Clinical Trials Register

Summary
EudraCT Number:	2016-005119-42
Sponsor's Protocol Code Number:	MO39193
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:	2017-12-21
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2016-005119-42

A.3

Full title of the trial

A PHASE III, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTRE STUDY OF THE EFFICACY AND SAFETY OF ATEZOLIZUMAB PLUS CHEMOTHERAPY FOR PATIENTS WITH EARLY RELAPSING RECURRENT (INOPERABLE LOCALLY ADVANCED OR METASTATIC) TRIPLE-NEGATIVE BREAST CANCER

ESTUDIO DE FASE III MULTICÉNTRICO, DOBLE CIEGO, RANDOMIZADO, CONTROLADO CON PLACEBO PARA EVALUAR LA EFICACIA Y LA SEGURIDAD DE ATEZOLIZUMAB MÁS QUIMIOTERAPIA EN PACIENTES CON CÁNCER DE MAMA TRIPLE NEGATIVO RECURRENTE (LOCALMENTE AVANZADO O METASTÁSICO INOPERABLE) CON RECIDIVA PRECOZ

A.3.1

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

A Study of the Efficacy and Safety of Atezolizumab Plus Chemotherapy for Patients with Early Relapsing Recurrent Triple-Negative Breast Cancer

Un Estudio de la Eficacia y Seguridad de Atezolizumab más Quimioterapia para Pacientes con Recaída Recurrente Triple-Negativo de Cáncer de Mama

A.4.1

Sponsor's protocol code number

MO39193

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 S.A. ( Soc.Unipersonal) que realiza el ensayo en España y que actua como representante de Hoffmann-La Roche.
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	913257300
B.5.6	E-mail	spain.start_up_unit@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	atezolizumab
D.3.2	Product code	RO5541267
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.3.9.2	Current sponsor code	RO5541267
D.3.9.3	Other descriptive name	MPDL3280A
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	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: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Carbosin
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Pharma Belgium AG
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	Carboplatin
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	carboplatin
D.3.9.3	Other descriptive name	CARBOPLATIN
D.3.9.4	EV Substance Code	SUB06614MIG
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	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	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	Xeloda
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.3.1	Product name	Capecitabine
D.3.2	Product code	RO 0091978
D.3.4	Pharmaceutical form	Film-coated 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	CAPECITABINE
D.3.9.2	Current sponsor code	Ro 009-1978/J12-00
D.3.9.3	Other descriptive name	CAPECITABINE
D.3.9.4	EV Substance Code	SUB12474MIG
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CAPECITABINE
D.3.9.2	Current sponsor code	Ro009-1978/J13-00
D.3.9.3	Other descriptive name	CAPECITABINE
D.3.9.4	EV Substance Code	SUB12474MIG
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	500
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: 4
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	Gitrabin 200mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis Group PTC ehf
D.2.1.2	Country which granted the Marketing Authorisation	Romania
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	Gemcitabine
D.3.4	Pharmaceutical form	Powder 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	GEMCITABINE
D.3.9.1	CAS number	95058-81-4
D.3.9.4	EV Substance Code	SUB07892MIG
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	38
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: 5
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	Gitrabin 1000mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis Group PTC ehf
D.2.1.2	Country which granted the Marketing Authorisation	Romania
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	Gemcitabine
D.3.4	Pharmaceutical form	Powder 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	GEMCITABINE
D.3.9.1	CAS number	95058-81-4
D.3.9.4	EV Substance Code	SUB07892MIG
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	38
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
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

Triple-Negative Breast Cancer (TNBC)

Cáncer de mama triple negativo (CMTN)

E.1.1.1

Medical condition in easily understood language

TNBC refers to a type of breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PgR) or HER2/neu

CMTN se refiere a un tipo de cáncer de mama que no expresa los genes de receptor de estrógeno (ER), receptor de progesterona (PgR) o HER2 / neu

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10075566
E.1.2	Term	Triple negative 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 atezolizumab plus chemotherapy compared to placebo plus chemotherapy based on overall survival

Evaluar la eficacia de atezolizumab más quimioterapia en comparación con placebo más quimioterapia basada en la supervivencia global

