Clinical Trials Register

Summary
EudraCT Number:	2017-004566-99
Sponsor's Protocol Code Number:	CO39612
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-07-09
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

2017-004566-99

A.3

Full title of the trial

A PHASE Ib/II, OPEN-LABEL, MULTICENTER, RANDOMIZED UMBRELLA STUDY EVALUATING THE EFFICACY AND SAFETY OF MULTIPLE IMMUNOTHERAPY-BASED TREATMENT COMBINATIONS IN PATIENTS WITH METASTATIC COLORECTAL CANCER (MORPHEUS-CRC)

ESTUDIO EN PARAGUAS DE FASE IB/II, ABIERTO, MULTICÉNTRICO, ALEATORIZADO QUE EVALÚA LA EFICACIA Y LA SEGURIDAD DE MÚLTIPLES COMBINACIONES DE TRATAMIENTOS BASADOS EN INMUNOTERAPIA EN PACIENTES CON CÁNCER COLORRECTAL METASTÁSICO (MORPHEUS-CCR)

A.3.1

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

A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients with Metastatic Colorectal Cancer (Morpheus-CRC)

Estudio para evaluar la eficacia y seguridad de multiples combinaciones de tratamientos basados en inmunoterapia en pacientes con cáncer colorectal metastasico (Morpheus-CCR)

A.4.1

Sponsor's protocol code number

CO39612

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	4047
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+34913257300
B.5.5	Fax number	+34913248195
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	Yes
D.2.1.1.1	Trade name	TECENTRIC
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
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	Atezolizumab
D.3.2	Product code	RO5541267
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	ATEZOLIZUMAB
D.3.9.2	Current sponsor code	RO5541267
D.3.9.3	Other descriptive name	TECENTRIC
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	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	AVASTIN
D.2.1.1.2	Name of the Marketing Authorisation holder	EU/1/04/300/002
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	BEVACIZUMAB
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	BEVACIZUMAB
D.3.9.1	CAS number	216974-75-3
D.3.9.4	EV Substance Code	SUB16402MIG
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	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 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	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	COBIMETINIB
D.3.2	Product code	RO5514041
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	COBIMETINIB
D.3.9.2	Current sponsor code	RO5514041
D.3.9.3	Other descriptive name	COBIMETINIB HEMIFUMARATE
D.3.9.4	EV Substance Code	SUB168371
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	20
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	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	IMPRIME PGG
D.3.2	Product code	RO7234832
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	Imprime PGG
D.3.9.3	Other descriptive name	PGG BETA GLUCAN
D.3.9.4	EV Substance Code	SUB30829
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	1
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)	Yes
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	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	ISATUXIMAB
D.3.2	Product code	RO7268598
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	ISATUXIMAB
D.3.9.2	Current sponsor code	RO7268598
D.3.9.3	Other descriptive name	SAR650984
D.3.9.4	EV Substance Code	SUB187359
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	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 6
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	STIVARGA
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer AG
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	REGORAFERIB
D.3.2	Product code	RO7069680
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	REGORAFENIB
D.3.9.1	CAS number	755037-03-7
D.3.9.2	Current sponsor code	RO7069680
D.3.9.3	Other descriptive name	REGORAFENIB
D.3.9.4	EV Substance Code	SUB73090
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.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

Colorectal cancer (CRC)

Cancer colorectal (CCR)

E.1.1.1

Medical condition in easily understood language

CRC is the development of cancer from the colon or rectum (parts of the large intestine)

El CCR es el desarrollo del cáncer desde el colon o el recto (partes del intestino grueso)

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	LLT
E.1.2	Classification code	10052362
E.1.2	Term	Metastatic colorectal 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 evaluate the efficacy (objective response) of immunotherapy-based treatment combinations
• To evaluate the safety of immunotherapy-based treatment combinations

• Evaluar la eficacia (respuesta objetiva) de las combinaciones de tratamientos basados en inmunoterapias
•Evaluar la seguridad de las combinaciones de tratamientos basados en inmunoterapias

E.2.2

Secondary objectives of the trial

• To evaluate the efficacy (progression free survival, overall survival, overall survival at specific time points, duration of response, and disease control) of immunotherapy-based treatment combinations
• To characterize the pharmacokinetic profile of drugs that are administered as part of an immunotherapy-based treatment combination
• To evaluate the immune response (immunogenicity) to drugs that are administered as part of an immunotherapy-based treatment combination

