Clinical Trials Register

Summary
EudraCT Number:	2016-001314-25
Sponsor's Protocol Code Number:	PEMBRACA
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:	2020-12-11
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

2016-001314-25

A.3

Full title of the trial

A phase II study of Pembrolizumab plus Carboplatin in BRCA-related metastatic breast cancer

Studio di Fase II della combinazione di Pembrolizumab e Carboplatino nelle pazienti con tumore della mammella metastatico con mutazione BRCA

A.3.1

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

A phase II study of Pembrolizumab plus Carboplatin in BRCA-related metastatic breast cancer

Studio di Fase II della combinazione di Pembrolizumab e Carboplatino nelle pazienti con tumore della mammella metastatico con mutazione BRCA

A.3.2

Name or abbreviated title of the trial where available

PEMBRACA

A.4.1

Sponsor's protocol code number

PEMBRACA

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 OSPEDALIERO-UNIVERSITARIA DI MODENA
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	MERCK SHARP & DOHME CORP
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Azienda Ospedaliero-Universitaria di Modena
B.5.2	Functional name of contact point	Clinical Trials Quality Team
B.5.3	Address:
B.5.3.1	Street Address	Via del Pozzo 71
B.5.3.2	Town/ city	Modena
B.5.3.3	Post code	41124
B.5.3.4	Country	Italy
B.5.4	Telephone number	0594225868
B.5.5	Fax number	0594224369
B.5.6	E-mail	ricercarcainnovazione@policlinico.mo.it

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	Pembrolizumab
D.3.2	Product code	[MK-3475]
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	PEMBROLIZUMAB
D.3.9.1	CAS number	1374853-91-4
D.3.9.2	Current sponsor code	-
D.3.9.3	Other descriptive name	PEMBROLIZUMAB
D.3.9.4	EV Substance Code	SUB167136
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	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)	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	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

BRCA-related metastatic breast cancer

pazienti affetti da tumore mammario (BC) avanzato con mutazione BRCA1/2 germline

E.1.1.1

Medical condition in easily understood language

BRCA-related metastatic breast cancer

pazienti affetti da tumore mammario (BC) avanzato con mutazione BRCA1/2 germline

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	10006178
E.1.2	Term	Breast adenocarcinoma 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

The objective response rate (ORR)

il tasso di risposte obiettive (ORR)

E.2.2

Secondary objectives of the trial

- The time to progression (TTP)
- The duration of response (DOR)
- The Disease Control Rate (DCR)
- The overall survival (OS)
- Assessment biological parameters of PD-1+TILs
-

- il tempo alla progressione (TTP)
- la durata della risposta (DOR)
- il tasso di controllo della malattia (DCR)
- la sopravvivenza globale (OS)
- Valutazione dei parametri biologici di PD-1 +TILs
-

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Be willing and able to provide written informed consent/assent for the trial.
2. Be ¿ 18 years of age on day of signing informed consent.
3. Patients must have metastatic confirmed breast cancer
4. Disease progression by radiological techniques within 12 months prior to signing informed consent
5. Documented mutation in BRCA1 or BRCA2 genes that is predicted to be deleterious or suspected deleterious (unknown significance variants)
6. Have measurable disease based on RECIST 1.1.
7. Prior chemotherapy with anthracyclines and taxanes has to be administered in neoadjuvant or adjuvant setting.
8. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen
9. Have a performance status of 0 or 1 on the ECOG Performance Scale.
10. Life expectancy of greater than 3 months
11. Demonstrate adequate organ function as defined. All screening labs should be performed within 10 days of treatment initiation.

