Clinical Trials Register

Summary
EudraCT Number:	2012-000660-22
Sponsor's Protocol Code Number:	BO27952
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:	2012-08-09
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

2012-000660-22

A.3

Full title of the trial

A randomized, multicenter, adaptive phase II/III study to evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) versus taxane (docetaxel or paclitaxel) in patients with previously treated locally advanced or metastatic HER2-positive gastric cancer, including adenocarcinoma of the gastroesophageal junction.

ESTUDIO ADAPTATIVO DE FASE II/III, ALEATORIZADO, MULTICÉNTRICO, PARA EVALUAR LA EFICACIA Y SEGURIDAD DE TRASTUZUMAB EMTANSINA (T-DM1) VERSUS TAXANOS (DOCETAXEL O PACLITAXEL) EN PACIENTES CON CÁNCER GÁSTRICO METASTÁSICO O LOCALMENTE AVANZADO, HER2-POSITIVO INCLUIDO ADENOCARCINOMA DE LA UNIÓN GASTROESOFÁGICA TRATADOS PREVIAMENTE.

A.3.1

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

A study to evaluate the efficacy and safety of trastuzumab emtansine compared to a taxane (docetaxel or paclitaxel), in patients with previously treated gastric cancer that spread to other tissues, including adenocarcinoma of the gastroesophageal junction.

Estudio para evaluar la eficacia y seguridad de trastuzumab emtansina comparado con un taxano (docetaxel o paclitaxel), en pacientes con cáncer gástrico extendido a otros téjidos, incluyendo adenocarcinoma de la unión gastroesofágica tratados previamente.

A.4.1

Sponsor's protocol code number

BO27952

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	F. Hoffmann?La Roche Ltd
B.1.3.4	Country	Switzerland
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	F. Hoffmann?La Roche Ltd
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	F. Hoffmann?La Roche Ltd
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.6	E-mail	global.rochegenentechtrials@roche.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	trastuzumab emtansine
D.3.2	Product code	RO5304020/F03
D.3.4	Pharmaceutical form	Powder for 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	trastuzumab emtansine
D.3.9.1	CAS number	1018448-65-1
D.3.9.2	Current sponsor code	RO5304020
D.3.9.3	Other descriptive name	T-DM1, Trastuzumab-MCC-DM1
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	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	Yes
D.3.11.13.1	Other medicinal product type	Conjugado fármaco-anticuerpo formado por la unión de un anticuerpo monoclonal humanizado (trastuzumab) y un agente citotóxico (DM1).
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.2.1.2	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.3.4	Pharmaceutical form	Concentrate and solvent 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	DOCETAXEL
D.3.9.1	CAS number	114977-28-5
D.3.9.2	Current sponsor code	n/a
D.3.9.3	Other descriptive name	n/a
D.3.9.4	EV Substance Code	SUB12492MIG
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	40
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.2.1.2	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.3.4	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	PACLITAXEL
D.3.9.1	CAS number	33069-62-4
D.3.9.2	Current sponsor code	n/a
D.3.9.3	Other descriptive name	n/a
D.3.9.4	EV Substance Code	SUB09583MIG
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	6
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

Human Epidermal growth factor Receptor 2 (HER2) positive locally advanced or metastatic Gastric Cancer (GC), including adenocarcinoma of the gastroesophageal junction (GEJ).

Cáncer gástrico metastásico o localmente avanzado (incluido el adenocarcinoma de la unión gastroesofágica) con receptor del factor de crecimiento epidérmico humano (HER2) positivo.

E.1.1.1

Medical condition in easily understood language

Gastric cancer that spread to other tissues.

Adenocarcinoma gástrico metastásico o localmente avanzado

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	LLT
E.1.2	Classification code	10066896
E.1.2	Term	HER-2 positive gastric cancer
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

? Phase II: To select a trastuzumab emtansine dose and schedule for Phase III assessment. ? Phase III: To compare the overall survival (OS) of patients treated with trastuzumab emtansine to that of patients treated with physician?s choice of taxane (docetaxel or paclitaxel).

Fase II: Seleccionar una dosis de trastuzumab emtansina y programar la valoración de la Fase III.
Fase III: Comparar la supervivencia global (SG) de los pacientes tratados con trastuzumab emtansina en la dosis y pauta seleccionada en el estadio Fase II del estudio frente a la de los pacientes tratados con el taxano elegido por el médico (docetaxel o paclitaxel).

E.2.2

Secondary objectives of the trial

? Objective response rate (ORR)
? Progression-free survival (PFS)
? Duration of response (DOR)
? Characterization of clinical safety
? Assessment of Quality of Life

?Tasa de respuesta objetiva (TRO).
?Supervivencia libre de progresión (SLP).
?Duración de la respuesta (DR).
?Caracterización de la seguridad clínica.
?Evaluación de la Calidad de vida

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

Roche Clinical Repository (RCR) que está incluido dentro del protocolo principal BO27952
Objetivos:
?Estudiar la asociación de los biomarcadores con la eficacia, acontecimientos adversos u otros efectos asociados con los medicamentos
?Aumentar el conocimiento de la biología de la enfermedad
?Estudiar la respuesta al fármaco, tal como sus efectos y los procesos de absorción y eliminación
?Desarrollar biomarcadores o análisis diagnósticos para conocer las características del funcionamiento de estos análisis.

