Clinical Trials Register

Summary
EudraCT Number:	2009-010273-20
Sponsor's Protocol Code Number:	18081
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-04-22
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2009-010273-20

A.3

Full title of the trial

Adjuvant peginterferon alda-2b for 2 years vs Observation in patients with an ulcerated primary cutaneous melanoma with T(2-4)bN0M0: a randomized phase III trial of the EORTC Melanoma Group.

Peginterferon alfa-2b adyuvante durante 2 ãnos frente a observación en pacientes con melanoma cutáneo primario ulcerado con T(2-4)bN0M0: ensayo fase III aleatorizado del Grupo de Melanoma de la EORTC.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Adjuvant peginterferon alda-2b for 2 years vs Observation in patients with an ulcerated primary cutaneous melanoma with T(2-4)bN0M0: a randomized phase III trial of the EORTC Melanoma Group.

A.3.2

Name or abbreviated title of the trial where available

Adjuvant Pegylated Interferon in Ulcerated Melanoma

El interferón pegilado adyuvante en melanoma ulcerado

A.4.1

Sponsor's protocol code number

18081

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01502696

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	European organisation for research and treatment of Cancer
B.1.3.4	Country	Belgium
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	MERCK and Co. Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	EORTC
B.5.2	Functional name of contact point	Project Mgt & Regulatory Unit
B.5.3	Address:
B.5.3.1	Street Address	avenue E. Mounier 83/11
B.5.3.2	Town/ city	Brussels
B.5.3.3	Post code	1200
B.5.3.4	Country	Belgium
B.5.4	Telephone number	3227741072/
B.5.5	Fax number	3227741030/
B.5.6	E-mail	regulatory@eortc.be

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	PegIntron (PEG-IFN alfa-2b), Powder for Injection (100mcg strength)
D.2.1.1.2	Name of the Marketing Authorisation holder	Schering-Plough Europe
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	PegIntron
D.3.4	Pharmaceutical form	Powder for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PEGINTERFERON ALFA-2B
D.3.9.1	CAS number	215647-85-1
D.3.9.4	EV Substance Code	SUB12549MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Cylatron (PEG-IFN), Powder for Injection (200mcg strength)
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharpe & Dohme
D.2.1.2	Country which granted the Marketing Authorisation	Switzerland
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Cylatron
D.3.4	Pharmaceutical form	Powder for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PEGINTERFERON ALFA-2B
D.3.9.1	CAS number	215647-85-1
D.3.9.4	EV Substance Code	SUB12549MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Cylatron (PEG-IFN), Powder for Injection (300mcg strengths)
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharpe & Dohme
D.2.1.2	Country which granted the Marketing Authorisation	Switzerland
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Cylatron
D.3.4	Pharmaceutical form	Powder for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PEGINTERFERON ALFA-2B
D.3.9.1	CAS number	215647-85-1
D.3.9.4	EV Substance Code	SUB12549MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	SYLATRON (PEG-IFN), for Injection (200mcg strengths)
D.2.1.1.2	Name of the Marketing Authorisation holder	Schering Corporation
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	SYLATRON
D.3.4	Pharmaceutical form	Powder for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PEGINTERFERON ALFA-2B
D.3.9.1	CAS number	215647-85-1
D.3.9.4	EV Substance Code	SUB12549MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 5
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	SYLATRON (PEG-IFN), for Injection (300mcg strengths)
D.2.1.1.2	Name of the Marketing Authorisation holder	Schering Corporation
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	SYLATRON
D.3.4	Pharmaceutical form	Powder for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PEGINTERFERON ALFA-2B
D.3.9.1	CAS number	215647-85-1
D.3.9.4	EV Substance Code	SUB12549MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Ulcerated primary cutaneous melanoma >1mm (T2b-4bN0M0)

melanoma cutáneo primario ulcerado > 1 mm (T2b-4bN0M0)

E.1.1.1

Medical condition in easily understood language

Ulcerated primary cutaneous melanoma >1mm (T2b-4bN0M0)

melanoma cutáneo primario ulcerado > 1 mm (T2b-4bN0M0)

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.0
E.1.2	Level	HLT
E.1.2	Classification code	10027156
E.1.2	Term	Skin melanomas (excl ocular)
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main objective of the trial is to prospectively assess the effricacy, toxicity, quality of life with PEG IFN alfa-2b as compared to observation after adequate surgery for ulcerated primary cutaneous melanomas with T(2-4)bN0M0. The primary objective is to determine whether post-operative adjuvant therapy with PEG IFN alfa-2b improves relapse-free survival (PFS) as compared to observation.