E.2.2

Secondary objectives of the trial

• To evaluate the efficacy of atezolizumab plus chemotherapy compared to placebo plus chemotherapy based on survival rate, progression free survival, objective response rate, duration of objective response, clinical benefit rate
• To evaluate patient-reported outcomes (PROs) of global health status (GHS)/health-related quality of life (HRQoL) associated with atezolizumab plus chemotherapy compared with chemotherapy alone, as measured by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
• To evaluate the safety of atezolizumab plus chemotherapy compared with placebo plus chemotherapy
• To characterize the pharmacokinetics (PK) of atezolizumab when administered with carboplatin/gemcitabine or with capecitabine in patients with breast cancer
• To evaluate the immunogenicity of atezolizumab
• To assess the efficacy and safety of atezolizumab plus chemotherapy according to programmed death−ligand 1 (PD-L1) status

Evaluar eficacia de atezolizumab más quimioterapia en comparación con placebo más quimioterapia basada en la tasa de supervivencia, supervivencia libre de progresión, tasa de respuesta objetiva, duración de la respuesta objetiva, tasa de beneficio clínico. Evaluar los resultados reportados por los pacientes(PRO) correspondientes al estado salud general (ESG)/calidad de vida relacionada con la salud (CVRS), asociados con atezolizumab más quimioterapia comparado con quimioterapia sola, basándose en el cuestionario de calidad de vida Questionnaire Core 30 (EORTC QLQ-C30)Evaluar seguridad de atezolizumab más quimioterapia en comparación con placebo más quimioterapia, Caracterizar la farmacocinética (PK) de atezolizumab cuando se administra con carboplatino / gemcitabina o con capecitabina en pacientes con cáncer de mama, Evaluar la inmunogenicidad del atezolizumab, Evaluar la eficacia y seguridad de atezolizumab más quimioterapia según el estado programado de muerte-ligando 1 (PD-L1)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male or female >= 18 years of age
- Histologically confirmed TNBC that is either locally recurrent, inoperable and cannot be treated with curative intent or is metastatic
- Documented disease progression occurring within 12 months (<12 months) from the last treatment with curative intent
- Have not received prior chemotherapy or targeted systemic therapy for their locally advanced inoperable or metastatic recurrence
- Measurable or non-measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- Availability of a representative formalin-fixed paraffin-embedded (FFPE) tumour block (preferred) or at least 25 unstained slides with an associated pathology report, if available
- Eastern Cooperative Oncology Group performance status 0-1
- Life expectancy >= 12 weeks
- Adequate haematologic and end-organ function, Negative human immunodeficiency virus (HIV) test at screening
- Negative hepatitis B surface antigen (HBsAg) test at screening
- Negative total hepatitis B core antibody (HBcAb) test at screening, or positive HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening
- Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening
- The HCV RNA test will be performed only for patients who have a positive HCV antibody test
- Women of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of <=1% per year during the treatment period and for at least 5 months after the last dose of study treatment
- Men must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agree to refrain from donating sperm, with female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 6 months after the last dose of carboplatin/gemcitabine to avoid exposing the embryo.