• Evaluar la eficacia (supervivencia libre de progresión, supervivencia global, supervivencia global en puntos temporales específicos, duración de la respuesta y control de la enfermedad) de las combinaciones de tratamientos basados en inmunoterapias
• Establecer el perfil farmacocinético de los fármacos que se administran como parte de una combinación de tratamientos basados en inmunoterapias
• Evaluar la respuesta inmunitaria (inmunogenicidad)a los fármacos que se administran como parte de una combinación de tratamientos basados en inmunoterapias

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Age >=18 years
-Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
-Life expectancy >= 3 months, as determined by the investigator
-Disease progression during or following two separate lines of treatment for mCRC that consisted of fluoropyrimidine-, oxaliplatin-, or irinotecan-containing chemotherapy in combination with a biologic agent
-Availability of a representative tumor specimen that is suitable for determination of Programmed cell Death-1 (PD-L1) and/or additional biomarker status by means of central testing
-Measurable disease according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
-Adequate hematologic and end-organ function
-For patients receiving therapeutic anticoagulation: stable anticoagulant regimen during the 14 days prior to initiation of study treatment
-Negative HIV test and hepatitis B surface antigen test at screening
-Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total 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
- Tumor accessible for biopsy
- For women and men: agreement to remain abstinent or use contraceptive measures as outlined for each specific treatment arm

-Edad ≥ 18 años
-Estado funcional de 0 o 1 en la escala ECOG
-Esperanza de vida ≥ 3 meses, determinada por el investigador
-Evolución de la enfermedad durante o después de dos líneas de tratamiento independientes para el CCRm en las que se administró quimioterapia con fluoropirimidina, oxaliplatino o irinotecán en combinación con un fármaco biológico
-Disponibilidad de una muestra de tumor representativa que sea adecuada para determinar la expresión de PD-L1 o el estado de otros biomarcadores mediante una prueba central
-Enfermedad cuantificable según los criterios RECIST v. 1.1
-Función hemática y del órgano afectado adecuada
-Para los pacientes que reciban tratamiento con anticoagulantes: régimen estable de anticoagulantes durante los 14 días previos al inicio del tratamiento del estudio
-Resultado negativo en el VIH y en la prueba del antígeno de superficie del virus de la hepatitis B en el momento de la selección
-Resultado negativo total en la prueba de anticuerpos contra el núcleo de la hepatitis B (HBcAb) en el momento de la selección, o resultado positivo en la prueba del HBcAb total seguido de un resultado negativo en la prueba de ADN del virus de la hepatitis B (VHB) en la selección
-Resultado negativo en la prueba del virus de la hepatitis C (VHC) o resultado positivo en la prueba de anticuerpos contra el VHC seguido de un resultado negativo en la prueba de ARN del VHC en el momento de la selección
-Tumor accesible para biopsia
-Para mujeres y hombres: acceder a mantenerse en abstinencia o utilizar los métodos anticonceptivos indicados para cada grupo de tratamiento específico

E.4

Principal exclusion criteria

-High microsatellite instability tumor
-Mutation in the BRAF oncogene
-Prior treatment with any of the protocol-specified study treatments with the exception of patients who received bevacizumab for treatment of CRC.
-Prior allogeneic stem cell or solid organ transplantation
-Symptomatic, untreated, or actively progressing central nervous system metastases
-History of leptomeningeal disease
-Active or history of autoimmune disease or immune deficiency, idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
-History of malignancy other than CRC within 2 years prior to screening
-Active tuberculosis
-Severe infection within 4 weeks prior to initiation of study treatment
-Significant cardiovascular disease
-Grade >= 3 hemorrhage or bleeding event within 28 days prior to initiation of study treatment
-Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
-Adverse events from prior anti-cancer therapy that have not improved to Grade <= 1 or better, with the exception of alopecia of any grade and Grade <= 2 peripheral neuropathy

-Tumor de inestabilidad de microsatélites alta
-Mutación en el oncogén BRAF
-Tratamiento anterior con alguno de los tratamientos del estudio indicados en el protocolo, con la excepción de pacientes que reciben bevacizumab para el tratamiento de la CCR
-Alotrasplante de células madre o trasplante de órganos sólidos previos
-Metástasis del SNC sintomática, no tratada o con evolución activa.
-Antecedentes de enfermedad leptomeníngea
-Antecedentes de fibrosis pulmonar idiopática, neumonía organizada, neumonitis provocada por fármacos, neumonitis idiopática o indicios de neumonitis activa en la tomografía axial computarizada (TAC) de tórax obtenida durante la selección.
-Antecedentes de neoplasia maligna distinta al CCR en los 2 años anteriores a la selección
-Tuberculosis activa
-Infección grave en las 4 semanas anteriores al inicio del tratamiento del estudio
-Cardiovasculopatía significativa
-Hemorragia de grado ≥ 3 o episodio hemorrágico en los 28 días previos al inicio del tratamiento del estudio
-Procedimiento quirúrgico importante para fines distintos al diagnóstico en las 4 semanas anteriores al inicio del tratamiento del estudio o previsión de necesitar un procedimiento quirúrgico importante durante el transcurso del estudio
-Acontecimientos adversos a causa de un tratamiento antineoplásico anterior que no haya mejorado a grado ≤ 1 o mejor, con la excepción de la alopecia de cualquier grado y la neuropatía periférica de grado ≤ 2