El principal objetivo del ensayo es evaluar prospectivamente la eficacia, toxicidad y calidad de vida con PEG IFN alfa-2b en comparación con la observación después de la cirugía adecuada para ulceradas melanomas cutáneos primarios con T (2-4) bN0M0.
El objetivo principal es determinar si el post-operatorio terapia adyuvante con PEG IFN alfa-2b mejora la supervivencia libre de recaída (PFS) en comparación con la observación.

E.2.2

Secondary objectives of the trial

The secondary objectives are:
- to compare adverse event profiles between patients receiving PEG IFN
alfa-2b versus patients in the observation arm
- to determine whether post-operative adjuvant therapy with PEG IFN
alfa-2b improves overall survival (OS) as compared to observation
- to determine whether post-operative adjuvant therapy with PEG IFN
alfa-2b improves distant metastases-free survival (DMFS) as compared
to observation
- to compare quality of life between the two arms (PEG IFN alfa-2b
versus observation)

Los objetivos secundarios son:
- Para comparar los perfiles de eventos adversos entre los pacientes tratados con PEG IFN alfa-2b versus los pacientes en el grupo de observación
- Para determinar si el post-operatorio de la terapia adyuvante con PEG IFN alfa-2b mejora la supervivencia global (OS) en comparación con la observación
- Para determinar si el post-operatorio de la terapia adyuvante con PEG IFN alfa-2b mejora distante supervivencia libre de metástasis (CPOS) en comparación con la observación
- Para comparar la calidad de vida entre los dos brazos (PEG IFN alfa-2b versus observación)

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Translational research/Objectives:
In order to explore the biological significance of melanoma ulceration on patient outcome and response to treatment, and in parallel assessing the prognostic and/or predictive value of potential biomarkers, this protocol includes a prospective biobanking in view of translational research. The objectives of this prospective biobanking are to:
♦ To prospectively collect biological material (whole blood, plasma, serum and tissue) for translational research projects for patients who have consented to take part in this research. Projects may include but are not restricted to:
♦ Single-nucleotide polymorphisms and correlation to peginterferon alfa-2b sensitivity.
♦ Analyze the association of potential biomarkers present in the subject’s blood, serum/plasma and/or tumor tissue with clinical benefit post-treatment in the form of Relapse Free Survival, Distant-Metastasis Free Survival and Overall Survival in order to identify candidate markers predictive of response to peginterferon alfa-2b.
♦ Determination of prognostic value of biomarkers on human plasma/serum and tissue in correlation to other validated prognostic factors and to the clinical course of melanoma patients / CRP, neutrophils, circulating micro-RNAs, vitamin D level, and Th1 response amongst others.
♦ Assessment of the risk of false-negativity of SNB. Allow the collection and storage of whole blood, serum/plasma and melanoma tumor tissue samples from patients enrolled in the main protocol for use in future biomarker research studies.
To ensure confidentiality, all samples and the information associated with the samples will be coded to prevent the exposure of subject information and identity. These evaluations are not expected to benefit the subject directly or to alter their treatment course. The results will not be communicated or placed in their medical record and will not be made available to members of their family, treating physicians, or other third parties except as specified in the informed consent.
Translational Research Project 1: Molecular characterization of ulcerated melanoma sensitivity to peginterferon alfa-2b/Objectives:
♦ To determine of genomic instability in ulcerated melanoma in order to evaluate biomarkers predictive of IFN-sensitivity in correlation with the clinical outcome of the EORTC 18081 trial.
♦ To determine of gene expression profile in ulcerated melanoma in order to evaluate biomarkers predictive of IFN-sensitivity in correlation with and the clinical outcome of the EORTC 18081 trial.
Translational Research Project 2: Characterization of prognostic biomarkers on human plasma/serum samples and tissue/Objectives: Determination of evolution and prognostic value of biomarkers (CRP, neutrophils, vitamin D amongst others…) on human plasma/serum in correlation to the clinical course of ulcerated melanoma patients. CRP and neutrophil analyses which will be performed for all patients using data from the routine hematology panel collected in the main protocol.
To investigate if exogenous IFN given during adjuvant therapy palliates an insufficient Th1 response. Translational Research 3: Prognostic germline hereditary variations/Objectives:To test the hypothesis that inherited variation in immune response genes is prognostic of disease outcome in melanoma patients independent of therapy (peginterferon alfa-2b/observation).
Additionally to test the hypothesis that inherited variation in immune response genes modifies response to peginterferon alfa-2b adjuvant therapy (identification of predictive markers of peginterferon alfa-2b adjuvant therapy efficacy).
Sentinel Node Translational Research Objectives:
To assess the risk of the false-negativity of SNB.
To understand the biology of removed sentinel nodes in ulcerated melanoma.

