Clinical trial NCT00002763: High-Dose or Low-Dose Interferon Alfa Compared With No Further Therapy Following Surgery in Treating Patients With Stage III Melanoma
Official title: POST-OPERATIVE ADJUVANT INTERFERON-ALFA-2B (INTRON-A) TREATMENT AFTER RESECTION OF THICK PRIMARY MELANOMA AND/OR REGIONAL LYMPHNODE METASTASES 'INTERMEDIATE-HIGH DOSE' VS INTERMEDIATE-LOW DOSE' IFN-ALFA VS OBSERVATION: A 3-ARM MULTICENTER RANDOMIZED PHASE III TRIAL
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Melanoma (Skin)
Keywords: stage III melanoma
recurrent melanoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2004-07-19
Enrollment: 1000
Sex: ALL
Minimum age (years): 16
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: RATIONALE: Interferon alfa may interfere with the growth of cancer cells. It is not known whether giving high-dose or low-dose interferon alfa is more effective than no further therapy in treating patients with stage III melanoma.

PURPOSE: Randomized phase III trial to compare the effectiveness of high- or low-dose interferon alfa with that of no further therapy following surgery in treating patients who have stage III melanoma.

Detailed description: OBJECTIVES: I. Evaluate the time to distant metastasis, death due to melanoma, and overall survival in patients with high-risk stage III melanoma treated with 10 MU of interferon alfa (IFN-A) for 4 weeks followed by 1 year of IFN-A at 10 MU three times per week vs. 2 years of IFN-A at 5 MU three times per week vs. observation alone. II. Assess the toxicity associated with IFN-A. III. Compare the quality of life, costs, and compliance associated with each treatment regimen.

OUTLINE: Randomized study. Following definitive surgical resection, patients are randomly assigned in a 2:2:1 ratio to Arms A, B, and C, respectively. Arm A: Biological Response Modifier Therapy. Interferon alfa-2b (Schering), IFN-A, NSC-377523. Higher dose. Arm B: Biological Response Modifier Therapy. IFN-A. Lower dose. Arm C: Control. Observation.

PROJECTED ACCRUAL: A total of 1,000 patients will be entered over approximately 4 years in this multicenter study.

Eligibility criteria: DISEASE CHARACTERISTICS: Cutaneous melanoma in one of the following categories: T4, N0, M0 Deep primary tumor with Breslow depth greater than 4.0 cm Tx, N1, M0 Primary tumor with regional lymph node metastases found at lymphadenectomy but clinically undetectable Tx, N2, M0 Clinically apparent regional lymph node metastases (synchronous or metachronous) confirmed by lymphadenectomy Definitive surgical resection and lymphadenectomy with pathologically confirmed adequate surgical margins required Minimum 2 cm margin for primary lesions with Breslow depth greater than 2 mm Distal interphalangeal amputation required for subungual melanomas No primary melanoma originating apart from the skin No multiple in transit metastases in an extremity No lymph node involvement outside the operative area resected by radical neck, axillary lymph node, or ilioinguinal dissection

PATIENT CHARACTERISTICS: Age: 16 to 75 Performance status: ECOG 0 or 1 Hematopoietic: WBC at least 4,000 Platelets at least 125,000 Hemoglobin at least 9.8 g/dL (6.1 mmol/L) Hepatic: Bilirubin no greater than 2 times normal AST no greater than 2 times normal Renal: Creatinine no greater than 1.6 mg/dL (140 micromoles/L) Cardiovascular: No ventricular or supraventricular arrhythmia requiring treatment No congestive heart failure (NYHA class 3/4 status) Other: No uncontrolled infection No requirement for ongoing steroids, NSAIDs, or other immunomodulators No organic brain syndrome or significant impairment of basal cognitive function No psychiatric disorder that would preclude study participation or would be exacerbated by study therapy (e.g., depression) No second malignancy except: In situ cervical cancer Nonmelanomatous skin cancer No pregnant or nursing women

PRIOR CONCURRENT THERAPY: No prior treatment on this protocol for patients with recurrent melanoma at regional lymph nodes No preoperative infusion or perfusion therapy Biologic therapy: No prior adjuvant immunotherapy Chemotherapy: No prior adjuvant systemic chemotherapy No prior anthracyclines Endocrine therapy: Not specified Radiotherapy: No prior adjuvant radiotherapy Surgery: See Disease Characteristics