-Varones o mujeres >= 18 años de edad
-Presentar CMTN confirmado histológicamente, con recurrencia local o metastásica inoperable y que no pueda ser tratado con intención curativa
-Progresión de la enfermedad documentada (p. ej. Con muestra de biopsia, informe histopatológico o radiológico) producida en los <12 meses siguientes al último tratamiento con intención curativa
-No haber recibido previamente quimioterapia o tratamiento sistémico dirigido para la enfermedad recurrente localmente avanzada o metastásica inoperable
-Presentar enfermedad medible o no medible, definida de acuerdo con los criterios RECIST 1.1
-Disponibilidad de un bloque de tejido tumoral representativo, fijado en formalina e incluido en parafina (FFPE) (opción preferida), o de un mínimo de 25 laminillas no teñidas junto con el correspondiente informe histopatológico, si está disponible.
-Estado funcional del Eastern Cooperative Oncology Group (ECOG) 0-1.
-Esperanza de vida ≥ 12 semanas.
-Función hematológica y de órganos diana adecuada,Prueba del Virus de la Inmunodeficiencia Humana (VIH) negativa en el período de selección.
-Prueba del antígeno de superficie de la hepatitis B (HBsAg) negativa en el período de selección.
-Resultado negativo para el anticuerpo contra el antígeno del núcleo del virus de la hepatitis B (HBcAb) en el periodo de selección, o resultado positivo en la prueba de HBcAb seguido de un resultado negativo en la prueba del ácido desoxirribonucleico (ADN) del virus de la hepatitis B (VHB) en el periodo de selección.
-Resultado negativo en el análisis del anticuerpo contra el virus de la hepatitis C (VHC) o positivo para el anticuerpo contra VHC, seguido de un resultado negativo en la prueba del ácido ribonucleico (ARN) del VHC, en el período de selección.
-La prueba de ARN de VHC se realizará únicamente en los pacientes que sean positivos para el anticuerpo contra VHC.
-Las mujeres potencialmente fértiles deben comprometerse a practicar la abstinencia sexual (es decir, abstenerse de mantener relaciones heterosexuales) o a usar un método anticonceptivo con una tasa de fracaso ≤1% al año, durante el período de tratamiento y como mínimo hasta 5 meses después de la administración de la última dosis del tratamiento del estudio.
-Los varones deben comprometerse a practicar la abstinencia sexual (es decir, abstenerse de mantener relaciones heterosexuales) o a usar métodos anticonceptivos, así como a no donar semen.Los varones con pareja femenina potencialmente fértil o embarazada deben comprometerse a practicar la abstinencia sexual o a usar preservativos durante el período de tratamiento y como mínimo, hasta 6 meses después de la administración de la última dosis de carboplatino/gemcitabina, para evitar la exposición del embrión

E.4

Principal exclusion criteria

- 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 randomisation
- Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
- Symptomatic or rapid visceral progression
- No prior treatment with an anthracycline and taxane
- History of leptomeningeal disease
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
- Uncontrolled tumour-related pain
- Uncontrolled or symptomatic hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy
- Malignancies other than TNBC within 5 years prior to randomisation, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year OS rate  90%) and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, non melanoma skin carcinoma, localised prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer)
- Significant cardiovascular disease
- Presence of an abnormal ECG that is clinically significant in the investigator’s opinion
- Severe infection requiring oral or IV antibiotics within 4 weeks prior to randomisation, including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia
- Current treatment with anti-viral therapy for HBV
- Major surgical procedure within 4 weeks prior to randomisation or anticipation of the need for a major surgical procedure during the course of the study other than for diagnosis
- Treatment with investigational therapy within 28 days prior to randomisation
- Pregnant or lactating, or intending to become pregnant during or within 5 months after the last dose of study treatment

- Compresión de médula espinal no tratada de forma definitiva con cirugía y/o radioterapia o diagnosticada y tratada previamente, sin evidencia de estabilización clínica de la enfermedad durante > 2 semanas antes de la randomización.
- Metástasis del sistema nervioso central (SNC) sintomáticas, no tratadas o progresivas.
metastases
- Progresion visceral sintomatica o rapida
-No tratamiento previo con antraciclina o taxano
- Antecedentes de enfermedad leptomeníngea
- Derrame pleural, pericárdico o ascitis no controlados que requieran procedimientos de drenaje recurrente.
- Dolor relacionado con el tumor, no controlado.
- Hipercalcemia no controlada o sintomática o hipercalcemia sintomática que requiera el uso continuado de bifosfonatos.
-Neoplasias malignas distintas de CMTN en los 5 años previos a la randomización, exceptuando aquellas que tengan un riesgo insignificante de metástasis o muerte (p. ej. tasa de SG a 5 años >90%) y hayan sido tratadas con intención curativa con el resultado esperado (tales como carcinoma in situ de cérvix, carcinoma de piel distinto de melanoma, cáncer de próstata localizado, carcinoma ductal in situ o cáncer de útero en estadio I tratados adecuadamente)
- Enfermedades cardiovasculares significativas,
- Presencia de anomalías en el ECG que sean clínicamente significativas de acuerdo con la opinión del investigador.
- Infecciones graves que han requerido antibióticos por vía oral o IV en las 4 semanas previas a la randomización, incluyendo aunque no exclusivamente, infecciones complicadas que requieran hospitalización, bacteremia o neumonía grave.
- Tratamiento actual con terapia antiviral para el VHB.
-Procedimientos de cirugía mayor que no sean con fines diagnósticos en las 4 semanas previas a la randomización o que previsiblemente sean necesarios en el transcurso del estudio.
-Tratamiento con un agente en investigación en los 28 días previos a la randomización.
- Mujeres embarazadas o en período de lactancia o que tengan intención de quedarse embarazadas durante el estudio o en los 5 meses siguientes a la administración de la última dosis del tratamiento del estudio