E.5 End points

E.5.1

Primary end point(s)

1. Objective response rate
2. Incidence, nature, and severity of adverse events and laboratory abnormalities
3. Change from baseline in vital signs and ECG parameters
4. Change from baseline in targeted clinical laboratory test results

1. Tasa de respuesta objetiva
2. Incidencia, naturaleza, y severidad de los acontecimientos adversos y las anormalidades de laboratorio
3. Cambios desde basal en signos vitales y parámetros de ECG
4. Cambio desde basal en los resultados clinicos diana de laboratorio

E.5.1.1

Timepoint(s) of evaluation of this end point

1. From Randomization until disease progression or loss of clinical benefit (up to 5 years)
2-4. From first study treatment administration until 30 days after the last dose or until initiation of new systemic anti-cancer therapy, whichever occurs first (up to 5 years)

1. Desde randomizacion hasta progresión de la enfermedad o perdida de beneficio clínico (hasta un máximo de 5 años).
2-4. Desde la primera administración de tratamiento del ensayo hasta 30 días después de la ultima dosis o hasta el inicio de nuevas terapias anticancerígenas sistémicas, lo que ocurra antes (hasta un máximo de 5 años)

E.5.2

Secondary end point(s)

1. Progression-free survival
2. Overall survival after randomization
3. Overall survival at specific time points
4. Duration of response
5. Disease control rate
6. Plasma or serum concentration of each drug at specified time points
7. Presence of antidrug antibody (ADAs) during the study relative to the presence of ADAs at baseline

1. Supervivencia libre de progresión
2. Supervivencia global después de la randomización
3. Superviviencia global en puntos temporales específicos
4. Duración de la respuesta
5. Tasa de control de la enfermedad
6. Concentración en plasma o suero de cada fármaco en puntos temporales específicos.
7. Presencia de anticuerpos antifármaco (AAF) durante el ensayo referidos a la presencia de AAFs en basal.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. From randomization to the first occurrence of disease (up to 5 years)
2. From randomization to death from any cause (up to 5 years)
3. Month 6
4. From the date of first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to 5 years)
5. From randomization until disease progression or loss of clinical benefit (up to 5 years)
6-7. During treatment and at treatment discontinuation

1. Desde randomizacion a la primera recurrencia de la enfermedad (hasta un máximo de 5 años)
2. Desde randomización a muerte por cualquier causa (hasta un máximo de 5 años)
3. Mes 6
4. desde la fecha de la primera ocurrencia de una respuesta objetiva documentada a progresión de la enfermedad o muerte por cualquier causa, la que ocurra antes (hasta un máximo de 5 años)
5. Desde randomizacion hasta progresión de la enfermedad o perdida de beneficio clínico (hasta un máximo de 5 años)
6-7. Durante el tratamiento y en la discontinuación del tratamiento

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

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

phase Ib/II multiple drug combination

Fase Ib/II de combinacion de multiples fármacos

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

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

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

France

Korea, Republic of

Spain

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

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 this study is defined as the date when the last patient completes the last visit in both stages, including survival follow-up visits conducted by telephone or on-site visit. The total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 3-5 years.

El final de este estudio se define como la fecha en la que el último paciente lleva a cabo la última visita de ambas fases, incluidas las visitas de seguimiento de la supervivencia realizadas por teléfono o en la clínica. La duración total del estudio desde la selección del primer paciente hasta el final del estudio se espera que sea de aproximadamente 3-5 años

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

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:

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

120

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, the Sponsor does not have any plans to provide the Roche IMPs (atezolizumab, bevacizumab, or cobimetinib) or any other study treatments or interventions to patients who have completed the study. The Sponsor may evaluate whether to continue providing atezolizumab, cobimetinib, and bevacizumab in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product,
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf

Actualmente, el promotor no tiene planes de proporcionar los IMPs de Roche (atezolizumab, bevacizumab o cobimetinib) o cualquier otro tratamiento o intervencion del estudio a pacientes que han completado el ensayo. El promotor podrá evaluar si continua proporcionando atezolizumab, cobimetinib y bevacizumab de acuerdo con la política global de Roche de acceso continuado a fármacos en investigación, http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf

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

2018-10-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-10-22

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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