Clinical Trials Register

Summary
EudraCT Number:	2017-005154-11
Sponsor's Protocol Code Number:	GECP17/05
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:	2018-05-21
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

2017-005154-11

A.3

Full title of the trial

Phase II non-randomized study of Atezolizumab (MPDL3280A) in combination with Carboplatin Plus Pemetrexed in patients who are chemotherapy-naïve and have stage IV non-squamous non-small cell lung cancer with asymptomatic brain metastases (ATEZO-BRAIN)

Ensayo clínico Fase II, no randomizado en primera línea de Atezolizumab en combinación con Carboplatino y Pemetrexed en pacientes con cáncer de pulmón no microcítico estadio IV con metástasis cerebrales asintomáticas

A.3.1

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

Study to assess efficacy of Atezolizumab in combination with Carboplatin Plus Pemetrexed in patients who are chemotherapy-naïve and have stage IV non-squamous non-small cell lung cancer with asymptomatic brain metastases (ATEZO-BRAIN)

Ensayo clínico para evaluar la eficacia del tratamiento de Atezolizumab en combinación con Carboplatino y Pemetrexed en pacientes con cáncer de pulmón no microcítico estadio IV con metástasis cerebrales asintomáticas

A.3.2

Name or abbreviated title of the trial where available

ATEZO-BRAIN

A.4.1

Sponsor's protocol code number

GECP17/05

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	Spanish Lung Cancer Group (SLCG/GECP)
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Spanish Lung Cancer Group (SLCG/GECP)
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Spanish Lung Cancer Group (SLCG/GECP)
B.5.2	Functional name of contact point	Eva Pereira
B.5.3	Address:
B.5.3.1	Street Address	Avenida Meridiana, 358, 6ª Planta
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08027
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34934302006205
B.5.5	Fax number	+34934191768
B.5.6	E-mail	epereira@gecp.org

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	Tecentriq
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	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	Tecentriq
D.3.9.4	EV Substance Code	SUB178312
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	1200
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.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

Atezolizumab combined with carboplatin and pemetrexed

Atezolizumab en combinación con carboplatino y pemetrexed

E.1.1.1

Medical condition in easily understood language

Patients with asymptomatic brain metastasis with advanced non-squamous non-small cell lung cancer (NSCLC)

Pacientes con metástasis cerebrales asintomáticas con cáncer de pulmón no microcítico (CPNM) no-escamoso avanzado

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10025055
E.1.2	Term	Lung cancer non-small cell stage IV
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 of atezolizumab combined with CBDCA and pemetrexed in patients with NSCLC and asymptomatic BM based on PFS according to RANO and RECIST v1.1 criteria for brain and systemic disease respectively

To evaluate the safety of atezolizumab combined with CBDCA and pemetrexed in patients with NSCLC and asymptomatic BM based on the NCI CTCAE v4.0

Evaluar la eficacia del atezolizumab en combinación con CBDCA y pemetrexed en pacientes con CPNM y metástasis cerebrales (MC) asintomáticas en base a la SLP de acuerdo con los criterios RANO y RECIST v1.1 para enfermedad cerebral y sistémica respectivamente

Evaluar la seguridad del atezolizumab en combinación con CBDCA y pemetrexed en pacientes con NSCLC y MC asintomáticas según NCI CTCAE v4.0

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of atezolizumab combined with carboplatin and pemetrexed in patients with NSCLC and asymptomatic BM by measuring objective response and duration of response (RANO in CNS and RECIST v1.1 out of CNS)

