Clinical Trials Register

Summary
EudraCT Number:	2011-005132-26
Sponsor's Protocol Code Number:	CA209-025
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:	2012-10-02
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

2011-005132-26

A.3

Full title of the trial

A Randomized, Open-Label, Phase 3 Study of BMS-936558 vs. Everolimus in Subjects with Advanced or Metastatic Clear-Cell Renal Cell Carcinoma Who Have Received Prior Anti-Angiogenic Therapy

Estudio fase 3, aleatorizado, abierto, de BMS-936558 frente a everolimus en sujetos con carcinoma renal de células claras avanzado o metastásico que han recibido terapia antiangiogénica previa.

A.3.1

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

Study of BMS-936558 vs. Everolimus in Pre-Treated Advanced Or Metastatic Clear-cell RCC

Estudio de BMS-936558 frente a everolimus en sujetos con carcinoma renal de células claras avanzado o metastásico que han recibido terapia antiangiogénica previa.

A.4.1

Sponsor's protocol code number

CA209-025

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, 8
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.3.2	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	BMS-936558-01
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	Anti-PD-1 Human Monoclonal Antibody; MDX-1106
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	Comparator
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	Afinitor 5 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	everolimus
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EVEROLIMUS
D.3.9.1	CAS number	159351-69-6
D.3.9.3	Other descriptive name	EVEROLIMUS
D.3.9.4	EV Substance Code	SUB02065MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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	Comparator
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	Afinitor 10 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	everolimus
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EVEROLIMUS
D.3.9.1	CAS number	159351-69-6
D.3.9.3	Other descriptive name	EVEROLIMUS
D.3.9.4	EV Substance Code	SUB02065MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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

Advanced or metastatic (medically or surgically unresectable) clear-cell Renal Cell Carcinoma

Carcinoma renal de células claras (médica o quirúrgicamente resecable) avanzado o metastásico

E.1.1.1

Medical condition in easily understood language

Advanced or metastatic (medically or surgically unresectable) clear-cell Renal Cell Carcinoma

Carcinoma renal de células claras (médica o quirúrgicamente resecable) avanzado o metastásico

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10038414
E.1.2	Term	Renal cell carcinoma stage IV
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10050513
E.1.2	Term	Metastatic renal cell carcinoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10067946
E.1.2	Term	Renal cell carcinoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 the study is to compare the clinical benefit, as measured by duration of overall survival, of BMS-936558 vs. Everolimus in subjects with advanced or metastatic clear-cell renal cell carcinoma who have received prior anti-angiogenic therapy.

Comparar el beneficio clínico, medido por la duración de la SG, proporcionado por BMS-936558 frente a everolimus en sujetos con carcinoma de células renales avanzado o metastásico que han recibido tratamiento antiangiogénico previo.

E.2.2

Secondary objectives of the trial

1.Progression-free survival
2.Objective response rate
3.Duration of objective response
4.Duration of OS in PD-L1 positive vs negative subgroups
5.Overall safety & tolerability
6.Disease related symptom progression rate

?Duración de la supervivencia libre de progresión (SLP)
? Tasa de respuestas objetivas (TRO)
?Duración de la respuesta objetiva
?Duración de la SG en los subgrupos positivos para PD-L1 frente a negativos para PD-L1
?Seguridad y tolerabilidad globales
?Tasa de progresión de los síntomas relacionados con la enfermedad

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 Amendment 01- dated 18-jun-12, version 1.0

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, CA209025 to study the association between genetic variation and drug response.

Enmienda 01 de muestra de sangre para farmacogenética de fecha 18-jun-12, version 1.0

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,CA209025, para estudiar la asociación entre la variación genética y la respuesta a los medicamentos.

E.3

Principal inclusion criteria

1.Men & women ? 18 years of age
2.Histologic confirmation of RCC with clear-cell component
3.Advanced/metastatic RCC
4.Measurable disease per RECIST 1.1 criteria
5.Received 1 or 2 prior anti-angiogenic therapy regimens in advanced or metastatic setting
6.No more than 3 total prior systemic treatment regimens in the advanced or metastatic setting, and evidence of progression on or after last treatment regimen received and within 6 months of enrollment
7.Karnofsky Performance Score ? 70%

1.Varones y mujeres ? 18 años
2.Confirmación histológica de CCR con un componente de células claras.
3.CCR avanzado o metastásico
4.Enfermedad medible (definida por RECIST 1.1).
5.Deben haber recibido uno o más regímenes previos de terapia antiangiogénica en el contexto avanzado o metastásico.
6.No deben haber recibido más de tres regímenes previos de tratamiento sistémico en el contexto avanzado o metastásico y deben tener pruebas de progresión durante o después del último régimen de tratamiento recibido y dentro de los 6 meses previos a la inclusión en el estudio.
7.Puntuación de estado funcional de Karnofsky (KPS) >= 70%.

