Clinical Trials Register

Summary
EudraCT Number:	2015-000298-11
Sponsor's Protocol Code Number:	ISS22810078
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-12-18
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2015-000298-11

A.3

Full title of the trial

A phase II, open label, controlled study of olaparib in locally advanced ER, PgR and HER2 negative (Triple Negative) and in locally advanced germline BRCA mutation-positive breast cancer patients: biological evaluation from a ¿window of opportunity¿ trial

A.3.1

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

Study with olaparib in patients with locally advanced breast cancer triple negative or with mutations

Studio con olaparib in pazienti con tumore mammario localmente avanzato triplo negativo o con mutazioni

A.3.2

Name or abbreviated title of the trial where available

OLTRE

A.4.1

Sponsor's protocol code number

ISS22810078

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	AZIENDA OSPEDALIERA "ISTITUTI OSPITALIERI" DI CREMONA
B.1.3.4	Country	Italy
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	Astrazeneca
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	ARCO Onlus
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	Peter MacCallum Cancer Centre
B.4.2	Country	Australia
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	A.O. Istituti Ospitalieri di Cremona
B.5.2	Functional name of contact point	US Terapia Molecolare e Farmacogeno
B.5.3	Address:
B.5.3.1	Street Address	Viale Concordia, 1
B.5.3.2	Town/ city	Cremona
B.5.3.3	Post code	26100
B.5.3.4	Country	Italy
B.5.4	Telephone number	0372408042
B.5.5	Fax number	0372405172
B.5.6	E-mail	daniele.generali@gmail.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	Capsule, hard
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.3.9.2	Current sponsor code	AZD2281
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Locally advanced breast cancer

Tumore mammario localmente avanzato

E.1.1.1

Medical condition in easily understood language

Locally advanced breast cancer

Tumore del seno diffuso localmente

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10072740
E.1.2	Term	Locally advanced breast 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

Correlation between baseline gene and protein expression profile and clinical response evaluated after a short administration of olaparib alone at three weeks to examine baseline patterns of gene and protein expression for potential early predictors of response or non-response to the administered treatment in triple negative locally advanced breast cancer compared to all subtype of BC carrying gBRCAmut.

Correlazione tra il profilo di espressione genica e proteica basale e risposta clinica valutata dopo una somministrazione di Olaparib di tre settimane per individuare potenziali fattori predittivi di risposta o resistenza al trattamento somministrato nel tumore mammario localmente avanzato triplo negativo confrontato con tumori mammari localmente avanzati portatori di gBRCAmut.

E.2.2

Secondary objectives of the trial

1) To assess of overall response rate evaluated clinically in each treatment group.
2) To correlate between baseline mutations, gene and protein expression profile and clinical response.
3) To assess genetic and non-genetic biomarkers relating to treatment efficacy. Tumor mutations may be explored including somatic BRCA1 and 2 mutations, reversion mutations, loss of heterozygosity as well as genome landscape and transcriptional or functional measures of homologous recombination (HR) deficiency).
4) To correlate between baseline mutations, gene and protein expression profile and PET-TC Scan and/or Breast TC response after a short administration of olaparib measured at three weeks to examine baseline patterns of gene expression for potential early predictors of response or non-response to olaparib.

1) Valutare di tasso di risposta globale (valutate clinicamente) in ciascun gruppo di trattamento.
2) Correlare lo stato mutazionale basale e risposta clinica.
3) Valutare biomarcatori genetici e non in relazione all¿efficacia del trattamento: mutazioni somatiche di BRCA1 e 2, mutazioni di ricombinazione, perdita di eterozigosi.
4) Correlare lo stato mutazionale, genico e proteico basale con PET-TC Scan e/o la risposta TC dopo una somministrazione di Olaparib di tre settimane.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients (female) must be 18 years of age.
- Germline BRCA1 or BRCA2 mutation that is considered deleterious or suspected deleterious for the control arm.
- Measurable disease according to RECIST criteria v. 1.1.
- ECOG performance status 0-1.
- Patient able to swallow and maintain oral caps.
- Patients must have a life expectancy = 16 weeks.
- Non-childbearing or breast feeding patients. Female patient of childbearing potential must have a negative serum pregnancy test (ß-human chorionic gonadotropin [ß-hCG]) within 72 hours prior to the first dose).
Patients of child bearing potential and their partners with whom they are sexually active must agree to the use of 2 highly effective forms of contraception from the allocation into the study, throughout the study and until 3 months after the last dose of study drug.
Women are considered of childbearing potential if they are not post-menopausal, free from menses for > 1 year or surgically sterilized.
- Absence of psychological, familiar, sociologic or geographic conditions that may interfere with study protocol adherence and follow-up program. These conditions must be discussed with the patient before the entry into the study.
- Patients should acknowledge that they are at an increased risk of infection with conventional chemotherapy drugs and since the effects with Olabarib are unknown they must accept that live virus and bacterial vaccines should not be administered to them for the duration of the study and for 3 months after last dose of study medication. If patients are blood donors they should accept not to donate blood during the study and for 3 months after the last dose of study drug.
- Patients must have voluntarily agreed to participate by given informed consent. Written informed consent must be dated and signed by both patients and investigator.

