Clinical Trials Register

Summary
EudraCT Number:	2012-005371-13
Sponsor's Protocol Code Number:	CA209-067
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2013-06-10
Trial 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

2012-005371-13

A.3

Full title of the trial

A Phase 3, Randomized, Double- Blind Study of Nivolumab Monotherapy or Nivolumab Combined with Ipilimumab Versus Ipilimumab Monotherapy in Subjects with Previously Untreated, Unresectable or Metastatic Melanoma

Pharmacogenetics Blood Sample Protocol Amendment 01, version 1.0,
dated 19-Mar-2013

Estudio fase 3, aleatorizado, doble ciego, de nivolumab en monoterapia o nivolumab combinado con ipilimumab frente a ipilimumab en monoterapia en sujetos con melanoma irresecable o metastásico no tratado previamente.

Enmienda 01 de muestra de sangre para farmacogenética, version 1.0,
fecha 19-Mar-2013

A.3.1

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

Phase 3 Study of Nivolumab or Nivolumab plus Ipilimumab Versus Ipilimumab Alone in Previously Untreated Advanced Melanoma

Estudio fase 3 de nivolumab en monoterapia o nivolumab combinado con ipilimumab frente a ipilimumab en monoterapia en sujetos con melanoma irresecable o metastásico no tratado previamente.

A.4.1

Sponsor's protocol code number

CA209-067

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	Bristol-Myers Squibb International Corporation
B.1.3.4	Country	Belgium
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Bristol-Myers Squibb International Corporation
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Bristol-Myers Squibb International Corporation
B.5.2	Functional name of contact point	EU Study Start-Up Unit
B.5.3	Address:
B.5.3.1	Street Address	Parc de l'Alliance - Avenue de Finlande, 4
B.5.3.2	Town/ city	Braine-l'Alleud
B.5.3.3	Post code	1420
B.5.3.4	Country	Belgium
B.5.6	E-mail	clinical.trials@bms.com

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	No
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	Nivolumab
D.3.2	Product code	BMS-936558
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NIVOLUMAB
D.3.9.1	CAS number	946414-94-4
D.3.9.2	Current sponsor code	BMS-936558-01
D.3.9.3	Other descriptive name	BMS936558
D.3.9.4	EV Substance Code	SUB32944
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	No
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	Ipilimumab
D.3.2	Product code	BMS-734016
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IPILIMUMAB
D.3.9.1	CAS number	477202-00-9
D.3.9.2	Current sponsor code	BMS-734016 / MDX010
D.3.9.3	Other descriptive name	BMS734016
D.3.9.4	EV Substance Code	SUB22577
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Unresectable or metastatic melanoma

Melanoma irresecable o metastásico no tratado previamente.

E.1.1.1

Medical condition in easily understood language

Unresectable or metastatic melanoma

Melanoma irresecable o metastásico no tratado previamente.

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	LLT
E.1.2	Classification code	10053571
E.1.2	Term	Melanoma
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.0
E.1.2	Level	LLT
E.1.2	Classification code	10027481
E.1.2	Term	Metastatic melanoma
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 purpose of this study is to show that Nivolumab and/or Nivolumab in combination with Ipilimumab will extend survival compared to Ipilimumab alone

Comparar la supervivencia global (SG) con monoterapia con nivolumab frente a la obtenida con monoterapia con ipilimumab y la de nivolumab combinado con ipilimumab con la obtenida con ipilimumab en monoterapia en sujetos con melanoma irresecable o metastásico no tratado previamente.

E.2.2

Secondary objectives of the trial

? PFS
? ORR
? Differences in OS, PFS and ORR between experimental arms
? OS based on PD-L1 expression
? Mean changes from baseline in EORTC-QLQ-C30

?Comparar la supervivencia libre de progresión (SLP)
?Comparar la tasa de respuesta objetiva (TRO)
?Evaluar las diferencias en la SG, la SLP y la TRO entre nivolumab combinado con ipilimumab y nivolumab en monoterapia en sujetos con melanoma avanzado
?Evaluar si la expresión de PD-L1 es un biomarcador predictivo de la SG.
?Evaluar la calidad de vida relacionada con la salud (CdVRS) valorada según el QLQ-C30 de la Organización Europea para la Investigación y el Tratamiento del Cáncer (EORTC).

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

Pharmacogenetics Blood Sample Protocol Amendment 01, version 1.0, dated 19-Mar-2013
The objective of this Amendment is to permit the collection and storage of blood samples for use in future exploratory pharmacogenetic research. Bristol-Myers Squibb will use DNA obtained from the blood sample and health information collected from the main clinical trial, CA209-067 to study the association between genetic variation and drug response. Bristol-Myers Squibb may also use the DNA to study the causes and further progression of lung cancer. Samples from this study may also be used in conjunction with pharmacogenetic research results from other clinical studies to accomplish this objective.

Enmienda 01 de muestra de sangre para farmacogenética, versión 1.0, fecha 19-Mar-2013

El objetivo de esta enmienda es permitir la recogida y la conservación de muestras de sangre para uso en estudios de investigación farmacogenética exploratorios futuros. Bristol-Myers Squibb usará el ADN obtenido de la muestra de sangre y la información de salud recogida del cuaderno de recogida de datos del ensayo clínico principal, CA209-067 para estudiar la asociación entre la variación genética y la respuesta a los medicamentos. BMS también puede usar el ADN para estudiar las causas y progresión adicional del melanoma. Para conseguir este objetivo pueden usarse conjuntamente muestras de este y otros estudios de investigación farmacogenética.

