Clinical Trials Register

Summary
EudraCT Number:	2012-002018-37
Sponsor's Protocol Code Number:	BO27938
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:	2013-04-09
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

2012-002018-37

A.3

Full title of the trial

A RANDOMIZED, MULTICENTER, OPEN LABEL PHASE III STUDY TO EVALUATE THE EFFICACY AND SAFETY OF TRASTUZUMAB EMTANSINE VERSUS TRASTUZUMAB AS ADJUVANT THERAPY FOR PATIENTS WITH HER2-POSITIVE PRIMARY BREAST CANCER WHO HAVE RESIDUAL TUMOR PRESENT PATHOLOGICALLY IN THE BREAST OR AXILLARY LYMPH NODES FOLLOWING PREOPERATIVE THERAPY.

ESTUDIO DE FASE III, ABIERTO, MULTICÉNTRICO, ALEATORIZADO PARA EVALUAR LA EFICACIA Y SEGURIDAD DE TRASTUZUMAB EMTANSINE VERSUS TRASTUZUMAB COMO TRATAMIENTO ADYUVANTE EN PACIENTES CON CÁNCER DE MAMA PRIMARIO HER2-POSITIVO CON PRESENCIA PATOLÓGICA DE TUMOR RESIDUAL EN LA MAMA O NÓDULO LINFÁTICO AXILAR TRAS TRATAMIENTO PREOPERATORIO

A.3.1

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

Phase III, randomized, multicenter, multinational, open label study in patients with HER2-positive primary breast cancer following neoadjuvant chemotherapy and surgery.

Estudio de fase III, abierto, multicéntrico, internacional, aleatorizado en pacientes con cáncer de mama primario HER2-positivo seguido de quimioterapia neoadjuvante y cirugía.

A.4.1

Sponsor's protocol code number

BO27938

A.5.4

Other Identifiers

Name:	National Surgical Adjuvant Breast & Bowel Project	Number:	NSABP B-50-I
Name:	German Breast Group	Number:	GBG 77

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 (T-DM1)
D.3.2	Product code	RO5304020/F02
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.3.9.4	EV Substance Code	SUB35467
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	160
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)	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	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	Yes
D.3.11.13.1	Other medicinal product type	Conjugado anticuerpo-fármaco (ADC) compuesto por un anticuerpo monoclonal humanizado (trastuzumab) y 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.2.1.1.1	Trade name	Herceptin®
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration 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.3.4	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
D.3.9.1	CAS number	180288-69-1
D.3.9.2	Current sponsor code	RO0452317
D.3.9.4	EV Substance Code	SUB12612MIG
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	150
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

HER2-positive primary breast cancer.

Cáncer de mama primario HER2-positivo.

E.1.1.1

Medical condition in easily understood language

HER2-positive primary breast cancer.

Cáncer de mama primario HER2-positivo.

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	10065430
E.1.2	Term	HER-2 positive breast cancer
E.1.2	System Organ Class	100000004864

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	10027475
E.1.2	Term	Metastatic breast cancer
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

To compare the length of time it takes for the primary breast cancer to recur after treatment with preoperative chemotherapy followed by surgery between the 2 treatment arms.

Comparar entre los dos grupos de tratamiento, el tiempo del intervalo sin recidivas de cáncer de mama primario tras el tratamiento preoperatorio con quimioterapia seguido de cirugía.

E.2.2

Secondary objectives of the trial

To compare the length of time it takes for:
? the primary breast cancer to develop in other location(s)
? occurrence of secondary cancers in other organs
? death
To compare side effects of the study medication between the 2 treatment arms.

