Clinical Trials Register

Summary
EudraCT Number:	2016-002029-12
Sponsor's Protocol Code Number:	ETOP10-16
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:	2017-03-31
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

2016-002029-12

A.3

Full title of the trial

A randomised phase II trial of osimertinib and bevacizumab versus osimertinib alone as second-line treatment in stage IIIb-IVb NSCLC with confirmed EGFRm and T790M

“Ensayo clínico aleatorizado Fase II de terapia combinada de osimertinib y bevacizumab frente al uso de osimertinib en monoterapia como tratamiento de segunda línea en pacientes con cáncer de pulmón no microcítico estadío IIIb-IVb con EGFRm y T790M confirmadas”

A.3.1

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

A research study to compare the combined treatment of osimertinib and bevacizumab with osimertinib treatment alone in patients with lung cancer that has progressed or spread to other parts of the body (metastatic) and with confirmed specific gene mutations (changes) in the epithelial growth factor receptor (EGFR)

Un estudio de investigación para comparar el tratamiento combinado de osimertinib y bevacizumab con tratamiento con osimertinib solo en pacientes con cáncer de pulmón que ha progresado o se ha diseminado a otras partes del cuerpo (metastásico) y confirmó mutaciones genéticas específicas (cambios) en el receptor del factor de crecimiento epitelial (EGFR)

A.3.2

Name or abbreviated title of the trial where available

BOOSTER

A.4.1

Sponsor's protocol code number

ETOP10-16

A.5.4

Other Identifiers

Name:	Astra Zeneca	Number:	ESR-15-11666
Name:	Roche	Number:	MO39447

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	ETOP (European Thoracic Oncology Platform)
B.1.3.4	Country	Switzerland
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	Astra Zeneca
B.4.2	Country	United Kingdom
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	ETOP
B.5.2	Functional name of contact point	ETOP Coordinating Office
B.5.3	Address:
B.5.3.1	Street Address	Effingerstrasse 40
B.5.3.2	Town/ city	Bern
B.5.3.3	Post code	3008
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+4131511 94 00
B.5.5	Fax number	+4131511 94 01
B.5.6	E-mail	BOOSTER@etop-eu.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	Tagrisso
D.2.1.1.2	Name of the Marketing Authorisation holder	Astra Zeneca
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	Osimertinib
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	Osimertinib
D.3.9.1	CAS number	1421373-65-0
D.3.9.3	Other descriptive name	OSIMERTINIB
D.3.9.4	EV Substance Code	SUB176340
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	80
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: 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	Tagrisso
D.2.1.1.2	Name of the Marketing Authorisation holder	Astra Zeneca
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	Osimertinib
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	Osimertinib
D.3.9.1	CAS number	1421373-65-0
D.3.9.3	Other descriptive name	OSIMERTINIB
D.3.9.4	EV Substance Code	SUB176340
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.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	Avastin
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited, Welwyn Garden City, UK
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	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/ml milligram(s)/millilitre
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.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

Patients with locally advanced or metastatic (stage IIIb-IVb) EGFRm (exon 19 deletion or exon 21 L858R) NSCLC with T790M resistance mutation at progression on prior EGFR TKI therapy

Los pacientes con CPNM con EGFRm (exon 19 deleción o exón 21 L858R) localmente avanzado o metastásico (etapa IIIb-IVb) con mutación de resistencia a T790M con progresión en la terapia previa con TKI de EGFR

E.1.1.1

Medical condition in easily understood language

Patients who already received EGFR Inhibitor therapy against their lung cancer that has progressed or spread to other parts of the body and that has specific changes in the EGFR gene

Los pacientes que ya recibieron tratamiento con inhibidores de EGFR que ha progresado o hayan progresado a otras partes del cuerpo y que tiene cambios específicos en el gen de EGFR

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	19.1
E.1.2	Level	PT
E.1.2	Classification code	10029521
E.1.2	Term	Non-small cell lung cancer stage IIIB
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	19.1
E.1.2	Level	PT
E.1.2	Classification code	10059515
E.1.2	Term	Non-small cell lung cancer metastatic
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	19.1
E.1.2	Level	PT
E.1.2	Classification code	10061873
E.1.2	Term	Non-small cell lung 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 assess the efficacy of the combination of osimertinib and bevacizumab versus osimertinib alone in terms of progression-free survival (PFS) assessed by RECIST 1.1.

Evaluar la eficacia de la combinación de osimertinib y bevacizumab versus osimertinib solo en términos de supervivencia libre de progresión (PFS) evaluada por RECIST 1.1.

E.2.2

Secondary objectives of the trial

To compare short and long term clinical efficacy outcomes as well as tolerability of the two treatments.

