Clinical Trials Register

Summary
EudraCT Number:	2019-003465-18
Sponsor's Protocol Code Number:	BCT1902
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:	2021-10-07
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

2019-003465-18

A.3

Full title of the trial

A randomised phase II trial evaluating the efficacy of a nivolumab monotherapy lead in “window” or commencement of nivolumab concurrently with paclitaxel and carboplatin as neoadjuvant therapy in early stage triple negative breast cancers

Sperimentazione di fase II randomizzata per valutare l’efficacia di una “finestra” preliminare di monoterapia con nivolumab rispetto all’inizio della somministrazione di nivolumab in concomitanza con paclitaxel e carboplatino come terapia neoadiuvante nel cancro al seno triplo negativo allo stadio iniziale

A.3.1

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

Neoadjuvant Nivolumab and chemotherapy in stage I-II triple negative breast cancer.

Nivolumab neoadiuvante e chemioterapia nel TNBC allo
stadio I-II

A.3.2

Name or abbreviated title of the trial where available

Neo-N

A.4.1

Sponsor's protocol code number

BCT1902

A.5.4

Other Identifiers

Name:

ANZCTR

Number:

ACTRN12619001308189

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	Breast Cancer Trials
B.1.3.4	Country	Australia
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	Breast Cancer Trials, Australia and New Zealand
B.4.2	Country	Australia
B.4.1	Name of organisation providing support	Bristol-Myers Squibb
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	International Breast Cancer Study Group IBCSG
B.5.2	Functional name of contact point	Regulatory 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	+41315119400
B.5.5	Fax number	+41315119401
B.5.6	E-mail	regulatoryoffice@ibcsg.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	OPDIVO - 10 MG/ML- CONCENTRATO PER SOLUZIONE PER INFUSIONE- USO ENDOVENOSO- FLACONCINO (VETRO)- 10 ML- 1 FLACONCINO
D.2.1.1.2	Name of the Marketing Authorisation holder	BRISTOL-MYERS SQUIBB PHARMA EEIG
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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	Nivolumab
D.3.2	Product code	[Nivolumab]
D.3.4	Pharmaceutical form	Concentrate for solution for injection/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	NIVOLUMAB
D.3.9.2	Current sponsor code	BMS-936558-01
D.3.9.4	EV Substance Code	SUB122750
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	10
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)	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

Early stage triple negative breast cancer

cancro al seno triplo negativo allo stadio iniziale

E.1.1.1

Medical condition in easily understood language

Early stage triple negative breast cancer

cancro al seno triplo negativo allo stadio iniziale

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 efficacy of two parallel cohorts of the neoadjuvant immune-chemotherapy (Nivolumab lead in vs concurrent) combination in participants with TNBC primary breast cancer

Valutare l’efficacia della immunochemioterapia combinata neoadiuvante (nivolumab preliminare rispetto a nivolumab
concomitante) in due coorti parallele con partecipanti affette/i da
cancro al seno triplo negativo (TNBC) primario.

E.2.2

Secondary objectives of the trial

* To evaluate efficacy in the two cohorts in TNBC with higher TIL levels
* To evaluate efficacy in the two cohorts in TNBC that are PD-L1 positive
* To evaluate efficacy using other endpoints
* To investigate safety of the treatment combinations
* To determine associations between baseline TILs level as evaluated on diagnostic H&E slide and efficacy by cohort
* To determine associations between TIL values Days 8-14 by cohort and efficacy endpoints by cohort
* To determine association between change in TILs from baseline and Days 8-14 and efficacy endpoints by cohort
* To describe TIL levels in the persistent (residual) disease (ypINV Stage) according to RCB by cohort, and determine their associations with post-surgical outcomes