Objetivos de la investigación traslacional:Para recoger prospectivamente material biológico(sangre entera, plasma, suero y tejido)para proyectos de investigación traslacional para los pacientes que han accedido a participar en esta investigación.Los proyectos pueden incluir,pero no se limitan a:polimorfismos de un solo nucleótido y la correlación con la sensibilidad peginterferón alfa-2b.Analizar la asociación de posibles biomarcadores presentes en la sangre del sujeto, suero/plasma y/o el tejido tumoral con beneficio clínico después del tratamiento en la forma de supervivencia libre de recidiva,Distante,sobrevida libre de metástasis y la supervivencia global con el fin de identificar candidatos marcadores predictivos de respuesta a peginterferón alfa-2b.Determinación del valor pronóstico de biomarcadores en plasma humano/suero y tejido en correlación con otros factores pronósticos validados y para el curso clínico de pacientes con melanoma/PCR, neutrófilos, micro-ARN, el nivel de vitamina D,y la respuesta Th1 entre otros circulantes.Evaluación del riesgo de falsos negatividad del SNB.Permitir la recolección y almacenamiento de sangre entera, suero/plasma y muestras de tejido tumoral de melanoma de los pacientes incluidos en el protocolo principal para su uso en futuros estudios de investigación de biomarcadores.Para garantizar la confidencialidad,todas las muestras y la información asociada con las muestras serán codificados para evitar la exposición de la información y la identidad del sujeto.No se espera que estas evaluaciones sea beneficiar al sujeto directa o para alterar su curso de tratamiento.Los resultados no serán comunicados o colocadas en su expediente médico y no serán puestos a disposición de los miembros de su familia,los médicos tratantes,o terceros,excepto como se especifica en el consentimiento informado.Proyecto de Investigación Traslacional 1:Caracterización molecular de la sensibilidad melanoma ulcerado de alfa-2b/Objectives peginterferón:Para determinar de inestabilidad genómica en el melanoma ulcerado con el fin de evaluar los biomarcadores predictivos de IFN-sensibilidad en correlación con el resultado este estudio.Para determinar de perfil de expresión génica en el melanoma ulcerado con el fin de evaluar los biomarcadores predictivos de IFN-en correlación con la sensibilidad y el resultado clínico del este estudio.Proyectos de Investigación Traslacional 2: Caracterización de biomarcadores pronósticos en plasma humano/muestras de suero y tejido/Objetivos:Determinación de la evolución y el valor pronóstico de los marcadores biológicos (CRP,los neutrófilos,la vitaminaD,entre otros) en plasma/suero humano en correlación con la evolución clínica de los pacientes con melanoma ulceradas.PCR y análisis de neutrófilos, que se llevará a cabo en todos los pacientes a partir de datos desde el panel de hematología rutinaria recogida en el protocolo principal.Para investigar si el IFN exógeno administrado durante la terapia adyuvante palia la insuficiente Th1 response.Investigación traslacional3:pronósticos línea germinal variaciones hereditarias/Objetivos:Para probar la hipótesis de que la variación hereditaria en los genes de respuesta inmune es pronóstico de la evolución de la enfermedad en pacientes con melanoma independientes de la terapia (peginterferón alfa-2b/observation).Además de probar la hipótesis de que la variación hereditaria en los genes de respuesta inmune modifica la respuesta a peginterferón alfa-2b terapia adyuvante (identificación de marcadores predictivos de peginterferón alfa-2b adyuvante de la terapia de eficacia).Sentinel Node Traslacional Objetivos de investigación:Para evaluar el riesgo de la falsa negatividad del SNB.
Para entender la biología de los ganglios centinela en el melanoma ulcerado eliminado