1. Accettare la partecipazione ed essere capace di fornire consenso/assenso informato scritto al trial
2. Essere maggiorenne (18 anni compiuti) il giorno della firma del consenso informato
3. Avere diagnosi confermata di tumore mammario metastatico
4. Avere malattia in progressione alla valutazione radiologica entro 12 mesi dalla firma del consenso informato
5. Avere una mutazione documentata del gene BRCA1 o BRCA2 che sia considerata patogenetica o sospetta patogenetica (variante di incerto significato)
6. Avere malattia misurabile sulla base dei criteri RECIST 1.1
7. Essere stato precedentemente sottoposto a chemioterapia con antracicline e taxani nel setting neoadiuvante o adiuvante
8. Accettare di fornire tessuto di una lesione tumorale recentemente biopsiata tramite ago-biopsia o biospia escissionale. “Recentemente biopsiata” significa prelevata entro 6 settimane (42 giorni) prima dell’inizio del trattamento il Giorno 1. Nei soggetti per cui non è possibile ottenere un campione recentemente biopsiato (es. lesione inaccessibile o preoccupazioni per quanto riguarda la sicurezza del paziente nella proceduta) può essere sottomesso un campione archiviato
9. Avere un performance status di 0 o 1 secondo l’ECOG Performance Scale
10. Avere aspettativa di vita superiore a 3 mesi
11. Dimostrare adeguata funzione d’organo. Tutti gli screening di laboratorio dovrebbero essere effettuati entro 10 giorni dall’inizio del trattamento.

E.4

Principal exclusion criteria

1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
2. Has a benign variant of BRCA1/2 genes
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
4. Has a known history of active TB (Bacillus Tuberculosis)
5. Hypersensitivity to pembrolizumab or any of its excipients.
6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., = Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., = Grade 1 or at baseline) from adverse events due to a previously administered agent.
- Note: Subjects with = Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
- Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
8. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
9. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
10. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
11. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
12. Has an active infection requiring systemic therapy.
13. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
19. Has received a live vaccine within 30 days of planned start of study therapy.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

1. Contemporanea o precedete partecipazione a un trial clinico che prevede l’assunzione della terapia in studio o altro intervento sperimentale entro le 4 settimane dall’inizio del trattamento in studio
2. Presenza di una variante benigna dei geni BRCA1/2
3. Diagnosi di immunodeficienza o terapia cortico-steroidea o altra forma di terapia immunosoppressiva entro 7 giorni dalla prima dose del trattamento in studio
4. Storia nota di tubercolosi attiva (Bacillus Tubercolosis)
5. Ipersensibilità al pembrolizumab o a uno dei suoi eccipienti
6. Somministrazione di anticorpo monoclonale anti-tumorale entro 4 settimane dal Giorno 1 dello studio o in caso di non completo recupero (es. tossicità di grado 1 o superiore al baseline) da eventi avversi causati da farmaci somministrati più di 4 settimane prima
7. Somministrazione di chemioterapia, terapia targeted a bersaglio molecolare o radioterapia entro 2 settimane dal Giorno 1 dello studio o in caso di non completo recupero (es. tossicità di grado 1 o superiore al baseline) da eventi avversi causati da trattamenti somministrati in precedenza.
- Nota: soggetti con neuropatia G2 o inferiore sono da escludersi da questo criterio e possono essere considerati per lo studio
- Nota: se un soggetto è stato sottoposto a chirurgia maggiore, deve aver recuperato adeguatamente dalla tossicità e/o dalle complicanze legate all’intervento prima di iniziare la terapia
8. Presenza di altra neoplasia che è in progressione o che richiede trattamento attivo, ad eccezione del carcinoma basocellulare o squamocellulare della cute sottoposto a trattamento potenzialmente curativo o il tumore in situ della cervice uterina.
9. Presenza di metastasi attive del SNC e/o carcinomatosi meningea. Soggetti con metastasi cerebrali in precedenza trattate possono partecipare quando viene documentata stabilità di malattia (non segni di progressione radiologica almeno 4 settimane prima della prima dose di trattamento in studio e nessun sintomo neurologico al baseline), a condizione che non abbiano lesioni cerebrali nuove o in crescita e che non abbiano utilizzato steroidi per almeno 7 giorni prima dell’inizio del trattamento in studio. Questa eccezione non include la carcinomatosi meningea che è esclusa dallo studio a prescindere dalla stabilità clinica.
10. Presenza di patologia autoimmune attiva che ha richiesto trattamento sistemico negli ultimi 2 anni (es. utilizzo di agenti biologici, corticosteroidi o farmaci immunosoppressori). La terapia sostitutiva (es. tiroxina, insulina o terapia sostitutiva corticosteroidea fisiologica per insufficienza adrenocorticale o pituitaria, etc.) non è considerata una forma sistemica di trattamento.
11. Storia di polmonite (non infettiva) che richiede steroidi o polmonite attiva.
12. Infezione attiva che richiede una terapia sistemica.
13. Presenza attuale o passata di qualsiasi condizione, terapia o alterazione di un valore di laboratorio che possa rappresentare un fattore di confondimento per i risultati dello studio, interferire con la partecipazione del soggetto alla totale durata dello studio o che, a opinione dell’investigatore, rappresenta una ragione per cui la partecipazione allo studio non è nel miglior interesse del soggetto.
14. Patologie psichiatriche o abuso di sostanze che potrebbero interferire con la compliance al trial.
15. Gravidanza, allattamento o ricerca di una gravidanza per tutta la durata prevista dello studio, a cominciare dalla fase di pre-screening o visita di screening fino a 120 giorni dopo l’ultima dose del trattamento in studio.
16. Precedente trattamento con un agente anti-PD1, anti-PDL1, o anti-PDL2.
17. Anamnesi positiva per HIV (anticoropi HIV1/HIV2)
18. Anamnesi positiva per Epatite B (HBsAg reattivo) o Epatite C (HCV RNA [qualitativo] rilevato) attive.
19. Somministrazione di vaccino vivo entro 30 giorni dall’inizio pianificato della terapia in studio.