Comparar el tiempo del intervalo en el que:
-Se desarrolla cáncer de mama primario en otras localización(es)
-Aparecen cánceres secundarios en otros órganos
-Se produce la muerte
Comparar las reacciones adversas de la medicación del ensayo entre los 2 grupos de tratamiento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

? Adult patients, aged at least 18 years
? Histologically confirmed invasive breast cancer with clinical staging T1-4, N0-3, M0 (no metastasis)
? HER2-positive tumor as confirmed by central laboratory HER2 testing (immunohistochemistry and/or in-situ hybridization)
? Patients must have received at least 6 cycles with 16 weeks of prior chemotherapy in the preoperative (neoadjuvant) setting including at least 9 weeks of a taxane and 9 weeks of HER2-directed therapy which may be given concurrently
? Surgical removal of all clinically-evident disease in the breast and lymph nodes
? Pathologic evidence of residual invasive cancer following completion of preoperative chemotherapy
? ECOG performance status of 0 or 1
? Life expectancy of at least 6 months from the first dose of study treatment
? Adequate organ function as determined by the following laboratory results, within 14 days prior to randomization.

1. Edad ? 18 años.
2.Carcinoma de mama invasivo confirmado por medios histológicos con estadio clínico: T1 a T4, N0 a N3, M0 (no metástasis)
3.Tumor HER2-positivo confirmado por un laboratorio central que analiza HER2 (inmunohistoquímica y/o hibridación in situ)
4. Las pacientes deben haber recibido al menos 6 ciclos de tratamiento preoperatorio con quimioterapia (neoadyuvancia) hasta 16 semanas incluyendo como mínimo 9 semanas con un taxano y 9 semanas de tratamiento dirigido contra el HER2, los cuales pueden administrarse simultáneamente.
5. Extirpación quirúrgica de toda la enfermedad clínicamente evidente de la mama y los ganglios linfáticos.
6. Hallazgos histopatológicos de carcinoma residual invasivo una vez finalizado el tratamiento preoperatorio.
7. Estado funcional del ECOG de 0 o 1.
8. Esperanza de vida de igual o superior a seis meses.
9. Función orgánica adecuada determinada por los siguientes valores de laboratorio, dentro de los 14 días previos a la aleatorización.

E.4

Principal exclusion criteria

? Metastatic breast cancer
? History of any prior breast cancer except for lobular carcinoma in situ
? Treatment with a cumulative dose of epirubicin greater than 480mg/m2 or any other anthracycline like doxirubicin greater than 240mg/m2
? Treatment with any investigational anticancer drug within 28 days prior to commencing study treatment
? History of other malignancy within the previous 5 years except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other malignancies with an expected curative outcome
? Peripheral neuropathy greater or equal to Grade 2
? Uncontrolled cardiopulmonary dysfunction (e.g., high blood pressure, angina, serious cardiac arrhythmia)
? Myocardial infarction within 12 months prior to randomization
? Active liver disease like hepatitis
? Other current, severe, uncontrolled systemic disease (e.g., clinically significant metabolic disease, wound healing disorders, ulcers)
? For female patients, current pregnancy or lactation
? Major surgical procedure or significant traumatic injury within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment
? Currrent, serious, uncontrolled Infections or known infection with HIV.

?Cáncer de mama metastásico.
?Antecedentes de cualquier cáncer de mama previo, excepto CLIS.
?Tratamiento con una dosis acumulada de epirubicina más de 480 mg/m2 o otra antraciclina como doxorrubicina más de 240 mg/m2.
?Tratamiento con cualquier antineoplásico en investigación en los 28 días previos al comienzo del tratamiento del estudio.
?Antecedentes de otro tumor maligno en los últimos cinco años, con la excepción del CIS del cuello uterino tratado correctamente, el carcinoma cutáneo distinto del melanoma, el cáncer de útero en estadio I u otros cánceres distintos del de mama que tengan un desenlace similar al de los mencionados anteriormente.
?Neuropatía periférica de grado 2 o superior según los CTCAE del NCI (versión 4.0).
?Disfunción cardiopulmonar no controlada (por ejemplo, hipertensión, angina de pecho, grave arritmia cardíaca),
?Infarto dentro de los 12 meses previos a la aleatorización
?Enfermedad hepática activa como hepatitis.
?Otras enfermedades sistémicas, no controladas, graves y activas, por ejemplo, enfermedades metabólicas clínicamente significativas, trastornos de la cicatrización de las heridas; úlceras.
?En las mujeres, embarazo o lactancia actuales.
?Intervención de cirugía mayor sin relación con el cáncer de mama o traumatismo importante en los aproximadamente 28 días anteriores a la aleatorización, o necesidad prevista de cirugía mayor durante el tratamiento del estudio.
?Infecciones concomitantes graves y no controladas, o infección por el VIH.