E.4

Principal exclusion criteria

1.Any CNS metastases or history of CNS metastases
2.Prior therapy with an mTOR inhibitor
3.Any active known or suspected autoimmune disease.
4.Uncontrolled adrenal insufficiency
5.Active chronic liver disease
6.Prior malignancy active within past 3 years, except for locally curable cancers

1.Antecedentes o presencia actual de metástasis en el SNC.
2.Tratamiento previo con un inhibidor de mTOR
3.Cualquier enfermedad autoinmunitaria activa conocida o sospechada.
4.Insuficiencia suprarrenal no controlada.
5. Enfermedad hepática crónica activa.
6. Enfermedad previa activa dentro de los últimos 3 años, excepto para los cánceres locales curables

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is overall survival.

El objetivo primario es la supervivencia global

E.5.1.1

Timepoint(s) of evaluation of this end point

Overall survival will be followed at every clinic visit (every 2-4 weeks) while on treatment and then every 3 months.

La supervivencia global se seguirá en cada visita clínica (cada 2-4 semanas) durante el tratamiento y luego cada 3 meses

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

1.Disease assessments Q 8 wks after randomization for 12 months then Q 12 wks until progression of disease
2.See above
3.See above
4.At time of OS analysis (see #38 for timeframe of collection of OS)
5.Continuously throughout study treatment and up to 100 days from last dose
6.Baseline, Day 1 of each cycle (starting with cycle 2), then at first 2 follow-up visits

1. Evaluaciones de la enfermedad cada 8 semanas después de la aleatorización durante 12 meses, a partir de aquí cada 12 semanas hasta la progresión de la enfermedad
2. véase más arriba
3. véase más arriba
4. En el momento del análisis OS (ver # 38 para plazos de recogida de OS)
5. Continuamente durante todo el tratamiento del estudio y hasta 100 días a partir de la última dosis
6. Visita basal, día 1 de cada ciclo (a partir de ciclo 2), y en principio 2 visitas de seguimiento

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

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Biomarker Assessments, Outcomes Research Assessments, Health Resource Utilization, Immunogenicity Assessments.

Evaluaciones de biomarcadores, evaluaciones de los resultados de investigación, Utilización de Recursos de Salud, Evaluaciones de 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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

Argentina

Austria

Belgium

Canada

Czech Republic

Denmark

Finland

France

Germany

Greece

Hungary

Ireland

Israel

Italy

Japan

Norway

Poland

Romania

Russian Federation

Spain

Sweden

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 primary analysis of survival will be conducted after approximately 569 subjects have died (approximately 42 months from start of randomization). Additional survival follow-up may continue for up to 5 years from the primary analysis of survival. The study will end once survival follow-up has concluded.

El análisis primario de supervivencia se llevará a cabo después de que aproximadamente 569 sujetos hayan muerto (aproximadamente 42 meses desde el inicio de la randomización). Seguimientos adicionales de supervivencia pueden continuar durante un máximo de 5 años a partir del análisis primario de supervivencia. El estudio 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:

493

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

329

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

439

F.4.2.2

In the whole clinical trial

975

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 study end, subjects who continue to demonstrate clinical benefit will be eligible to receive study drug via study extension, rollover study, or another mechanism at sponsor's discretion. Sponsor may terminate access to study drug if any of the following occur: marketing application rejected by health authority; study terminated due to safety concerns; subject can obtain medication from a government sponsored/private health program; or therapeutic alternatives become available in local market.

Al final del estudio,sujetos que continuen para demostrar beneficio clínico serán elegibles para recibir el medicamento del estudio a través de la extensión de éste,estudio de extensión, u otro mecanismo a discreción del Promotor.El Promotor puede terminar el acceso al medicamento si ocurriera: solicitud de comercialización rechazado por una autoridad sanitaria; estudio terminado debido a preocupaciones de seguridad o el sujeto pueda obtener la medicación de un programa gubernamental de salud

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

2012-11-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-11-14

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-07-19

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