E.5 End points

E.5.1

Primary end point(s)

The objective response rate (ORR) (complete response plus partial response) will be evaluated according to RECIST criteria

tasso di risposte obiettive (ORR) (risposte complete + risposte parziali) valutato in accordo con i criteri RECIST

E.5.1.1

Timepoint(s) of evaluation of this end point

every cycle in phase COMBO / every 4 cycle in phase MONO

ogni 3 cicli nella fase COMBO / ogni 4 cicli nella fase MONO

E.5.2

Secondary end point(s)

The time to progression (TTP) will be calculated as the interval between the enrolment and the occurrence of local tumor progression (including ipsilateral and contra-lateral breast) or distant tumor progression; The duration of response (DOR) will be measured from the time of the first ORR is recorded to the date of progression is objectively documented.; The Disease Control Rate (DCR) will be evaluated as the percentage of patients with ORR and stable disease; The overall survival (OS) will be calculated as the interval between the enrolment and the death from any cause or the last date the patient was known to be alive; The biological parameters of PD-1+TILs will be evaluated by immunohistochemistry on primary surgical specimen, and, when evaluable, on metastatic biopsy.

tempo alla progressione (TTP) calcolato come il tempo tra l’arruolamento e la progressione di malattia; la durata della risposta (DOR) misurata dal tempo della prima ORR registrata e la data di progressione obiettivamente documentata; il tasso di controllo della malattia (DCR) valutato come la percentuale di pazienti con ORR e malattia stabile; sopravvivenza globale (OS) considerata come l’intervallo tra l’arruolamento e la morte o l’ultima data in cui il paziente è stato registrato come in vita.; parametro biologico dei PD-1 + TILs sarà valutato tramite immunoistochimica sul campione chirurgico primario e, quando valutabile sulla biopsia della metastasi.

E.5.2.1

Timepoint(s) of evaluation of this end point

every cycle in phase COMBO / every 4 cycle in phase MONO; every cycle in phase COMBO / every 4 cycle in phase MONO; every cycle in phase COMBO / every 4 cycle in phase MONO; interval between the enrolment and the death; screening

ogni 3 cicli nella fase COMBO / ogni 4 cicli nella fase MONO; ogni 3 cicli nella fase COMBO / ogni 4 cicli nella fase MONO; ogni 3 cicli nella fase COMBO / ogni 4 cicli nella fase MONO; intervallo tra l’arruolamento e la morte; screening

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

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

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.8.2.4

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

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)

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

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)

the best Therapy available

la miglior terapia disponibile

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

2018-10-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-09-24

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

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