Clinical Trials Register

Summary
EudraCT Number:	2015-004189-27
Sponsor's Protocol Code Number:	WO30085
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:	2016-05-26
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

2015-004189-27

A.3

Full title of the trial

A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE II STUDY OF THE EFFICACY AND SAFETY OF TRASTUZUMAB EMTANSINE IN COMBINATION WITH ATEZOLIZUMAB OR ATEZOLIZUMAB-PLACEBO IN PATIENTS WITH HER2-POSITIVE LOCALLY ADVANCED OR METASTATIC BREAST CANCER WHO HAVE RECEIVED PRIOR TRASTUZUMAB AND TAXANE BASED THERAPY.

ESTUDIO DE FASE II MULTICÉNTRICO, RANDOMIZADO, DOBLE CIEGO, CONTROLADO CON PLACEBO, PARA EVALUAR LA EFICACIA Y LA SEGURIDAD DE TRASTUZUMAB EMTANSINA EN COMBINACIÓN CON ATEZOLIZUMAB O ATEZOLIZUMAB-PLACEBO EN PACIENTES CON CÁNCER DE MAMA HER2-POSITIVO, LOCALMENTE AVANZADO O METASTÁSICO, QUE HAN RECIBIDO PREVIAMENTE TRATAMIENTO BASADO EN TRASTUZUMAB Y TAXANOS

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 in Combination With Atezolizumab or Atezolizumab-Placebo in Participants With HER2-Positive Locally Advanced or Metastatic Breast Cancer who Have Received Prior Trastuzumab and Taxane Based Therapy.

Estudio para evaluar la eficacia y seguridad de trastuzumab emtansine en combinación con Atezolizumab o Atezolizumab con placebo en los participantes con HER2-positivo de cáncer de mama localmente avanzado o metastásico que han recibido antes Trastuzumab y terapia basada en taxano.

A.4.1

Sponsor's protocol code number

WO30085

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	Roche Farma que representa en España a 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.5.4	Telephone number	34913257300
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	Yes
D.2.1.1.1	Trade name	KADCYLA®
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 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	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	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	Atezolizumab
D.3.2	Product code	RO5541267/F03-01
D.3.4	Pharmaceutical form	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	ATEZOLIZUMAB
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	RO5541267
D.3.9.3	Other descriptive name	MPDL3280A, Anti-PDL1, Anti-PD-L1
D.3.9.4	EV Substance Code	SUB178312
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	60
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	Antineoplastic agent, humanized immunoglobulin G1 (IgG1) monoclonal antibody.

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 infusion
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 locally advanced or metastatic breast cancer (MBC).

Cáncer no resecable localmente avanzado o metastásico de mama (CMM).

E.1.1.1

Medical condition in easily understood language

Locally advanced breast cancer is an advanced-stage non-metastatic disease. Metastatic breast cancer is a cancer of breast that may spread beyond the breast to other organs in the body.

Cáncer de mama localmente avanzado es enfermedad no metastásica en etapa avanzada. Cáncer de mama metastásico es un cáncer de mama, que puede extenderse más allá del seno a otros órganos en el cuerpo.

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	19.0
E.1.2	Level	PT
E.1.2	Classification code	10065430
E.1.2	Term	HER-2 positive breast cancer
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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10027475
E.1.2	Term	Metastatic breast cancer
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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10072740
E.1.2	Term	Locally advanced breast 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

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of the combination of trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo as measured by progression free survival (PFS) using Response Evaluation Criteria in Solid tumors (RECIST) v1.1.

Evaluar la eficacia de la combinación de trastuzumab emtansina más atezolizumab, comparado con trastuzumab emtansina más placebo, basándose en la Supervivencia libre de progresión (SLP) usando RECIST v1.1.

E.2.2

Secondary objectives of the trial

• To evaluate the efficacy of the combination of trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo as measured by overall survival (OS), objective response rate (ORR), and duration of response (DOR) using RECIST v1.1
• To evaluate the overall safety of trastuzumab emtansine in combination with atezolizumab compared with trastuzumab emtansine in combination with placebo
• To characterize the pharmacokinetics of atezolizumab in the presence of trastuzumab emtansine and trastuzumab emtansine in the presence and absence of atezolizumab
• To characterize the incidence of anti-therapeutic antibody (ATA) to atezolizumab and trastuzumab emtansine.