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Linz
country: Austria
facility: Krankenhaus der Elisabethinen
city: Salzburg
country: Austria
facility: Landeskrankenanstalten - Salzburg
city: Brussels (Bruxelles)
country: Belgium
facility: Institut Jules Bordet
city: Brussels (Bruxelles)
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Brussels
country: Belgium
facility: Hopital Universitaire Erasme
city: Charleroi
country: Belgium
facility: Centre Hospitalier Notre Dame - Reine Fabiola
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Ghent (Gent)
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Leuven
country: Belgium
facility: U.Z. Gasthuisberg
city: Sofia
country: Bulgaria
facility: Alexander's University Hospital
city: Sofia
country: Bulgaria
facility: National Centre of Oncology
city: Zagreb
country: Croatia
facility: University Hospital Sestre Milosrdnice
city: Tallinn
country: Estonia
facility: Estonian Cancer Center
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Turku
country: Finland
facility: Turku University Central Hospital
city: Bordeaux
country: France
facility: CHU de Bordeaux - Hopital Pellegrin
city: Bordeaux
country: France
facility: Institut Bergonie
city: Boulogne Billancourt
country: France
facility: CHU Ambroise Pare
city: Caen
country: France
facility: CHRU de Caen
city: Lyon
country: France
facility: Centre Leon Berard
city: Nice
country: France
facility: Centre Antoine Lacassagne
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: Paris
country: France
facility: Hopital Cochin
city: Pessac
country: France
facility: Hopital Haut Leveque
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: Toulouse
country: France
facility: Institut Claudius Regaud
city: Tours
country: France
facility: Centre Hospitalier Universitaire Bretonneau de Tours
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Berlin
country: Germany
facility: Universitaetsklinikum Benjamin Franklin
city: Berlin
country: Germany
facility: Robert Roessle Klinik
city: Erlangen
country: Germany
facility: Universitaets-Augenklinik - Erlangen
city: Goettingen
country: Germany
facility: Georg August Universitaet
city: Hamburg
country: Germany
facility: Universitats-Krankenhaus Eppendorf
city: Hamburg
country: Germany
facility: Haematologisch-Onkologische Praxis Altona
city: Hannover
country: Germany
facility: Department of Dematology, Hannover Medical School
city: Heidelberg
country: Germany
facility: Universitaets-Hautklinik Heidelberg
city: Homburg/Saar
country: Germany
facility: Universitatsklinik, Saarland
city: Mannheim
country: Germany
facility: III Medizinische Klinik Mannheim
city: Regensburg
country: Germany
facility: Klinikum der Universitat Regensburg
city: Tubingen
country: Germany
facility: Universitatshautklinik Eberhard - Karlsuniversitat Tubingen
city: Ulm
country: Germany
facility: Department of Dermatology
city: Wuerzburg
country: Germany
facility: Universitaet Wuerzburg/Hautkrankheiten
city: Holon
country: Israel
facility: Wolfson Medical Center
city: Tel-Aviv
country: Israel
facility: Tel-Aviv Medical Center-Ichilov Hospital
city: Milano
country: Italy
facility: Istituto Europeo Di Oncologia
city: Amsterdam
country: Netherlands
facility: Academisch Ziekenhuis der Vrije Universiteit
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoekhuis
city: Groningen
country: Netherlands
facility: Academisch Ziekenhuis Groningen
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Nijmegen
country: Netherlands
facility: University Medical Center Nijmegen
city: Rotterdam
country: Netherlands
facility: Rotterdam Cancer Institute
city: Utrecht
country: Netherlands
facility: Academisch Ziekenhuis Utrecht
city: Gdansk
country: Poland
facility: Medical University of Gdansk
city: Krakow (Cracow)
country: Poland
facility: Maria Sklodowska-Curie M.C.C.I.O. Krakow
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
city: Porto
country: Portugal
facility: Instituto Portugues de Oncologia do Porto
city: Moscow
country: Russian Federation