- Pazienti (donne) di età =18 anni.
- Mutazione germinale di BRCA1 o BRCA2 considerata deleteria o sospetta deleteria per il braccio di controllo.
- Malattia misurabile in base ai criteri RECIST v. 1.1.
- Indice di performance ECOG pari a 0-1.
- Pazienti in grado di deglutire e trattenere compresse orali.
- Pazienti con aspettativa di vita = 16 settimane.
- Le pazienti non devono essere in gravidanza o allattamento. Le pazienti in età fertile devono presentare risultato negativo a un test di gravidanza su siero (ß-gonadotropina corionica umana [ß-hCG]) effettuato nelle 72 ore precedenti la prima dose.
Le pazienti in età fertile sessualmente attive e i rispettivi partner devono acconsentire a utilizzare 2 metodi di contraccezione altamente efficaci per l’intera durata dello studio a partire dalla randomizzazione e fino a 3 mesi successivi all’ultima dose di farmaco in studio.
Le pazienti sono considerate in età fertile se non sono in post-menopausa, non presentano assenza di ciclo da >1 anno né sono chirurgicamente sterili.
- Assenza di condizioni psicologiche, familiari, sociologiche o geografiche in grado di interferire con l’aderenza al protocollo di studio e al programma di follow-up. Tali condizioni devono essere discusse con il/la paziente prima dell’ingresso nello studio.
- Le pazienti devono essere consapevoli che i farmaci chemioterapici convenzionali comportano un rischio maggiore di infezione e, poiché non sono noti gli effetti con olaparib, devono acconsentire a non essere inoculati con vaccini virali e batterici vivi per l’intera durata dello studio e nei 3 mesi successivi all’ultima dose di farmaco in studio.
- Le pazienti devono aver acconsentito volontariamente a prendere parte allo studio prestando il consenso informato.

E.4

Principal exclusion criteria

- Previous enrolment in the present study
- Participation in another clinical study with an investigational product during the last 12 months
- Any previous treatment with a PARP inhibitor, including olaparib.
- Patients with-out any sign or symptoms of distant metastases.
- Major surgery within 14 days of starting study treatment and patients must have recovered from any effects of any major surgery.
- Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord compression (untreated and unstable for at least 28 days prior to study entry), superior vena cava syndrome, extensive bilateral lung disease on HRCT scan or any psychiatric disorder that prohibits obtaining informed consent.
- Immunocompromised patients (e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy).
- Patients with known active hepatic disease (i.e., Hepatitis B or C).
- Patients with a known hypersensitivity to olaparib or any of the excipients of the product.

- Precedente arruolamento nel presente studio.
- Partecipazione in un altro studio clinico con un farmaco sperimentale negli ultimo 12 mesi.
- Trattamento precedente con un inibitore della PARP, incluso olaparib.
- Pazienti con segni o sintomi di metastasi a distanza.
- Intervento di chirurgia maggiore nelle 2 settimane precedenti l’ingresso nello studio. Prima dell’arruolamento i pazienti devono essersi ristabiliti da precedenti interventi di chirurgia maggiore.
- Pazienti considerati ad alto rischio medico a causa di una malattia seria non controllata, una patologia sistemica non maligna o un’infezione attiva non controllata. Esempi di questi disturbi includono, a titolo puramente indicativo, aritmia ventricolare non controllata, infarto miocardico recente (nei 3 mesi precedenti), disturbo convulsivo maggiore non controllato, compressione del midollo spinale instabile, sindrome della vena cava superiore o qualsiasi disturbo psichiatrico che impedisca di ottenere il consenso informato.
- Pazienti immunocompromessi (ovvero pazienti sieropositivi per il virus dell’immunodeficienza umana [HIV] e che stanno ricevendo terapia antivirale).
- Pazienti con nota malattia epatoca attiva (i.e. epatite B o C).
- Pazienti con ipersensibilità nota ai componenti di olaparib o di eventuali farmaci analoghi.

E.5 End points

E.5.1

Primary end point(s)

Relationship between the response to treatment and biological markers

Correlazione tra la risposta al trattamento e i marker biologici

E.5.1.1

Timepoint(s) of evaluation of this end point

After 21 days and before definitive surgery

Dopo 21 giorni e prima della chirurgia definitiva

E.5.2

Secondary end point(s)

Best response to treatment (CR, PR, SD, and PD)

Miglior risposta al trattamento (CR, PR, SD, and PD)

E.5.2.1

Timepoint(s) of evaluation of this end point

3 weeks

3 settimane

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

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

Yes

E.8.2.3.1

Comparator description

Stesso farmaco allo stesso disaggio in due gruppi di popolazione differenti (30 con tumore mammario

Same IMP at same dosage in two different groups of population (30 with locally advanced triple-negat

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

LVLS

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:

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

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

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)

Patients will be treated according to the local clinical practice of the centre

I soggetti riceveranno il trattamento in base alla pratica clinica locale del centro

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

2015-09-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-10

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

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