* Valutare l’efficacia in due coorti nel TNBC con livelli più elevati di linfociti infiltranti il tumore
* Valutare l’efficacia in due coorti nei TNBC PD-L1 positivi.
* Valutare l’efficacia utilizzando altri endpoint.
* Studiare la sicurezza e l’efficacia delle combinazioni terapeutiche.
* Determinare le associazioni tra il livello basale di TIL secondo la valutazione su vetrino con colorazione ematossilina/eosina e l’efficacia per coorte.
* Determinare le associazioni tra i valori di TIL al giorno 8-14 per coorte e gli endpoint di efficacia per coorte.
* Determinare l’associazione tra la variazione dei TIL dal basale al giorno 8-14 e gli endpoint di efficacia per coorte.
* Descrivere i livelli di TIL nella malattia persistente in base al carico tumorale residuo per coorte e determinare le loro associazioni con gli esiti postoperatori.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Female or male, age >= 18 years
2) ECOG performance status 0-1
3) Previously untreated non-metastatic (M0) TNBC meeting Stage I or II criteria as assessed by the local investigator on the basis of mammogram (MMG) and/or ultrasound (US) of the breasts, and US or clinical examination of the axilla
a) Stage I c T1c cN0; Stage IIA cT1 cN1; cT2 cN0; Stage IIB cT2 cN1; cT3 cN0
4) Clinically node positive participants should undergo computed tomography (CT) scan or PET CT of chest/abdomen (and bone scan if clinically indicated) to exclude metastases.
5) Non-metastatic, potentially operable, unilateral triple negative breast cancer, histologically defined as:
a) ER negative: with < 1% of tumour cells positive for ER by IHC irrespective of staining intensity AND
b) PR negative: with < 10% tumour cells positive for PR by IHC irrespective of staining intensity; AND
c) HER2 negative: IHC 0 or 1+, or ISH (FISH or SISH) negative
6) Able to start study treatment within 14 days of randomisation
7) Surgery able to be undertaken within 4 weeks of final dose of neoadjuvant IV therapy. Pre-operative radiation is not permitted for any participant with operable cancer after final study treatment
8) Adequate organ function. All screening laboratory tests should be performed within 14 days of randomisation.

1) Donna o uomo, età = 18 anni.
2) Performance status (stato di performance) dell’Eastern
Cooperative Oncology Group (ECOG) pari a 0 o 1.
3) TNBC non metastatico (M0) precedentemente non trattato
che soddisfa i criteri per lo stadio I o II secondo l’Atlante per
la stadiazione dei tumori maligni dell’AJCC, 8a Edizione, 2017,
secondo la valutazione dello sperimentatore locale sulla base
di mammografia (MMG) e/o ecografia (US) della mammella
ed ecografia o esame clinico dell’ascella.
a) Stadio I cT1c cN0;
Stadio IIA cT1 cN1; cT2 cN0;
Stadio IIB cT2 cN1; cT3 cN0.
b) È consentita solo la malattia controlaterale in situ;Breast Cancer Trials
Protocollo: BCT 1902 Neo-N Pagina 5 di 21
Modifica 2 alla versione del protocollo, 30 novembre 2020 CONFIDENZIALE
c) In caso di immagini anomale dell’ascella, lo stato
linfonodale deve essere confermato dalla citologia.
4) Le/I partecipanti con linfonodi clinicamente positivi devono
essere sottoposte/i a tomografia computerizzata (TC) o PETTC del torace/addome (e a scintigrafia ossea se clinicamente
indicato) per escludere metastasi. Le/I partecipanti con
riscontri incerti alla stadiazione devono sottoporsi a biopsie
per confermare o escludere, se possibile, una malattia
metastatica.
5) Cancro al seno triplo negativo unilaterale, non metastatico,
potenzialmente operabile, definito istologicamente
6) Soggetto in grado di iniziare il trattamento in studio entro 14
giorni dalla randomizzazione.
7) L’intervento chirurgico può essere eseguito entro 4 settimane
dalla terapia e.v. neoadiuvante finale. Non è consentita la
radioterapia preoperatoria per le/i partecipanti con tumore
operabile dopo il paclitaxel finale.
8) Funzionalità degli organi adeguata. Tutti gli esami di
laboratorio di screening devono essere eseguiti entro 14
giorni dalla randomizzazione.

E.4

Principal exclusion criteria

1) Confirmed presence of AJCC 8th Edition anatomic Stage 3 or 4 disease
2) Tumour of any size considered inoperable at presentation
3) Multifocal or bilateral invasive breast cancer
4) Has received prior chemotherapy, targeted therapy, radiation therapy, immunotherapy that target immune checkpoints, co-stimulatory or co-inhibitory pathways for T-cell receptors within the past 12 months
5) Will be offered neoadjuvant breast radiation therapy
6) Undergone or planned for sentinel lymph node biopsy before study therapy
7) Currently participating and receiving study therapy or has participated in a study of an investigational therapeutic agent and received study therapy within 4 weeks before randomisation.
Note: participant will be excluded if he/she received an investigational therapeutic agent with anticancer or anti-proliferative intent within the last 12 months
8) Any concurrent anti-neoplastic therapy (i.e. chemotherapy, hormonal therapy, immunotherapy, extensive, non-palliative radiation therapy, or standard or investigational agents for treatment of breast cancer) not already specified in the protocol
9) Prior malignancy active within the previous 3 years before randomisation, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
10) Other active malignancy requiring concurrent intervention
11) Has significant cardiovascular disease such as myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last 6 months, congestive cardiac failure NYHA classification IV or history of CHF NYHA III or IV

