Clinical Trials Register

Summary
EudraCT Number:	2013-003839-30
Sponsor's Protocol Code Number:	D081CC00006
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:	2014-05-08
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

2013-003839-30

A.3

Full title of the trial

A randomised, double-blind, parallel group, placebo-controlled multi-centre Phase III study to assess the efficacy and safety of olaparib versus placebo as adjuvant treatment in patients with germline BRCA1/2 mutations and high risk HER2 negative primary breast cancer who have completed definitive local treatment and neoadjuvant or adjuvant chemotherapy.

Ensayo fase III, multicéntrico, aleatorizado, doble ciego, de grupos
paralelos, controlado con placebo, para evaluar la eficacia y la seguridad de
olaparib frente a placebo como tratamiento adyuvante de pacientes con
cáncer de mama HER2 negativo de alto riesgo y mutaciones germinales de
BRCA1/2, que han finalizado el tratamiento local y la quimioterapia
neoadyuvante o adyuvante

A.3.1

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

Olaparib as adjuvant treatment in patients with germline BRCA mutated high risk HER2 negative primary breast cancer.

Olaparib como tratamiento adyuvante en pacientes con cáncer de mama HER2 negativo de alto riesgo y mutaciones germinales de
BRCA1/2

A.3.2

Name or abbreviated title of the trial where available

Olympia

A.4.1

Sponsor's protocol code number

D081CC00006

A.5.4

Other Identifiers

Name:

Protocol Study Code

Number:

BIG 6-13

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	AstraZeneca AB
B.1.3.4	Country	Sweden
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	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca Farmaceutica Spain, S.A.
B.5.2	Functional name of contact point	Information Center
B.5.3	Address:
B.5.3.1	Street Address	C/ Serrano Galvache 56
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28033
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034900 162 001
B.5.6	E-mail	informacionEECC-spain@astrazeneca.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	olaparib
D.3.2	Product code	AZD2281
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	OLAPARIB
D.3.9.1	CAS number	763113-22-0
D.3.9.3	Other descriptive name	OLAPARIB
D.3.9.4	EV Substance Code	SUB32234
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.3.11 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	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	olaparib
D.3.2	Product code	AZD2281
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	OLAPARIB
D.3.9.1	CAS number	763113-22-0
D.3.9.3	Other descriptive name	OLAPARIB
D.3.9.4	EV Substance Code	SUB32234
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	100
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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Adjuvant breast cancer

Adyuvancia en cáncer de mama

E.1.1.1

Medical condition in easily understood language

Breast cancer

Cáncer de mama

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	17.0
E.1.2	Level	PT
E.1.2	Classification code	10006187
E.1.2	Term	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

Efficacy of adjuvant treatment with olaparib on Invasive Disease Free Survival (IDFS).

evaluar el efecto del tratamiento adyuvante con olaparib sobre la supervivencia libre de enfermedad infiltrante (SLEI).

E.2.2

Secondary objectives of the trial

- Efficacy of adjuvant treatment with olaparib on overall survival (OS).
- Efficacy of adjuvant treatment with olaparib on Distant Disease Free Survival (DDFS)
- Efficacy of adjuvant treatment with olaparib on the incidence of new invasive breast primary cancer and/or new epithelial ovarian cancer.
- Efficacy of olaparib on patient reported outcomes using the FACIT fatigue scale and EORTC QLQ-C30 QoL scale.
- Efficacy of olaparib in patients identified as having a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (gene sequencing and large rearrangement analysis).

- Evaluar el efecto del tratamiento adyuvante con olaparib sobre la supervivencia global (SG)
- Evaluar el efecto de tratamiento adyuvante con olaparib sobre la supervivencia libre de enfermedad a distancia (SLED)
- Evaluar el efecto del tratamiento adyuvante con olaparib sobre la incidencia de nuevo cáncer primario de mama infiltrante y/o nuevo cáncer epitelial de ovario
- Evaluar el efecto de olaparib sobre los resultados comunicados por los pacientes usando la escala FACIT-fatiga y la escala de calidad de vida relacionada con la salud (CdV-RS QLQ-C30) de la EORTC
- Evaluar la eficacia de olaparib en pacientes identificados como portadores de una variante deletérea o de la que se sospeche que sea deletérea en cualquiera de los genes BRCA usando variantes identificadas con estudios de mutación germinal de BRCA actuales y futuros (análisis de secuenciación de genes y de grandes reordenamientos)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Histologically confirmed non-metastatic primary triple negative invasive adenocarcinoma of the breast.
-Invasive TNBC
-Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function).
- Completed adequate breast and axilla surgery. Completed at least 6 cycles neoadjuvant or adjuvant chemotherapy containing anthracyclines, taxanes or the combination of both. Prior platinum as potentially curative treatment for prior cancer (e.g. ovarian) or as adjuvant or neoadjuvant treatment for breast cancer is allowed.
-ECOG 0-1.