Comparar los resultados de eficacia clínica a corto y largo plazo, así como la tolerabilidad de los dos tratamientos.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• NSCLC, stage IIIb/IIIc (not amenable to radical therapy) or IVa/IVb according to 8th TNM classification, after progression following prior EGFR TKI (erlotinib, gefitinib, dacomitinib or afatinib) therapy as the most recent treatment regimen.
• Pathological diagnosis of predominantly non-squamous NSCLC.
• Maximum of one line of previous platinum based chemotherapy.
• Histological or cytological confirmation of EGFRm (exon19 deletion or exon 21 L858R).
• Locally confirmed T790M mutation determined from biopsy (preferred) or on circulating tumour DNA, documented in tissue, plasma or serum after disease progression on the most recent EGFR TKI regimen.
• Plasma, serum, and tumour (preferred) tissue or cytology (if biopsy was taken and FFPE tumor material is not yet fully depleted) after disease progression on the most recent EGFR TKI treatment available for central confirmation of T790M.
• Measurable or evaluable disease
• Adequate haematological, renal and liver function
• Performance status 0-2

- Cancer de pulmón no microcítico, estadio IIIb / IIIc (no susceptible de terapia radical) o IVa / IVb de acuerdo con la 8ª clasificación TNM, después de la progresión después del tratamiento con TKI EGFR anterior (erlotinib, gefitinib, dacomitinib o afatinib) como el tratamiento más reciente.
• Diagnóstico patológico de NSCLC predominantemente no escamoso.
• Máximo de una línea de quimioterapia previa basada en platino.
• Confirmación histológica o citológica de EGFRm (exon19 deleción o exón 21 L858R).
• Mutación de T790M confirmada localmente determinada a partir de la biopsia (preferida) o del ADN circulante del tumor, documentado en tejido, plasma o suero después de la progresión de la enfermedad en el régimen de TKI EGFR más reciente.
• El tejido o la citología de plasma, suero y tumor (preferente) (si se tomó biopsia y el material tumoral de FFPE aún no se ha agotado completamente) después de la progresión de la enfermedad en el tratamiento con TKI EGFR más reciente disponible para la confirmación central de T790M.
• Enfermedad mensurable o evaluable
• Función hematológica, renal y hepática adecuada
• ECOG 0-2

E.4

Principal exclusion criteria

Patients with mixed NSCLC with predominantly squamous cell cancer, or with any small cell lung cancer (SCLC) component.
• Symptomatic or active central nervous system metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth.
• Previous treatment with osimertinib and/or bevacizumab
• Patients currently receiving medications or herbal supplements known to be potent CYP3A4 inducers
• Any unresolved toxicities from prior therapy greater than CTCAE V 4.0 grade 1
• Cualquier toxicidad no resuelta de terapia previa mayor que CTCAE V 4.0 grado 1

Pacientes con NSCLC mixto con predominio de cáncer de células escamosas, o con cualquier componente de cáncer de pulmón de células pequeñas (SCLC).
• Metástasis del sistema nervioso central sintomáticas o activas, según lo indicado por síntomas clínicos, edema cerebral y / o crecimiento progresivo.
• Tratamiento previo con osimertinib y / o bevacizumab
• Los pacientes que actualmente reciben medicamentos o suplementos de hierbas que se sabe son potentes inductores de CYP3A4
• Cualquier toxicidad no resuelta de terapia previa mayor que CTCAE V 4.0 grado 1

E.5 End points

E.5.1

Primary end point(s)

Progression-free survival (PFS) based on RECIST 1.1 criteria

Supervivencia libre de progresión basado en los criterios RECIST 1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

Time from the date of randomisation until documented progression or death, if progression is not documented

Tiempo desde la fecha de la asignación al azar hasta progresión documentada o muerte, si la progresión no está documentada

E.5.2

Secondary end point(s)

• Objective Response (OR), based on RECIST 1.1 criteria
• Disease control, defined as complete or partial response, or disease stabilisation, confirmed at subsequent radiological
assessment
•Adverse events graded by CTCAE V4.0
•Overall survival (OS)

Respuesta Objetiva (OR), basada en criterios RECIST 1.1
• Control de la enfermedad, definido como respuesta completa o parcial, o estabilización de la enfermedad, confirmado en
evaluación
• Eventos adversos clasificados por CTCAE V4.0
• Supervivencia general (SO)

E.5.2.1

Timepoint(s) of evaluation of this end point

• OR : across all assessment time-points during the period from randomisation to termination of trial Treatment
• Disease control: across all assessment time-points during the period from randomisation to termination of trial Treatment
• AEs:from date of signature of informed consent until 30 days after all Trial Treatment discontinuation
• OS: time from the date of randomisation until death from any cause

OR: en todos los puntos de tiempo de evaluación durante el período comprendido entre la asignación al azar y la terminación del ensayo. Tratamiento
• Control de la enfermedad: en todos los puntos de tiempo de evaluación durante el período comprendido entre la asignación al azar y la terminación del ensayo.
• AEs: a partir de la fecha de firma del consentimiento informado hasta 30 días después de la interrupción del tratamiento de todos los ensayos
• OS: tiempo desde la fecha de la asignación al azar hasta la muerte por cualquier causa

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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

Ireland

Korea, Republic of

Netherlands

Singapore

Switzerland

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 required total trial follow-up duration is expected to be 48 months. Estimating a run-in period of 6 months, and a 6-month preparation of the report, the total trial duration is expected to be 5 years from enrolement of the first Patient.

Se espera que la duración total requerida para el seguimiento del ensayo sea de 48 meses. La estimación de un período de ejecución de 6 meses, y una preparación de seis meses del informe, la duración total del ensayo se espera que sea de 5 años a partir del enrolamiento del primer paciente.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

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:

154

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

154

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

154

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

2017-04-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-27

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

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