E.5 End points

E.5.1

Primary end point(s)

Invasive disease-free survival (IDFS)

Supervivencia sin enfermedad invasiva

E.5.1.1

Timepoint(s) of evaluation of this end point

up to 10 years

Hasta 10 años

E.5.2

Secondary end point(s)

1. IDFS including second non-breast cancer
2. Disease-free survival (DFS), including second non-breast cancer or contralateral or ipsilateral ductal carcinoma in situ
3. Overall survival (OS)
4. Recurrence-free interval (RFI): time between randomization and local, regional or distant breast cancer recurrence
5. Distant recurrence-free interval (DRFI): time between randomization and distant breast cancer recurrence
6. Cardiac and overall safety: Incidence of adverse events
7. Quality of life: EORTC QLQ-C30, QLQ-BR23 and EQ-5D questionnaires.

1.SSEI incluidos los segundos cánceres distintos del de mama
2.Supervivencia sin enfermedad invasiva (SSEI), incluyendo segundos cánceres distintos del de mama o carcinoma homo o contralateral in situ
3.Supervivencia global (SG)
4.Intervalo sin recidivas: Tiempo desde la aleatorización hasta la recidiva a distancia del cáncer de mama.
5.Intervalo sin recidivas a distancia (ISRD): tiempo desde la aleatorización hasta la recidiva a distancia del cáncer de mama.
6.Seguridad cardíaca y seguridad global: Incidencia de acontecimientos adversos.
7.Calidad de vida: cuestionarios QLQ-C30 de la EORTC, QLQ-BR23 y EQ-5D

E.5.2.1

Timepoint(s) of evaluation of this end point

1 to 6. up to 13 years
7. up to 3 years

Del 1 al 6: hasta 13 años.
7. Hasta 3 años.

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

Quality of Life

Calidad de vida

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

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

125

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

Brazil

Canada

China

Colombia

Czech Republic

France

Germany

Greece

Hong Kong

Ireland

Israel

Italy

Mexico

Panama

Peru

Russian Federation

Serbia

South Africa

Spain

Sweden

Switzerland

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 study will end after the last patient randomized into the study has undergone the last follow-up assessment. To enable long-term follow-up for survival and safety information, the last follow-up assessment is scheduled to occur 10 years after the first patient is randomized.

El estudio finalizará después de que el último paciente aleatorizado en el estudio se haya sometido a la última evaluación de seguimiento. A fin de posibilitar el seguimiento a largo plazo para obtener información sobre la supervivencia y la seguridad, está previsto que la última evaluación de seguimiento tenga lugar diez años después de la aleatorización de la primera paciente.

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:

1200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

284

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

688

F.4.2.2

In the whole clinical trial

1484

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)

Currently, Roche/Genentech does not have any plans to provide trastuzumab emtansine or other study interventions to patients after the conclusion of the study. However, patients who discontinue trastuzumab emtansine before the end of the 14 cycle treatment period, may complete the duration of their study therapy with trastuzumab if appropriate based on toxicity considerations.

Actualmente Roche/Genentech no tiene intención de proporcionar trastuzumab emtansina o realizar otro ensayo intervencional con pacientes después de que el estudio finalice. Sin embargo, las pacientes que dejen de recibir trastuzumab emtansine antes de que termine el periodo de tratamiento con el ciclo 14 podrán completar la duración del tratamiento del estudio con trastuzumab, si se considera apropiado en base a la toxicidad.

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

2013-03-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-01-10

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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