- Evaluar la eficacia de la combinación de trastuzumab emtansina más atezolizumab, comparado con trastuzumab emtansina más placebo, basándose en la Supervivencia global (SG), Respuesta objetiva, y Duración de la respuesta objetiva usando RECIST versión 1.1.
- Evaluar la seguridad general de trastuzumab emtansina en combinación con atezolizumab, comparado con trastuzumab emtansina más placebo.
- Caracterizar la la farmacocinética de atezolizumab en presencia de trastuzumab emtansina y trastuzumab emtansina en presencia y ausencia de atezolizumab.
- Caracterizar la incidencia de anticuerpos antiterapéuticos (ATA) contra atezolizumab y trastuzumab emtansina.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age >=18 years
- Archival tumor samples must be obtained from primary and/or metastatic sites
- Able to submit tumor tissue that is evaluable for programmed death- ligand 1 (PD-L1) expression
- Human epidermal growth factor-2 positive breast cancer (BC) as defined by an immunohistochemistry score of 3 or gene amplified by in-situ hybridization as defined by a ratio of >= 2.0 for the number of HER2 gene copies to the number of chromosome 17
- Histologically or cytologically confirmed invasive BC incurable, unresectable, locally advanced BC previously treated with multimodality therapy or metastatic breast cancer
- Prior treatment for BC in the adjuvant, unresectable locally advanced or metastatic settings which must include both, a taxane and trastuzumab (alone or in combination with another agent)
- Progression must have occurred during or after most recent treatment for locally advanced BC/MBC or within 6 months after completing adjuvant therapy
- Participants must have measurable disease that is evaluable as per RECIST v1.1
- Eastern Cooperative Oncology Group Performance Status of 0 or 1
- Adequate hematologic and end-organ function as evidenced by the following local laboratory results obtained within 2 weeks prior to the first study treatment (Cycle 1, Day 1):
• Absolute neutrophil count >=1500 cells/microliter (µL) (without granulocyte-colony stimulating factor support) within 2 weeks prior to Cycle 1, Day 1
• Platelet count >=100,000/µL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
• Hemoglobin >=9.0 gram/deciliter (g/dL)
• Albumin > 2.5 g/dL
• Aspartate aminotransferase, alanine transaminase, and alkaline phosphatase <= 2.5 × the upper limit of normal (ULN)
• Total bilirubin <=1.5 × the ULN
• International normalized ratio and activated partial thromboplastin time <=1.5 × the ULN
• Calculated creatinine clearance >= 30 millilitre/min
- Negative serum pregnancy test for pre-menopausal women and for women less than 12 months after the onset of menopause
- For women of childbearing potential, agreement to remain abstinent or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 7 months after the last dose of study drug
- For men, agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm that together result in a failure rate of < 1% per year during the treatment period and for at least 7 months after the last dose trastuzumab emtansine.

- Tener >= 18 años de edad.
- Se deben obtener muestras de tumor conservadas de localizaciones del tumor primario y/o metastásicas.
- Para que los pacientes sean elegibles para este estudio, se deben enviar muestras de tejido tumoral que sean evaluables para la expresión de PD-L1.
- Cáncer de mama (CM) HER2-positivo, definido por una puntuación 3+ mediante inmunohistoquímica (IHC) o amplificación del gen en hibridación in situ (ISH), definida por un cociente >= 2,0 del número de copias del gen HER2 al número de copias del cromosoma 17.
- CM invasivo, confirmado histológica o citológicamente: CM localmente avanzado incurable, no resecable, tratado previamente con múltiples modalidades o CMM.
- Tratamiento previo para el CM en el entorno adyuvante, de la enfermedad localmente avanzada no resecable o metastásica, que debe incluir un taxano y trastuzumab (solos o en combinación con otro agente)
- Progresión de la enfermedad durante o después del tratamiento más reciente para CMLA/CMM o en los 6 meses siguientes a la terminación del tratamiento adyuvante.
- Los pacientes deben presentar enfermedad medible, que sea evaluable de acuerdo con los criterios RECIST 1.1.
- Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1.
- Función hematológica y de órganos diana adecuada, evidenciada por los resultados siguientes obtenidos en el laboratorio local en las 2 semanas previas a la administración de la primera dosis del tratamiento del estudio (día 1 del ciclo 1):
+ Recuento absoluto de neutrófilos >= 1500 células/µl (sin soporte de factores estimuladores de colonias de granulocitos) en las 2 semanas previas al día 1 del ciclo 1
+ Recuento de plaquetas >= 100.000/µL (sin transfusión en las 2 semanas previas al día 1 del ciclo 1)
Hemoglobina >= 9,0 g/dl
Los pacientes pueden recibir transfusiones o agentes estimuladores de la eritripoyesis para cumplir este criterio.
Albúmina >= 2,5 g/dl
+ AST, ALT y fosfatasa alcalina <= 2,5 * límite superior de normalidad (LSN)
+ Bilirrubina total <= 1,5 * LSN
+ INR y TTPa <= 1,5 * LSN
+ Aclaramiento de creatinina calculado >= 30 ml/min
- Prueba de embarazo en suero negativa en las mujeres premenopáusicas y en las que sean menopáusicas desde hace menos de 12 meses.
- Las mujeres potencialmente fértiles deben comprometerse a practicar la abstinencia sexual (es decir, abstenerse de mantener relaciones heterosexuales) o a utilizar métodos anticonceptivos que tengan una tasa de fallos 1% al año, durante el período de tratamiento y como mínimo hasta 7 meses después de la administración de la última dosis del fármaco del estudio.
- Los varones deben comprometerse a practicar la abstinencia sexual o a utilizar métodos anticonceptivos, así como abstenerse de donar semen, que conjuntamente tengan una tasa de fallos <1% año, durante el período de tratamiento y como mínimo hasta 7 meses después de la administración de la última dosis de trastuzumab emtansina.

