Clinical trial NCT00006249: Interferon Alfa Following Surgery in Treating Patients With Stage III Melanoma
Official title: PEG-Intron Observation After Regional Lymph Node Dissection in AJCC Stage III (TxN1-2MO) Melanoma Patients: a Randomized Phase III Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Melanoma (Skin)
Keywords: stage III melanoma
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
First posted: 2003-01-27
Enrollment: 1258
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Interferon alfa may interfere with the growth of the cancer cells. It is not yet known if this treatment is more effective than observation following surgery for stage III melanoma.

PURPOSE: Randomized phase III trial to determine the effectiveness of interferon alfa in treating patients who have undergone surgery for stage III melanoma.

Detailed description: OBJECTIVES:

* Compare the effect of adjuvant therapy with pegylated interferon alfa vs observation, in terms of distant metastases-free survival, in patients with previously resected stage III melanoma.
* Compare the overall survival in these patients after treatment with pegylated interferon alfa vs observation.
* Determine the toxicity of pegylated interferon alfa in these patients.
* Determine the compliance of these patients treated with pegylated interferon alfa.
* Compare the quality of life in these patients after treatment with pegylated interferon alfa vs observation.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to type of nodal involvement (N1 vs N2), number of positive nodes (1 vs 2-4 vs 5 or more vs not assessed), Breslow primary (T1-2 vs T3 vs T4 vs unknown), ulceration of primary tumor (absent vs present vs unknown), sex, and center. Patients are randomized to one of two treatment arms.

* Arm I: Patients receive pegylated interferon alfa subcutaneously weekly for 5 years.
* Arm II: Patients undergo observation only. Treatment continues in the absence of distant metastases or unacceptable toxicity.

Quality of life is assessed at baseline, and then at months 3, 12, 24, 36, 48, and 60.

Patients are followed every 6 months for 5 years.

PROJECTED ACCRUAL: A total of 1,200 patients (600 per treatment arm) will be accrued for this study within 1.5-2 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed previously resected stage III primary cutaneous melanoma or unknown primary with regional lymph node involvement

  * N1 disease

    * Microscopic, nonpalpable nodal involvement
    * Primary melanoma of any stage with clinically inapparent N1 regional lymph node metastases (T1-4, N1, M0) detected by elective lymph node dissection or sentinel node biopsy
  * N2 disease

    * Palpable nodal involvement with synchronous primary melanoma or apparent nodal disease after prior excision (any pT, N2, M0)
  * Regional lymph node recurrence at any interval after surgery for primary melanoma of any depth (T1-4, rN2, M0)
* Complete resection of primary melanoma with adequate surgical margins
* Full lymphadenectomy must be performed within 70 days of study
* No mucous membrane melanoma or ocular melanoma
* No evidence of distant or nonregional lymph node metastases or in transit metastases (even if previously resected)
* No incompletely resected disease due to gross extracapsular extension

PATIENT CHARACTERISTICS:

Age:

* 18 to 70

Performance status:

* ECOG 0-1

Life expectancy:

* Not specified

Hematopoietic:

* WBC at least 3,000/mm\^3
* Platelet count greater than 100,000/mm\^3
* Hemoglobin at least 9 g/dL

Hepatic:

* SGOT and SGPT less than 2 times upper limit of normal
* No active hepatitis

Renal:

* Creatinine less than 2.0 mg/dL

Cardiovascular:

* No severe cardiovascular disease including the following:

  * Arrhythmias requiring chronic treatment
  * Congestive heart failure (New York Heart Association class III or IV)
  * Symptomatic ischemic heart disease

Other:

* No other prior malignancy within the past 5 years except surgically cured nonmelanomatous skin cancer or carcinoma in situ of the cervix
* No thyroid dysfunction unresponsive to therapy
* No uncontrolled diabetes mellitus
* No active autoimmune disease
* No active and/or uncontrolled infection
* No history of neuropsychiatric disorder requiring hospitalization
* No known active alcohol or drug abuse
* HIV negative
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* No prior interferon alfa
* No prior immunotherapy for melanoma
* No other concurrent immunologic or biologic therapy
* No concurrent colony stimulating factors including epoetin alfa and filgrastim (G-CSF)