E.3

Principal inclusion criteria

- Subjects must have histologically documented ulcerated primary
cutaneous melanoma with a Breslow thickness > 1mm that has been
excised radically 3 months prior to randomization. Excision margins of at
least 1 cm are required. In the head and neck areas and in case of
locations distally on extremities narrower margins are acceptable as
long as they are radical.
- In case subjects have undergone Sentinel Node staging after the
excision of the primary, this must be done within the time frame of 3
months between the date of final excision of the primary and the date of
randomization.
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- Subjects must have an ECOG performance status of 0 or 1.
- Subjects must be between 18-70 years old.
- Subjects must have adequate hepatic, renal and bone marrow function
as defined by the following parameters obtained within 4 weeks prior to
initiation of study treatment
- Subject must give informed consent according to ICH-GCP or
national/local policy

- Los sujetos deben tener histológicamente documentado ulcerado melanoma cutáneo primario con un espesor Breslow> 1 mm que ha sido extirpado radicalmente 3 meses antes de la aleatorización. Los márgenes de escisión de al menos 1 cm se requieren. En las áreas de la cabeza y el cuello y en el caso de utilizar distalmente en las extremidades márgenes más estrechos son aceptables, siempre y cuando son radicales.
- En los sujetos de casos han sido objeto de puesta en escena del ganglio centinela después de la escisión de la primaria, esto se debe hacer en el plazo de 3 meses entre la fecha de la escisión final de la primaria y la fecha de la asignación al azar.
- Los sujetos deben tener un estado de rendimiento ECOG de 0 o 1.
- Los sujetos deben tener entre 18-70 años de edad.
- Los sujetos deben tener hepática, renal y función de la médula ósea tal como se define por los siguientes parámetros obtenidos dentro de las 4 semanas antes de la iniciación del tratamiento del estudio
- Reservado el derecho debe dar su consentimiento informado de acuerdo con ICH-GCP o nacional / política local

E.4

Principal exclusion criteria

- Subjects suffering from a mucous membrane melanoma or ocular
melanoma
- Subjects who have evidence of (non-)regional lymph node metastases
or intransit metastases (even if they have been resected)
- Subjects whose disease cannot be completely surgically resected
- Subjects who have not recovered from the effects of recent surgery
- Subjects with a history of prior malignancy within the past 10 years
other than surgically cured non-melanoma skin cancer or cervical
carcinoma in situ
- Subjects who have severe cardiovascular disease, i.e., arrhythmias
requiring chronic treatment, congestive heart failure (NYHA Class III or
IV) or symptomatic ischemic heart disease
- Subjects with thyroid dysfunction not responsive to therapy
- Subjects with uncontrolled diabetes mellitus
- Subjects suffering from an active autoimmune disease
- Subjects with active and/or uncontrolled infection, including active
hepatitis
- Subjects who have a history of seropositivity for HIV
- Subjects who have a history of neuropsychiatric disorder requiring
hospitalization
- Subjects who are known to be actively abusing alcohol or drugs
- Subjects who are pregnant, lactating, or of reproductive potential and
not practicing an effective means of contraception
- Subjects with a medical condition requiring chronic systemic
corticosteroids
- Subjects who have received any experimental therapy within 30 days
prior to randomization in this study
- Subjects who have received any prior chemotherapy, immunotherapy,
hormonal or radiation therapy for melanoma
- Subjects who have previously received interferon-alpha for any reason
- Subject having history of epilepsy or other major central nervous
system disease
- Subject having eyes disorders