E.4

Principal exclusion criteria

- Prior treatment with trastuzumab emtansine, cluster of differentiation 137 agonists, anti-programmed death 1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents
- Receipt of any anti-cancer drug/biologic or investigational treatment within 28 days prior to randomization except hormone therapy, which can be given up to 7 days prior to randomization; recovery of treatment related toxicity consistent with other eligibility criteria
- Radiation therapy within 2 weeks prior to Cycle 1, Day 1
- History of exposure to the cumulative doses of anthracyclines
- History of other malignancy within the previous 5 years
- Cardiopulmonary dysfunction
- Current severe, uncontrolled systemic disease
- 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
- Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, autoimmune hepatic disorders, sclerosis cholangitis or active infection with human immunodeficiency virus, hepatitis B virus, or hepatitis C virus
- Need for current chronic corticosteroid therapy
- Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to randomization
- Participants with known central nervous system disease
- Symptomatic pleural effusion, pericardial effusion, or ascites
- Uncontrolled hypercalcemia (>1.5 millimol/litre ionized calcium or calcium > 12 milligram/dL or corrected serum calcium greater than the ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy
- Current Grade >= 3 peripheral neuropathy
- History of autoimmune disease and idiopathic pulmonary fibrosis
- Prior allogeneic stem cell or solid organ transplantation
- Active tuberculosis
- Receipt of a live, attenuated vaccine within 4 weeks prior to randomization or anticipation that such a live, attenuated vaccine will be required during the study
- Treatment with systemic immunostimulatory agents
- Treatment with systemic corticosteroids or other systemic immunosuppressive medications.

- Tratamiento previo con trastuzumab emtansina, agonistas de CD137, anticuerpos terapéuticos anti-muerte celular programada 1 (PD-1) o anti PD L1 o agentes dirigidos contra vías específicas.
- Administración de cualquier fármaco/tratamiento biológico o experimental para el cáncer en los 28 días previos a la randomización, a excepción de la hormonoterapia, que puede administrarse hasta 7 días antes de la randomización; el paciente se debe haber recuperado de la toxicidad relacionada con el tratamiento en consonancia con otros criterios de selección.
- Administración de radioterapia en las 2 semanas previas al día 1 del ciclo 1.
- Exposición previa a cualquiera de las dosis acumuladas de antraciclinas
- Antecedentes de otras neoplasias en los 5 últimos años
- Disfunción cardiopulmonar
- Presencia de enfermedades sistémicas severas, no controladas
- Pacientes sometidos a un procedimiento de cirugía mayor o que han sufrido traumatismos significativos en los 28 días previos a la randomización o que previsiblemente requerirán un procedimiento de cirugía mayor en el transcurso del tratamiento del estudio.
- Antecedentes de hepatopatías clínicamente significativas, incluyendo cirrosis, abuso de alcohol en la actualidad, trastornos hepáticos autoinmunes, colangitis esclerosante o infección activa por VIH, virus de hepatitis B (VHB) o virus de hepatitis C (VHC)
- Necesidad de tratamiento crónico con corticosteroides
- Compresión de médula espinal no tratada de forma definitiva con cirugía y/o radioterapia o diagnosticada y tratada previamente, sin evidencia de que la enfermedad se ha mantenido clínicamente estable durante  2 semanas antes de la randomización
- Los pacientes con enfermedades conocidas del sistema nervioso central
- Derrame pleural, pericárdico o ascitis sintomáticos
- Hipercalcemia no controlada (> 1,5 mmol/l de calcio ionizado, calcio > 12 mg/dl o calcio corregido en suero > LSN) o hipercalcemia sintomática que requiera la administración continuada de bisfosfonatos
- Neuropatía periférica de grado >= 3
- Antecedentes de fibrosis pulmonar idiopática
- Trasplante alogénico de células madre o de órganos sólidos realizado previamente
- Tuberculosis activa
- Pacientes que han recibido vacunas vivas atenuadas en las 4 semanas previas a la randomización o que previsiblemente requerirán dichas vacunas durante el estudio
- Tratamiento sistémico con inmunoestimuladores
- Tratamiento sistémico con corticosteroides u otros inmunosupresores

E.5 End points

E.5.1

Primary end point(s)

PFS as determined by investigator’s tumor assessment.