Chemotherapy:

* No prior chemotherapy for melanoma
* No concurrent chemotherapy

Endocrine therapy:

* No prior hormonal therapy for melanoma
* No concurrent hormonal therapy
* No concurrent chronic systemic corticosteroid therapy

Radiotherapy:

* No prior radiotherapy for melanoma
* No concurrent radiotherapy

Surgery:

* See Disease Characteristics
* Recovered from any prior recent surgery

Other:

* At least 30 days since other prior experimental therapy
* No other concurrent investigational drugs

Primary outcomes:
measure: distant-metastasis free-survival (DMFS)
timeFrame: from randomization
Secondary outcomes:
measure: survival
timeFrame: from randomization till death
measure: toxicity
timeFrame: from randomization
Other outcomes:
measure: quality of life
timeFrame: from randomization
Locations:
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Institute
state: Victoria
city: Heidelberg West
country: Australia
facility: Austin and Repatriation Medical Centre
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Perth
country: Australia
facility: Sir Charles Gairdner Hospital, Perth
state: Western Australia
city: Newcastle
country: Australia
facility: David Maddison Clincial Sciences
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Brussels
country: Belgium
facility: Hopital Universitaire Erasme
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Gosselies
country: Belgium
facility: Clinique Notre Dame de Grace
city: Leuven
country: Belgium
facility: U.Z. Gasthuisberg
city: Sofia
country: Bulgaria
facility: National Centre of Oncology
city: Zagreb
country: Croatia
facility: University Hospital Sestre Milosrdnice
city: Prague (Praha)
country: Czech Republic
facility: Charles University Hospital
city: Tallinn
country: Estonia
facility: North-Estonian Regional Hospital Cancer Centre
city: Amiens
country: France
facility: Centre Hospitalier Universitare d'Amens
city: Besancon
country: France
facility: CHR de Besancon - Hopital Saint-Jacques
city: Bordeaux
country: France
facility: Hopital Saint Andre
city: Boulogne Billancourt
country: France
facility: CHU Ambroise Pare
city: Grenoble
country: France
facility: CHR de Grenoble - La Tronche
city: Lille
country: France
facility: Centre Hospitalier Regional et Universitaire de Lille
city: Limoges
country: France
facility: Centre Hospital Regional Universitaire de Limoges
city: Lyon
country: France
facility: Centre Leon Berard
city: Montpellier
country: France
facility: Hopital St. Eloi
city: Montpellier
country: France
facility: Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
city: Nice
country: France
facility: Hopital L'Archet - 2
city: Paris
country: France
facility: Hopital Bichat - Claude Bernard
city: Paris
country: France
facility: Hopital Saint-Louis
city: Pessac
country: France
facility: Hopital Haut Leveque
city: Reims
country: France
facility: Centre Hospitalier Universitaire
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Saint Cloud
country: France
facility: Centre Rene Huguenin
city: Saint Priest en Jarez
country: France
facility: Centre Hospitalier Regional et Universitaire de Saint-Etienne
city: Strasbourg
country: France
facility: Hopitaux Universitaire de Strasbourg
city: Thionville
country: France
facility: Centre Hospitalier Regional Metz Thionville
city: Tours
country: France
facility: Centre Hospitalier Universitaire Bretonneau de Tours
city: Vandoeuvre-les-Nancy
country: France
facility: Centre Alexis Vautrin
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Berlin
country: Germany
facility: Robert Roessle Klinik
city: Bochum 1
country: Germany
facility: Saint Josef Hospital
city: Dortmund
country: Germany
facility: Stadt. Kliniken
city: Erlangen
country: Germany
facility: Universitaet Erlangen
city: Goettingen
country: Germany