facility: Russian Academy of Medical Sciences Cancer Research Center
city: Belgrade
country: Serbia
facility: Institute of Oncology and Radiology of Serbia
city: Bratislava
country: Slovakia
facility: National Cancer Institute - Bratislava
city: Barcelona
country: Spain
facility: Hospital Clinic y Provincial de Barcelona
city: Zaragoza
country: Spain
facility: Hospital Clinico Universitario
city: Huddinge
country: Sweden
facility: Huddinge Hospital
city: Bellinzona
country: Switzerland
facility: Ospedale San Giovanni
city: Bern
country: Switzerland
facility: Inselspital, Bern
city: Chur
country: Switzerland
facility: Ratisches Kantons und Regionalspital
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: Saint Gallen
country: Switzerland
facility: Kantonsspital - Saint Gallen
city: Zurich
country: Switzerland
facility: Universitaetsspital
city: Adana
country: Turkey
facility: Cukurova University School of Medicine
city: Istanbul
country: Turkey
facility: Vakif Gureba Training Hospital
city: Istanbul
country: Turkey
facility: Istanbul University-Institute of Oncology
city: Istanbul
country: Turkey
facility: Cerrahpasa Medical School
city: Izmir
country: Turkey
facility: Ege University Medical School
city: Bristol
country: United Kingdom
facility: Bristol Oncology Centre
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's NHS Trust
state: England
city: Leeds
country: United Kingdom
facility: St. James's Hospital
state: England
city: London
country: United Kingdom
facility: Royal Marsden NHS Trust
state: England
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
state: England
city: Glasgow
country: United Kingdom
facility: Beatson Oncology Centre
state: Scotland
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: Bouwhuis MG, Suciu S, Collette S, Aamdal S, Kruit WH, Bastholt L, Stierner U, Sales F, Patel P, Punt CJ, Hernberg M, Spatz A, ten Hagen TL, Hansson J, Eggermont AM; EORTC Melanoma Group and the Nordic Melanoma Group. Autoimmune antibodies and recurrence-free interval in melanoma patients treated with adjuvant interferon. J Natl Cancer Inst. 2009 Jun 16;101(12):869-77. doi: 10.1093/jnci/djp132. Epub 2009 Jun 9.
citation: Eggermont AM, Punt CJ. Does adjuvant systemic therapy with interferon-alpha for stage II-III melanoma prolong survival? Am J Clin Dermatol. 2003;4(8):531-6. doi: 10.2165/00128071-200304080-00002.
citation: Bouwhuis MG, Collette S, Suciu S, de Groot ER, Kruit WH, Ten Hagen TL, Aarden LA, Eggermont AM, Swaak AJ; EORTC Melanoma Group. Changes of ferritin and CRP levels in melanoma patients treated with adjuvant interferon-alpha (EORTC 18952) and prognostic value on treatment outcome. Melanoma Res. 2011 Aug;21(4):344-51. doi: 10.1097/CMR.0b013e328346c17f.
citation: Bouwhuis MG, Suciu S, Kruit W, Sales F, Stoitchkov K, Patel P, Cocquyt V, Thomas J, Lienard D, Eggermont AM, Ghanem G; European Organisation for Research and Treatment of Cancer Melanoma Group. Prognostic value of serial blood S100B determinations in stage IIB-III melanoma patients: a corollary study to EORTC trial 18952. Eur J Cancer. 2011 Feb;47(3):361-8. doi: 10.1016/j.ejca.2010.10.005. Epub 2010 Nov 17.
citation: Bouwhuis M, Suciu S, Kruit W, et al.: Prognostic value of autoantibodies (auto-AB) in melanoma patients (pts) in the EORTC 18952 trial of adjuvant interferon (IFN) compared to observation (obs). [Abstract] J Clin Oncol 25 (Suppl 18): A-8507, 473s, 2007.
citation: Suciu S, Ghanem G, Kruit W, et al.: Serum S-100B protein is a strong independent prognostic marker for distant-metastasis free survival (DMFS) in stage III melanoma patients: an evaluation of the EORTC randomized trial 18952 comparing IFNα versus observation. [Abstract] J Clin Oncol 25 (Suppl 18): A-8518, 476s, 2007.
citation: Eggermont AM, Suciu S, MacKie R, Ruka W, Testori A, Kruit W, Punt CJ, Delauney M, Sales F, Groenewegen G, Ruiter DJ, Jagiello I, Stoitchkov K, Keilholz U, Lienard D; EORTC Melanoma Group. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005 Oct 1;366(9492):1189-96. doi: 10.1016/S0140-6736(05)67482-X.