E.3

Principal inclusion criteria

? Histologically confirmed stage III (unresectable) or stage IV melanoma
? Treatment naïve patients
? Measurable disease by CT or MRI per RECIST 1.1 criteria.
? Tumor tissue from an unresectable or metastatic site of disease for biomarker analyses.
? ECOG PS 0 or 1

?Melanoma confirmado histológicamente en estadio III (irresecable) o en estadio IV, según el sistema de estadificación del AJCC.
?Pacientes sin tratamiento previo (esto es, sin terapia oncológica sistémica anterior para melanoma irresecable o metastásico).
?Enfermedad medible mediante TC o RM según los criterios RECIST 1.1.
?Debe facilitarse tejido tumoral de una localización irresecable o metastásica de la enfermedad para el análisis de biomarcadores.
? PS 0 ó 1 del ECOG.

E.4

Principal exclusion criteria

? Active brain metastases or leptomeningeal metastases
? Ocular melanoma
? Subjects with active, known or suspected autoimmune disease
? Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment
? Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody

?Metástasis cerebrales activas o metástasis leptomeníngeas.
?Melanoma ocular.
?Sujetos con enfermedad autoinmunitaria activa, conocida o sospechada.
?Sujetos con un problema que precise tratamiento sistémico con corticosteroides (> 10 mg de prednisona al día o equivalente) u otros medicamentos inmunosupresores en el plazo de 14 días antes de la administración del fármaco del estudio. Se permiten esteroides inhalados o tópicos y dosis de reposición suprarrenal > 10 mg al día de prednisona o equivalentes en ausencia de enfermedad autoinmunitaria activa.
?Tratamiento previo con un anticuerpo anti-PD-1, anti-PD-L1, anti-PD-L2 o anti-CTLA-4 o cualquier otro anticuerpo o fármaco dirigido específicamente frente a la coestimulación de las vías de control inmunitarias.

E.5 End points

E.5.1

Primary end point(s)

Improvement in Overall Survival of investigational arms versus control arm

Mejorar la supervivencia global de los brazos de investigación frente al brazo control

E.5.1.1

Timepoint(s) of evaluation of this end point

OS: From the beginning of randomization period up to date of event (expected to be no more than 5 years)

Supervivencia global: Desde el principio del periodo de aleatorización hasta la fecha del evento (se espera no sea mas de 5 años).

E.5.2

Secondary end point(s)

? PFS
? ORR
? Differences in OS, PFS and ORR between experimental arms
? OS based on PD-L1 expression
? Mean changes from baseline in EORTC-QLQ-C30

E.5.2.1

Timepoint(s) of evaluation of this end point

? PFS: Baseline, Week 12, every 6 weeks thereafter up to week 49, and then every 12 weeks until disease progression is documented (expected to be no more than 5 years)
? ORR: Baseline, Week 12 every 6 weeks thereafter up to week 49, and then every 12 weeks until disease progression is documented (expected to be no more than 5 years)
? OS, PFS, and ORR at the same time points identified for the primary and first two secondary objectives
? OS at the same time points identified as the primary objective and PD-L1 expression at Baseline:
? Baseline, every 4 weeks for 6 months, then every 6 weeks until disease progression is documented, during follow-up (30 days after last dose, 100-114 days after last dose)

-SLP:Basal, semana 12, a partir de aqui cada 6 semanas hasta la semana 49,y después cada 12 semanas hasta progresión de la enfermedad (se espera no sea más de 5 años).
-TRO:Basal, semana 12, a partir de aqui cada 6 semanas hasta la semana 49 y después cada 12 semanas hasta progresión de la enfermedad ( se espera no sea más de 5 años).
-SG, SLP,TRO en los mismos momentos para los objetivos primarios y secundarios.
-SG en los mismos puntos temporales identificados para el objetivo principal y la expresión de PD-L1 basal.
-Basal, cada 4 semanas durante 6 meses, y luego cada 6 semanas hasta progresión documentada de la enfermedad, durante el seguimiento (30 días después de la última dosis, 100 a 114 días después de la última dosis)

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity

Inmunogenicidad

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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)

Yes

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

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

Australia

Austria

Belgium

Brazil

Canada

Czech Republic

Denmark

Finland

France

Germany

Ireland

Israel

Italy

Netherlands

New Zealand

Norway

Poland

Romania

Russian Federation

South Africa

Spain

Sweden

Switzerland

Turkey

United Kingdom

United States

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

The study will end once survival follow-up has concluded

El estudio se terminará una vez que la supervivencia de seguimiento haya concluido

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:

795

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

349

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

584

F.4.2.2

In the whole clinical trial

1144

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 the conclusion of the study, subjects who continue to demonstrate clinical benefit will be eligible to receive study drug. Study drug will be provided via an extension of the study, a rollover study requiring approval by responsible health authority and ethics committee or through another mechanism at the discretion of BMS

Al final del estudio, los sujetos que continúen demostrando un beneficio clínico serán elegibles para recibir medicación del estudio. La medicación del estudio se proporcionará a través de una extensión del estudio, un estudio de seguimiento que requiere la aprobación de las autoridades de salud competente y comités de ética o a través de otro mecanismo a discreción de BMS

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

2013-08-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-07-05

P. End of Trial
P.	End of Trial Status	Ongoing

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IMP with orphan designation in the indication
Orphan Designation Number:
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