- Adenocarcinoma de mama primario infiltrante, triple negativo, no metastásico, confirmado histológicamente
- CMTN infiltrante
- Mutación documentada de BRCA1 o BRCA2 que se predice que es deletérea o se sospecha que es deletérea (se sabe o se predice que es perjudicial/conduce a pérdida de la función de la proteína)
- Sometidos a cirugía adecuada de la mama y la axila
- Han terminado al menos 6 ciclos de quimioterapia neoadyuvante o adyuvante con antraciclinas, taxanos o la combinación de ambos. Se permite el tratamiento potencialmente curativo con platino para cáncer previo (p. ej., ovario) o como tratamiento adyuvante o neoadyuvante para el cáncer de mama
- Estado funcional del ECOG 0-1

E.4

Principal exclusion criteria

- Any previous treatment with a PARP inhibitor, including olaparib and/or known hypersensitivity to any of the
excipients of study treatment.
- Patients with second primary cancer, EXCEPTIONS: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, Ductal Carcinoma in situ (DCIS) of the breast, stage 1 grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ? 5 years prior to randomization. More than one course of chemotherapy for previous malignancies.
-Resting ECG with QTc > 470 msec detected on 2 or more time points within a 24 hour period or family history of long QT syndrome. If ECG demonstrates QTc >470 msec, patient will be eligible only if repeat ECG demonstrates QTc ?470 msec.
- Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.-Whole blood transfusions in the last 120 days prior to entry to the study which may interfere with gBRCA testing

- pacientes con algún tratamiento previo con PARP inhibidor, incluido olaparib y /o hipersensibilidad conocida a cualquiera de excipientes del tratamiento del estudio.
-Pacientes con un segundo cáncer primario, excepciones: carcinoma cutáneo no melanoma tratado adecuadamente, cáncer de cérvix in situ tratado curativamente, carcinoma ductal in situ (CDIS) de la mama, carcinoma endometrial de grado 1, estadio 1 u otros tumores sólidos incluidos los linfomas (sin afectación de la médula ósea) tratados de forma curativa sin pruebas de enfermedad durante ? 5 años antes de la aleatorización. Más de una línea de quimioterapia para tumores malignos previos (p. ej., cáncer de mama o cáncer de ovario hace > 5 años tratado con quimioterapia adyuvante)
-ECG en reposo con QTc > 470 ms detectado en 2 o más momentos dentro de un periodo de 24 h o antecedentes familiares de síndrome de QT largo. Si el ECG demuestra QTc >470 ms, el paciente será elegible sólo si la repetición del ECG demuestra QTc ?470 ms
- Uso simultáneo de inhibidores potentes conocidos de CYP3A4 como ketoconazol, itraconazol, ritonavir, indinavir, saquinavir, telitromicina, claritromicina y nelfinavir
- Transfusiones de sangre entera en los últimos 120 días antes de la entrada en el ensayo que puedan interferir con las pruebas de gBRCA

E.5 End points

E.5.1

Primary end point(s)

Invasive Disease Free Survival (IDFS)

supervivencia libre de enfermedad invasiva

E.5.1.1

Timepoint(s) of evaluation of this end point

Recurrent/new cancers assessments will be performed at day 1, weeks 12, 24, 38, 52. In follow-up period in year 2 every 3 months, in year 3, 4,5 every 6 months and year 6 to 10 every 12 months. MRI to be performed every 12 months after the 6 months scan.

Recurrentes / nuevas evaluaciones de los cánceres se llevarán a cabo en el día 1, semana 12, 24, 38, 52. En período de seguimiento en el año 2 cada 3 meses, en el año 3, 4,5 cada 6 meses y de 6 a 10 años cada 12 meses. Resonancia magnética para realizarse cada 12 meses después de la exploración 6 meses.

E.5.2

Secondary end point(s)

1. Efficacy of adjuvant treatment with olaparib on overall survival (OS).
2. Efficacy of adjuvant treatment with olaparib on Distant Disease Free Survival (DDFS)
3. Efficacy of adjuvant treatment with olaparib on the incidence of new invasive breast primary cancer and/or new epithelial ovarian cancer.
4. Efficacy of olaparib on patient reported outcomes using the FACIT fatigue scale and EORTC QLQ-C30 QoL scale.
5. Efficacy of olaparib in patients identified as having a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (gene sequencing and large rearrangement analysis).

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Day 1, 15, 29 week 8,12,16,20,24,38,52, 30 days after last dose of study medication, in year 2 every 3 months, in year 3, 4,5 every 6 months and above year 6 every 12 months
2 & 3.Physical examination will be performed at day 1, weeks 12, 24, 38, 52. In follow-up period in year 2 every 3 months, in year 3, 4,5 every 6 months and year 6 to 10 every 12 months. MRI to be performed every 12 months after the 6 months scan
4.EORTC QLQ-C30 and FACIT-Fatigue scale will be collected prior randomization, at weeks 24 and 52 and also every 6 months during the 2nd year post randomisation (months 18 and 24 only).
5. Within 15 years from last subject last visit

1. Días 1, 15, 29, semana 8,12,16,20, 24, 38, 52, 30 días después de l última dosis de medicación del estudio, en el año 2 cada 3 meses, en el año 3, 4, cada 6 meses y a partir del año 6 cada 12 meses.
2&3. los exámenes físicos se realizaran el día 1, semana 12, 24, 38, 52. en el periodo de seguimiento en el año 2 cada tres meses, en el año 3, 4, 5 cada 6 meses y desde el año 6 hasta el año 10 cada 12 meses. MRI se realizaran cada 12 meses después de 6 meses de exploración.
4. EORTC QLQ-C30 and FACIT-escala de fatiga, se realizaran antes de la randomización, en la semana 24 y 52 y también cada 6 meses durante el segundo año de la randomización ( solo los meses 18 y 24)
5. dentro de los 15 años tras la ultima visita del último paciente

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

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)

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

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)

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

224

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

Argentina

Australia

Austria

Belgium

Canada

China

France

Germany

Israel

Italy

Japan

Korea, Republic of

Netherlands

Poland

Portugal

Spain

Sweden

Switzerland

Taiwan

United Kingdom

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

Last subject last visit

última visita del ultimo 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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

660

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

660

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

873

F.4.2.2

In the whole clinical trial

1320

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)

Standard of care

tratamiento estandar

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Breast International Group (BIG)
G.4.3.4	Network Country	Belgium

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-07-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-14

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

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