- Los sujetos que sufren de un melanoma de mucosas o melanoma ocular
- Los sujetos que tienen evidencia de la (no-) metástasis a los ganglios linfáticos regionales o metástasis en tránsito (incluso si se han resecado)
- Los sujetos cuya enfermedad no puede ser completamente resecado quirúrgicamente
- Los sujetos que no se han recuperado de los efectos de la cirugía reciente
- Los sujetos con antecedentes de neoplasia previa dentro de los últimos 10 años, además del cáncer de piel curado quirúrgicamente no melanoma o carcinoma cervical in situ
- Sujetos que tienen enfermedad cardiovascular grave, es decir, arritmias que requieren tratamiento crónico, insuficiencia cardiaca congestiva (NYHA clase III o IV) o cardiopatía isquémica sintomática
- Los sujetos con disfunción de la tiroides no responde a la terapia
- Los sujetos con diabetes mellitus no controlada
- Los sujetos que sufren una enfermedad autoinmune activa
- Los sujetos con infección activa y / o fuera de control, incluyendo hepatitis activa
- Los sujetos que tienen una historia de seropositividad para el VIH
- Los sujetos que tienen un historial de trastorno neuropsiquiátrico que requiere hospitalización
- Los sujetos que se sabe que están activamente abusando del alcohol o las drogas
- Los sujetos que están embarazadas, lactando, o del potencial reproductivo y no practicar un medio eficaz de anticoncepción
- Los sujetos con una condición médica que requiere corticoides sistémicos crónicos
- Sujetos que han recibido cualquier terapia experimental en los 30 días anteriores a la aleatorización en este estudio
- Los sujetos que han recibido quimioterapia previa alguna, la inmunoterapia, hormonal o terapia de radiación para el melanoma
- Los sujetos que han recibido previamente interferón-alfa, por cualquier motivo
- Sujeto con antecedentes de epilepsia o otro gran enfermedad del sistema nervioso central
- Reservado el derecho que tienen trastornos de los ojos

E.5 End points

E.5.1

Primary end point(s)

Relapse free survival (RFS)

Relapse supervivencia libre (RFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

6 years and 3 months

6 años y 3 meses

E.5.2

Secondary end point(s)

- Distant metastasis free survival (DMFS)
- Overal survival (OS)
- Toxicity
- Quality of life

- Metástasis a distancia la supervivencia libre (CPOS)
- La supervivencia Overal (OS)
- Toxicidad
- Calidad de vida

E.5.2.1

Timepoint(s) of evaluation of this end point

- Distant metastasis free survival (DMFS): 8 years
- Overal survival (OS): 8 years
- Toxicity: during all the conduct of the trial
- Quality of life : 6 years and 3 months

- La metástasis distante supervivencia libre (CPOS): 8 años
- Overal supervivencia (SG): 8 años
- Toxicidad: durante todo el desarrollo del proceso
- Calidad de vida: 6 años y 3 meses

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belgium

France

Germany

Netherlands

Switzerland

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature (i.e. reached the required number of events) for each of the two final analyses of the endpoints (RFS and OS) as defined in the protocol.
3. The database has been fully cleaned and frozen for each of these 2 final analyses

Fin del estudio se produce cuando todos los siguientes criterios se han cumplido:
1. Treinta días después de que todos los pacientes que han interrumpido el tratamiento del protocolo
2. El juicio está maduro (es decir, alcanzar el número requerido de eventos) para cada uno de los dos análisis final de los puntos finales (SSR como la SG) como se define en el protocolo.
3. La base de datos se ha limpiado completamente y se congelaron para cada uno de estos 2 análisis finales

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

1080

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

120

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1000

F.4.2.2

In the whole clinical trial

1200

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

At physician's discretion, in the best interest of the patient

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-03-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-03-06

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-07-11

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