E.3

Principal inclusion criteria

? Adult patients >/=18 years of age
? Histologically or cytologically confirmed Her2+ AGC (advanced gastric cancer) and must have experienced documented objective
radiographic or pathologic disease progression during or after first-line therapy for their disease.
? must have received at least one prior chemotherapy regimen for
AGC; prior therapy does not need to have included HER2-directed therapy.
? Patients must have measurable and/or non-measurable disease which must be evaluable per RECIST 1.1 ? ECOG Performance Status 0 or 1
? Adequate organ function as determined by laboratory results.

- Edad ? 18 años
- Pacientes con CGA histo o citológicamente confirmado, y deben haber experimentado progresión de la enfermedad objetiva radiográfica o patológicamente documentada durante o después del tratamiento de primera línea para su enfermedad.
- Los pacientes deben haber recibido al menos una pauta quimioterápica previa para CGA; no es necesario que el tratamiento previo incluya tratamiento dirigido al HER2.
- Pacientes deben tener una enfermedad medible y/o no medible la cual debe ser evaluada por RECIST (Criterio de evaluación de la respuesta en tumores sólidos).
- Grado de actividad ECOG de 0 ó 1.
- Función orgánica adecuada de acuerdo con los resultados analíticos.

E.4

Principal exclusion criteria

? An interval shorter than 21 days from the last dose of chemotherapy or HER2-directed therapy until the time of randomization
? Prior treatment with trastuzumab emtansine, docetaxel, or paclitaxel either as single agents or as part of a treatment regimen. Prior treatment with trastuzumab, lapatinib, or pertuzumab is allowed
? Treatment with any anticancer investigational drug within 21 days prior to commencing study treatment ? Brain metastases that are untreated or symptomatic or require any radiation, surgery, or steroid therapy to control symptoms from brain
metastases within 1 month of randomization
? Inadequate cardiopulmonary function.

- Un intervalo menor a 21 días desde la última administración de quimioterapia o tratamiento dirigido contra HER2 hasta el momento de la aleatorización.
- Tratamiento previo con trastuzumab emtansina, docetaxel, o paclitaxel en monoterapia o asociados en una pauta de tratamiento. Se permite el tratamiento previo con trastuzumab, lapatinib o pertuzumab.
- Tratamiento con cualquier medicamento antineoplásico en investigación en los 21 días previos al comienzo del tratamiento del estudio.
- Metástasis cerebral sin tratamiento o sintomático o que requiere irradiación, cirugía o tratamiento con esteroides para controlar los síntomas de las metástasis cerebrales en el mes siguiente a la aleatorización.
- Disfunción cardiopulmonar inadecuada.

E.5 End points

E.5.1

Primary end point(s)

Overall Survival (OS)

Supervivencia global (SG)

E.5.1.1

Timepoint(s) of evaluation of this end point

The time from the date of randomization to the date of death, irrespective of the cause of death.

Tiempo transcurrido desde la fecha de la aleatorización hasta la fecha de la muerte, con independencia de la causa de la muerte.

E.5.2

Secondary end point(s)

Tumor response endpoints - Progression-Free Survival - Objective Response

-Variables de respuesta al tumor
-Supervivencia libre de progresión
-Respuesta objetiva

E.5.2.1

Timepoint(s) of evaluation of this end point

- Progression-Free Survival: the time from the date of randomization to the date of first occurrence of PD or death from any cause, whichever occurs first. - Objective Response?the achievement of a best overall response of PR or CR.

Supervivencia libre de progresión: el tiempo transcurrido desde la fecha de la aleatorización hasta la fecha en que se documenta por primera vez EP o muerte por cualquier causa, lo que ocurra primero.
Respuesta objetiva: definida como la consecución de una mejor respuesta global de remisión parcial (RP) o remisión completa (RC).

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

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

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Objective response rate (ORR)
Progression-free survival (PFS)
Duration of response (DOR)

Tasa de respuesta objetiva (TRO)
Supervivencia libre de progresión (SLP)
Duración de la respuesta (DR)

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)

Yes

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

Yes

E.8.1.7.1

Other trial design description

Adaptive design

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

Belgium

Brazil

Canada

China

Czech Republic

Finland

France

Germany

Guatemala

Hungary

Italy

Japan

Korea, Republic of

Malaysia

Mexico

Peru

Philippines

Poland

Romania

Russian Federation

Singapore

Slovakia

Spain

Taiwan

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 end of the study is defined as the maximum of the following two dates:
? The date when 83% of patients recruited into Stage 1 have died
? The date when 63% of patients recruited into Stage 2 have died
Alternatively, the study could end if both T-DM1 arms are discontinued.

El final del estudio se define como la última de las dos fechas siguientes:
-La fecha en que aproximadamente el 83% de los pacientes incluidos en el Estadio 1 han muerto.
-La fecha en que aproximadamente el 63% de los pacientes incluidos en Estadio 2 han muerto.
Opcionalmente, el estudio podría terminar si se interrumpen ambos brazos con T-DM1.

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:

232

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

180

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

134

F.4.2.2

In the whole clinical trial

412

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)

Patients will receive study treatment until PD, unacceptable toxicity, or study termination by the Sponsor. Following discontinuation of study treatment, patients will continue to be followed for survival.

Los pacientes recibirán el tratamiento del estudio hasta la progresión de la enfermedad (PE), toxicidad inaceptable o finalización del estudio por el promotor. Después de la suspensión del tratamiento del estudio, se mantendrá a los pacientes en seguimiento de supervivencia

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

2012-08-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-07-04

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-04-30

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