SLP basada en la evaluación del tumor realizada por el investigador

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to 28 months.

Hasta 28 meses.

E.5.2

Secondary end point(s)

Efficacy :
1. OS as determined by investigator’s tumor assessment
2. ORR as determined by investigator’s tumor assessment
3. DOR as determined by investigator’s tumor assessment
Safety:
4. Nature, frequency, severity, and timing of adverse events including cardiac, hepatic and pulmonary events
5. Clinical laboratory results during and following trastuzumab emtansine and atezolizumab administration
Pharmacokinetic:
6. Serum concentration of trastuzumab emtansine
7. Serum concentration of total trastuzumab
8. Plasma concentration of Deacetyl Mercapto 1 oxopropyl maytansine (DM1)
9. Serum concentration of atezolizumab
Immunogenicity:
10. Numbers and proportions of ATA-positive patients and ATA-negative patients during both the treatment and follow up phase.

Eficacia:
1. Supervivencia global (SG) determinada por el investigador
2. Respuesta objetiva determinada por el investigador
3. Duración de la respuesta objetiva determinada por el investigador
Seguridad:
4. Características, incidencia, severidad y momento de la aparición de los acontecimientos adversos, incluyendo acontecimientos cardíacos, hepáticos y pulmonares
5. Resultados de laboratorio clínico durante y después de la administración de trastuzumab emtansina y atezolizumab
Farmacocinéticos:
6. concentración sérica de trastuzumab emtansine
7. concentración sérica total de trastuzumab
8. concentraciones plasmáticas de DM1
9. concentración sérica de atezolizumab
Inmunogenicidad:
10. Número y la proporción de pacientes ATA positivo y ATA negativo durante los períodos de tratamiento y seguimiento

E.5.2.1

Timepoint(s) of evaluation of this end point

1-5. Up to 28 months
6. Day (D)1 of Cycle (C)1, C2, C4, and Study treatment(ST)/early discontinuation visit(EDV)
7. D1 of C1, C2 and C4
8. D1 of C1 and C4
9-10. D1 of C1, C2, C3, C4 and C8; thereafter every 8 cycles on D1 C8D1, ST/ EDV, and 120D (+/-28D) after treatment completion or discontinuation.

1-5. Hasta 28 meses
6. Dia (D)1 del Ciclo (C)1, C2, C4, y tratamiento del estudio/visita de terminación temprana
7. D1 del C1, C2 y C4
8. D1 del C1 y C4
9-10. D1 del C1, C2, C3, C4 y C8; después cada 8 ciclos en D1 C8D1, tratamiento del estudio/visita de terminación temprana, y 120D (+/-28D) tras completar el tratamiento o su discontinuación.

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

IMMUNOGENICITY and EXPLORATORY BIOMARKER.

Inmunogenicidad y biomarcadores exploratorios.

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)

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

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

Yes

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

Canada

France

Germany

Italy

Korea, Republic of

Netherlands

Spain

Taiwan

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 study is triggered by the final OS analysis following last patient last visit (LPLV) which is planned to occur approximately 9 months after the primary efficacy analysis. The Sponsor may also terminate the study at any time.

La terminación del estudio está determinada por el análisis final de la SG tras la última visita del último paciente, lo que se prevé que ocurra aproximadamente 9 meses después del análisis principal de eficacia. El estudio puede terminar también en cualquier momento, por decisión del promotor.

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:

200

F.1.3

Elderly (>=65 years)

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

F.4.2.2

In the whole clinical trial

200

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)

The Sponsor will evaluate the appropriateness of continuing to provide trastuzumab emtansine and atezolizumab (where applicable) to patients on protocol treatment at the end of the study as defined in Section 3.2. of the protocol.

El Promotor evaluará la conveniencia de continuar proporcionandotrastuzumab emtansine y atezolizumab (en su caso) a los pacientes en el protocolo de tratamiento al final del estudio como se define en la Sección 3.2. del protocolo

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

2016-07-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-07-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-02-06

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