Evaluar la eficacia de atezolizumab en combinación con carboplatino y pemetrexed en pacientes con CPNM y MC asintomáticas midiendo la respuesta objetiva y la duración de la respuesta (RANO en CNS y RECIST v1.1 fuera del SNC)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients must meet the following criteria for study entry:
- Signed Informed Consent Form
- Age ≥ 18 years at time of signing Informed Consent Form
- Ability to comply with the study protocol, in the investigator’s judgment
- ECOG Performance Status (PS) of 0 to 1
- Histologically or cytologically confirmed, Stage IV non-squamous NSCLC; patients with mixed non-small cell histology (i.e. squamous and non-squamous) are eligible whether the major component appears to be non-squamous
- No prior treatment or Stage IV non-squamous NSCLC: Patients with a sensitizing mutation in EGFR gene are excluded given that EGFR TKIs are the appropriate front-line treatment for those patients, patients with an ALK fusion are excluded given that ALK TKIs are the appropriate front-line treatment for those patients, patients with unknown EGFR and ALK status require test results at screening, they can be assessed at a local or central laboratory
- Patients who received prior neo-adjuvant, adjuvant chemotherapy or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months since the last dose of chemotherapy and/or radiotherapy
- Asymptomatic untreated brain metastases
- Steroids treatment (dexamethasone) is allowed and patients that remained asymptomatic for 2 weeks on steroids will be eligible when they were receiving ≤ 4mg dexamethasone once a day
- Systemic measurable disease by computed tomography (CT) per response evaluation criteria in solid tumors version (RECIST) 1.1 criteria AND brain measurable disease by magnetic resonance imaging (MRI) per RANO-BM criteria (at least two measurable lesions ≥10mm, see Appendix 3)
- Availability of a formalin-fixed paraffin-embedded block containing tumor tissue or 5 unstained slides
- Adequate hematopoietic, hepatic and renal function: ANC ≥ 1,500 cells/μL, Lymphocyte count ≥ 500 cells/μL, Platelet count ≥ 100,000 cells μL, Hemoglobin ≥ 9.0 g/dL (transfusion are allowed), INR or aPTT ≤ 1.5 x upper limit of normal (ULN); patients receiving therapeutic anticoagulation should be on a stable dose, ALT, AST and/or alkaline phosphatase ≤ 2.5 x ULN, with the following exceptions: -patients with known liver metastasis: ALT and/or AST ≤ 5 x ULN, -patients with known bone metastasis: alkaline phosphatase ≤ 5 x ULN, Serum bilirubin ≤ 1.5 x ULN; patients with known Gilbert disease who have serum bilirubin ≤ 3 x ULN may be recruited), Calculated creatinine clearance (CRCL) ≥ 45 mL/min (based on the standard Cockcroft and Gault formula)
- For women of childbearing potential: agreement to remain abstinent or use contraceptive non-hormonal methods with a failure rate of < 1% per year during the treatment period and for 3 months after the last dose of study treatment. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization and copper intrauterine devices
- For men: agreement to remain abstinent or use a condom, and agreement 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 3 months after the last dose of study treatment to avoid exposing the embryo. Men must refrain from donating sperm during this same period

Los pacientes deben cumplir los siguientes criterios para la inclusión en el estudio:
- Pacientes mayores de 18 años
- Consentimiento informado por escrito firmado
- ECOG (PS) de 0 a 1
- Sujetos con confirmación histológica o citológica de CPNM no escamoso en estadio IV que no recibieron quimioterapia ni radioterapia previa. Se excluirán los pacientes con mutación EGFR o fusión ALK
- Los pacientes que recibieron quimioterapia neoadyuvante, quimioterapia adyuvante o quimiorradioterapia previa con intención curativa para la enfermedad no metastásica deben haber experimentado un intervalo sin tratamiento de al menos 6 meses desde la última dosis de quimioterapia y / o radioterapia
- Metástasis cerebrales asintomáticas no tratadas. El tratamiento con esteroides (dexametasona) está permitido y los pacientes que hayan permanecido asintomáticos durante 2 semanas con esteroides serán elegibles cuando reciban ≤ 4 mg de dexametasona QD
- Enfermedad medible sistémica mediante tomografía computarizada (TC) según los criterios de evaluación de la respuesta en tumores sólidos (RECIST) versión 1.1 Y enfermedad cerebral medible por resonancia magnética (RM) según criterios RANO-BM (al menos dos lesiones medibles ≥10 mm, ver apéndice )
- Disponibilidad de un bloque incluido en parafina fijado con formalina que contenga tejido tumoral o 5 laminillas sin teñir
- Función hematopoyética, hepática y renal adecuada (incluido el aclaramiento de creatinina calculado de 45 ml / min basado en la fórmula estándar de Cockcroft y Gault)
- Pacientes dispuestos a usar anticonceptivos altamente efectivos (<1% de tasa de fracaso)

