: France
facility: Centre Alexis Vautrin
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Tuebingen
country: Germany
facility: Southwest German Cancer Center at Eberhard-Karls-University
city: Leon
country: Spain
facility: Complejo Hospitalario de Leon
city: Madrid
country: Spain
facility: Grupo Espanol de Investigacion del Cancer de Mama
city: Manchester
country: United Kingdom
facility: Christie Hospital
state: England
city: Glasgow
country: United Kingdom
facility: Gartnavel General Hospital
state: Scotland
Study officials:
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
name: Paolo G. Casali, MD
role: STUDY_CHAIR
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
name: Axel Le Cesne, MD
role: STUDY_CHAIR
affiliation: Instituto Valenciano De Oncologia
name: Andres Poveda, MD
role: STUDY_CHAIR
References:
citation: Gronchi A, Bonvalot S, Poveda Velasco A, Kotasek D, Rutkowski P, Hohenberger P, Fumagalli E, Judson IR, Italiano A, Gelderblom HJ, van Coevorden F, Penel N, Kopp HG, Duffaud F, Goldstein D, Broto JM, Wardelmann E, Marreaud S, Smithers M, Le Cesne A, Zaffaroni F, Litiere S, Blay JY, Casali PG. Quality of Surgery and Outcome in Localized Gastrointestinal Stromal Tumors Treated Within an International Intergroup Randomized Clinical Trial of Adjuvant Imatinib. JAMA Surg. 2020 Jun 1;155(6):e200397. doi: 10.1001/jamasurg.2020.0397. Epub 2020 Jun 17.
citation: Casali PG, Le Cesne A, Poveda Velasco A, Kotasek D, Rutkowski P, Hohenberger P, Fumagalli E, Judson IR, Italiano A, Gelderblom H, Adenis A, Hartmann JT, Duffaud F, Goldstein D, Broto JM, Gronchi A, Dei Tos AP, Marreaud S, van der Graaf WT, Zalcberg JR, Litiere S, Blay JY. Time to Definitive Failure to the First Tyrosine Kinase Inhibitor in Localized GI Stromal Tumors Treated With Imatinib As an Adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup Randomized Trial in Collaboration With the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas. J Clin Oncol. 2015 Dec 20;33(36):4276-83. doi: 10.1200/JCO.2015.62.4304. Epub 2015 Nov 16.