E.5 End points

E.5.1

Primary end point(s)

1. Overall survival

1. Supervivencia general

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Up to 30 months

1. Hasta 30 meses

E.5.2

Secondary end point(s)

1. 12-month survival rate
2. 18-month survival rate
3. Progression-free survival
4. Objective response rate
5. Duration of objective response
6. Clinical benefit rate
7. Time to deterioration (TTD) of GHS/HRQoL
8. Incidence, nature and severity of adverse events (AEs), with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0)
9. Change from baseline in targeted vital signs and physical findings
10. Change from baseline in targeted clinical laboratory test results
11. Maximum and minimum observed serum concentration (Cmax and Cmin) of atezolizumab
12. Incidence of anti-drug antibodies (ADAs) during the study relative to the prevalence of ADAs at baseline.
13. Relationship between PD-L1 protein expression by immunohistochemistry (Ventana® SP142 assay) in screening tumour tissue and clinical outcomes

1. Tasa de supervivencia a 12 meses
2. Tasa de supervivencia a 18 meses
3. Supervivencia libre de progresión
4. Tasa de respuesta objetiva
5. Duración de la respuesta objetiva
6. Tasa de beneficios clínicos
7. Tiempo hasta el deterioro (TD) de la ESG/CVRS
8.Incidencia, tipo y gravedad (determinada de acuerdo con los Criterios de Terminología Común para Acontecimientos Adversos del National Cancer Institute, Versión 4.0 [NCI CTCAE v4.0]) de los acontecimientos adversos (AA)
9.Cambio producido respecto al valor basal en las constantes vitales y los hallazgos de la exploración física específicos
10. Cambio respecto al valor basal en los resultados de las pruebas de laboratorio clínico específicas
11. Concentración sérica máxima y mínima observada (Cmax y Cmin) de atezolizumab
12.Incidencia de anticuerpos contra el fármaco (ADA) durante el estudio, en relación con su prevalencia en el período basal.
13. Relación entre la expresión de la proteína PD-L1 evaluada mediante inmunohistoquímica (ensayo SP142 de Ventana®) en muestras de tejido tumoral obtenidas y los resultados clínicos.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Month 12
2. Month 18
3-13. Up to 36 months

1. Mes 12
2. Mes 18
3-Hasta 36 meses

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 biomarker objectives

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

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)

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

Algeria

Bosnia and Herzegovina

Brazil

Cuba

Egypt

France

Germany

Hong Kong

Hungary

Italy

Kazakhstan

Korea, Republic of

Mexico

Morocco

Panama

Russian Federation

Serbia

Singapore

South Africa

Spain

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 last patient last visit (LPLV).

El final del estudio se define como la última visita del ultimo paciente (LPLV).

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 months

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:

292

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

120

F.4.2.2

In the whole clinical trial

350

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 offer continued access to Sponsor study drug (atezolizumab) free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product, as outlined in section 4.3.5 of the protocol.

El Promotor ofrecera acceso continuado al farmaco del estudio (Atezolizumab) gratis a los pacientes elegibles de acuerdo con la politica global de Roche de acceso continuado a farmacos en investigacion tal y como se refleja en la sección 4.3.5 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

2017-12-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-10-26

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

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