E.4

Principal exclusion criteria

Patients who meet any of the following criteria will be excluded from study entry:
- History of other malignancy within 3 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer
- Patients harboring an EGFR mutation or an ALK fusion will be excluded
- Leptomeningeal carcinomatosis or metastases in the brain stem, mid-brain, pons, medulla or lesions causing obstructive hydrocephalus
- Patients with neurological symptoms, including those receiving > 4mg of dexamethasone will not be eligible for this study
- Single exclusive brain metastasis amenable to surgical treatment or radiosurgery in patients not having metastasis in other organ
- Spinal hemorrhagic metastases will be excluded
- Prior surgical resection of brain or spinal lesions in the prior 28 days
- Previous systemic treatment or neo-adjuvant or adjuvant chemotherapy less than 6 months before enrollment
- Clinical significant comorbidities that impaired administration of platinum-based chemotherapy
- History of autoimmune disease, including but not limited to myasthenia gravis, myosistis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis or glomerulonephritis: patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone are eligible for this study, patients with controlled Type 1 diabetes mellitus on a stable dose of insulin are eligible for this study, patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only (e.g. patients with psoriasic arthritis would be excluded) are permitted provided that they meet the following conditions: rash covers less than 10% of body surface area, disease is well controlled at baseline and only requires low-potency topical steroids, no acute exacerbations during the last 12 months
- History of idiopathic pulmonary fibrosis, drug-induced pneumonitis or active radiation pneumonitis out of the radiation field
- Previous treatment with immune checkpoint inhibitors or CD137 and OX-40 agonists
- Treatment with investigational therapy within 28 days prior to initiation of study drug
- Positive for hepatitis C virus (HCV) antibody or for hepatitis B surface antigen (HBsAg) at screening. Patients with past or resolved hepatitis B virus (HBV) infection (HBcAb positive with absence of HBsAg) would be eligible whether they are negative for HBV DNA. Patients positive for HCV antibody would be eligible whether they are negative for HCV RNA
- Active tuberculosis or known HIV infection
- Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s judgment
- Serious infection requiring oral or IV antibiotics within 14 days prior to screening
- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in and completion of the study

Los pacientes que cumplan alguno de los siguientes criterios serán excluidos de la participación en el estudio:
- Antecedentes de otros tumores malignos dentro de los 3 años anteriores al reclutamiento, a excepción del carcinoma in situ del cuello uterino, el carcinoma cutáneo no melanoma o el cáncer uterino en estadio I adecuadamente tratados
- Mutación EGFR activante conocida o fusión ALK
- Carcinomatosis leptomeníngea o metástasis en el tallo cerebral, el cerebro medio, puente, médula o lesiones que causan hidrocefalia obstructiva
- Los pacientes con síntomas neurológicos, incluidos aquellos que reciben > 4 mg de dexametasona no serán elegibles para este estudio
- Metástasis cerebrales exclusivas únicas susceptibles de tratamiento quirúrgico o radiocirugía en pacientes que no tienen metástasis en otro órgano
- Las metástasis hemorrágicas espinales serán excluidas
- Resección quirúrgica previa de lesiones cerebrales o espinales en los 28 días anteriores
- Tratamiento sistémico previo o quimioterapia neoadyuvante o adyuvante menos de 6 meses antes del reclutamiento
- Comorbilidades clínicamente significativas que alteren la administración de quimioterapia basada en platino
- Historial de enfermedad autoinmune
- Infección severa activa
- Historial de fibrosis pulmonar idiopática, neumonitis inducida por fármacos o neumonitis por radiación fuera del campo de radiación
- Prueba positiva de VIH, hepatitis B o hepatitis C
- Tratamiento previo con inhibidores o agonistas del punto de control inmunitario (por ejemplo, CD137 y OX-40)
- Embarazo o lactancia

E.5 End points

E.5.1

Primary end point(s)

PFS after enrollment defined as the time from enrollment to the first occurrence of disease progression (intracranial or systemic) or death from any cause whichever occurs first as determined by the investigator according to RANO and RECIST v1.1. criteria for brain and systemic disease respectively
Occurrence and severity of adverse events, with severity determined according to NCI CTCAE v4.0 criteria
Change from baseline in targeted vital signs
Change from baseline in targeted clinical laboratory test results

Evaluar la eficacia del atezolizumab en combinación con CBDCA y pemetrexed en pacientes con CPNM y metástasis cerebrales (MC) asintomáticas en base a la SLP de acuerdo con los criterios RANO y RECIST v1.1 para enfermedad cerebral y sistémica respectivamente
Evaluar la seguridad del atezolizumab en combinación con CBDCA y pemetrexed en pacientes con NSCLC y MC asintomáticas según NCI CTCAE v4.0

E.5.1.1

Timepoint(s) of evaluation of this end point

3 years recruiting patients, 2 years of treatment atezolizumab combined with carboplatin and pemetrexed maximum

3 años de reclutamiento, 2 años de tratamiento de atezolizumab en combinación con carboplatino y pemetrexed máximo

E.5.2

Secondary end point(s)

Objective response, defined as a complete response or partial response on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RANO and RECIST v1.1. criteria for brain and systemic disease respectively
DOR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause whichever occurs first, as determined by the investigator according to RANO and RECIST v1.1. criteria for brain and systemic disease respectively
OS after enrollment defined as the time from enrollment to death from any cause

E.5.2.1

Timepoint(s) of evaluation of this end point

3 años de reclutamiento, 2 años de tratamiento de atezolizumab en combinación con carboplatino y pemetrexed

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

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)

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

LPLV

Ultima visita del último paciente

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

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.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)

None

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

2018-05-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-03-31

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