facility: Georg August Universitaet
city: Hamburg
country: Germany
facility: Haematologisch-Onkologische Praxis Altona
city: Heidelberg
country: Germany
facility: Universitaets-Hautklinik Heidelberg
city: Leipzig
country: Germany
facility: Universitaet Leipzig - Chirurgische Klinik und Poliklinik I
city: Magdeburg
country: Germany
facility: Otto - Von - Guericke - Universitaet Magdeburg
city: Mannheim
country: Germany
facility: Klinikum der Stadt Mannheim
city: Wuerzburg
country: Germany
facility: Universitaet Wuerzburg/Hautkrankheiten
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Holon
country: Israel
facility: Wolfson Medical Center
city: Tel-Aviv
country: Israel
facility: Tel-Aviv Sourasky Medical Center
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico - Aviano
city: Firenze
country: Italy
facility: Ospendale S.M. Annunziata-A.S.DI Firenze
city: Genoa (Genova)
country: Italy
facility: Istituto Nazionale per la Ricerca sul Cancro
city: Milano (Milan)
country: Italy
facility: Istituto Nazionale per lo Studio e la Cura dei Tumori
city: Milano
country: Italy
facility: European Institute of Oncology - Chemo Prevention
city: Naples
country: Italy
facility: Istituto Nazionale per lo Studio e la Cura dei Tumori
city: Rome
country: Italy
facility: Istituto Regina Elena
city: Torino
country: Italy
facility: Universita Degli Studi di Torino
city: Amsterdam
country: Netherlands
facility: Vrije Universiteit Medisch Centrum
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Nijmegen
country: Netherlands
facility: University Medical Center Nijmegen
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center
city: Utrecht
country: Netherlands
facility: Academisch Ziekenhuis Utrecht
city: Poznan
country: Poland
facility: Great Poland Cancer Center
city: Warsaw
country: Poland
facility: Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
city: Lisbon
country: Portugal
facility: Instituto Portugues de Oncologia de Francisco Gentil - Centro de Lisboa
city: Porto
country: Portugal
facility: Instituto Portugues de Oncologia Centro do Porto, SA
city: Ljubljana
country: Slovenia
facility: Institute of Oncology, Ljubljana
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Zaragoza
country: Spain
facility: Hospital Clinico Universitario
city: Aarau
country: Switzerland
facility: Kantonspital Aarau
city: Bern
country: Switzerland
facility: Inselspital, Bern
city: Chur
country: Switzerland
facility: Ratisches Kantons und Regionalspital
city: Zurich
country: Switzerland
facility: UniversitaetsSpital
city: Istanbul
country: Turkey
facility: Vakif Gureba Training Hospital
city: Izmir
country: Turkey
facility: Ege University Medical School
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's NHS Trust
state: England
city: Cheltenham
country: United Kingdom
facility: Cheltenham General Hospital
state: England
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
state: England
city: Guildford
country: United Kingdom
facility: Royal Surrey County Hospital
state: England
city: Hull
country: United Kingdom
facility: Princess Royal Hospital
state: England
city: Leeds
country: United Kingdom
facility: St. James's Hospital
state: England
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: England
city: London
country: United Kingdom
facility: Saint Bartholomew's Hospital
state: England
city: London
country: United Kingdom
facility: Royal Free Hospital
state: England
city: London
country: United Kingdom
facility: Guy's and St. Thomas' Hospitals NHS Trust
state: England
city: London
country: United Kingdom
facility: St. George's Hospital
state: England
city: London
country: United Kingdom
facility: Royal Marsden NHS Trust
state: England
city: Merseyside
country: United Kingdom
facility: Clatterbridge Centre for Oncology NHS Trust
state: England
city: Newcastle Upon Tyne
country: United Kingdom
facility: Newcastle General Hospital
state: England
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital
state: England
city: Westcliff-On-Sea
country: United Kingdom
facility: Southend NHS Trust Hospital
state: England
city: Belfast
country: United Kingdom
facility: Belfast City Hospital Trust
state: Northern Ireland
city: Dundee
country: United Kingdom
facility: Ninewells Hospital and Medical School
state: Scotland
city: Glasgow
country: United Kingdom
facility: Western Infirmary
state: Scotland
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Center at Velinde Hospital
state: Wales
city: Birmingham
country: United Kingdom
facility: Selly Oak Hospital at University Hospital NHS Trust
city: Oxford
country: United Kingdom
facility: Churchill Hospital
Study officials:
affiliation: Daniel Den Hoed Cancer Center at Erasmus Medical Center
name: Alexander M. M. Eggermont, MD, PhD
role: STUDY_CHAIR
References:
citation: Eggermont AM, Suciu S, Testori A, Kruit WH, Marsden J, Punt CJ, Santinami M, Sales F, Schadendorf D, Patel P, Dummer R, Robert C, Keilholz U, Yver A, Spatz A. Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991. Eur J Cancer. 2012 Jan;48(2):218-25. doi: 10.1016/j.ejca.2011.09.028. Epub 2011 Nov 5.
citation: Eggermont AM, Suciu S, Santinami M, et al.: EORTC 18991 phase III trial: Long-term adjuvant pegylated interferon-α2b (PEG-IFN) versus observation in resected stage III melanoma: long-term results at 7.6-years follow-up. [Abstract] J Clin Oncol 29 (Suppl 15): A-8506b, 2011.
citation: Bouwhuis MG, Suciu S, Testori A, Kruit WH, Sales F, Patel P, Punt CJ, Santinami M, Spatz A, Ten Hagen TL, Eggermont AM. Phase III trial comparing adjuvant treatment with pegylated interferon Alfa-2b versus observation: prognostic significance of autoantibodies--EORTC 18991. J Clin Oncol. 2010 May 10;28(14):2460-6. doi: 10.1200/JCO.2009.24.6264. Epub 2010 Apr 12.
citation: Eggermont AM, Bouwhuis MG, Kruit WH, Testori A, ten Hagen T, Yver A, Xu C. Serum concentrations of pegylated interferon alpha-2b in patients with resected stage III melanoma receiving adjuvant pegylated interferon alpha-2b in a randomized phase III trial (EORTC 18991). Cancer Chemother Pharmacol. 2010 Mar;65(4):671-7. doi: 10.1007/s00280-009-1072-z. Epub 2009 Jul 21.
citation: Bottomley A, Coens C, Suciu S, Santinami M, Kruit W, Testori A, Marsden J, Punt C, Sales F, Gore M, Mackie R, Kusic Z, Dummer R, Patel P, Schadendorf D, Spatz A, Keilholz U, Eggermont A. Adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma: a phase III randomized controlled trial of health-related quality of life and symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group. J Clin Oncol. 2009 Jun 20;27(18):2916-23. doi: 10.1200/JCO.2008.20.2069. Epub 2009 May 11.
citation: Fusi A, Collette S, Busse A, Suciu S, Rietz A, Santinami M, Kruit WH, Testori A, Punt CJ, Dalgleish AG, Spatz A, Eggermont AM, Keilholz U. Circulating melanoma cells and distant metastasis-free survival in stage III melanoma patients with or without adjuvant interferon treatment (EORTC 18991 side study). Eur J Cancer. 2009 Dec;45(18):3189-97. doi: 10.1016/j.ejca.2009.09.004. Epub 2009 Sep 28.
citation: Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, Punt CJ, Sales F, Gore M, MacKie R, Kusic Z, Dummer R, Hauschild A, Musat E, Spatz A, Keilholz U; EORTC Melanoma Group. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet. 2008 Jul 12;372(9633):117-126. doi: 10.1016/S0140-6736(08)61033-8.
citation: Eggermont AM, Suciu S, Santinami M, et al.: EORTC 18991: long-term adjuvant pegylated interferon-alpha2b (PEG-IFN) compared to observation in resected stage III melanoma, final results of a randomized phase III trial. [Abstract] J Clin Oncol 25 (Suppl 18): A-8504, 473s, 2007.