1) Presenza confermata di malattia in stadio 3 o 4 secondo
l’Atlante per la stadiazione dei tumori maligni dell’AJCC, 8a
edizione.
2) Tumore di qualsiasi dimensione ritenuto inoperabile alla
presentazione.
3) Cancro al seno multifocale o bilaterale invasivo.
4) La/Il partecipante ha ricevuto in precedenza chemioterapia,
terapia mirata, radioterapia o immunoterapia mirata ai
checkpoint immunitari o alle vie co-stimolatorie o co-inibitorie per i recettori dei linfociti T negli ultimi 12 mesi.
5) Pazienti a cui viene offerta una radioterapia mammaria
neoadiuvante.
6) Biopsia dei linfonodi sentinella già eseguita o pianificata prima
della terapia in studio.
7) Paziente che sta attualmente partecipando a una
sperimentazione e riceve la terapia in studio o ha partecipato
a una sperimentazione con un farmaco sperimentale e ha
ricevuto la terapia in studio o ha utilizzato un dispositivo
sperimentale entro 4 settimane prima della prima dose del
trattamento in studio.
8) Qualsiasi terapia antineoplastica concomitante (vale a dire
chemioterapia, terapia ormonale, immunoterapia,
radioterapia estensiva non palliativa o farmaci standard o
sperimentali per il trattamento del cancro al seno) non
prespecificata nel protocollo.
9) Tumori maligni pregressi attivi nei 3 anni precedenti la
randomizzazione, ad eccezione dei tumori trattabili
localmente che sono stati apparentemente curati come il
carcinoma basocellulare o squamocellulare, il cancro
superficiale della vescica o il carcinoma in situ della prostata,
della cervice o della mammella.
10) Altre neoplasie maligne attive non al seno che richiedono un
intervento concomitante.
11) Malattie cardiovascolari significative come infarto del
miocardio, sindrome coronarica acuta o angioplastica
coronarica/inserimento di stent/innesto di bypass negli ultimi
6 mesi, insufficienza cardiaca congestizia (CHF) di grado IV
secondo la classificazione della New York Heart Association
(NYHA) o CHF pregressa di grado III o IV NYHA.

E.5 End points

E.5.1

Primary end point(s)

Pathological complete response (pCR breast and nodes) as defined by ypT0/Tis/ypN0

Risposta patologica completa (pCR al seno e ai linfonodi) come definita da ypT0/Tis/ypN0

E.5.1.1

Timepoint(s) of evaluation of this end point

At the time of surgery

Al momento della chirurgia

E.5.2

Secondary end point(s)

* Pathological complete response (pCR as defined by ypT0/Tis/ypN0) in the higher TIL subgroup (%TIL on baseline H&E 30% or more)
* Pathological complete response (pCR as defined by ypT0/Tis/ypN0) in the PD-L1 positive subgroup (defined as 1% or more immune cell staining using the Ventana SP142 assay)
* Pathological complete response (pCR) in breast (ypT0/Tis)
* Residual cancer burden (RCB)0/1
* Tumour response by WHO Criteria
* Ki67 proliferation marker changes between baseline and surgery
* Safety and tolerability as documented according to NCI-CTCAE V5.0
* Event free survival and overall survival over a 3-year period

* Risposta patologica completa (pCR secondo la definizione di ypT0/Tis/ypN0) nel sottogruppo TIL più elevato (%TIL al basale H&E 30% o più)
* Risposta patologica completa (pCR come definita da ypT0/Tis/ypN0) nel sottogruppo PD-L1 positivo (definito come 1% o più di colorazione delle cellule immunitarie utilizzando il test Ventana SP142)
* Risposta patologica completa (pCR) nel seno (ypT0/Tis)
* Carico tumorale residuo (RCB) 0/1
* Risposta tumorale secondo i criteri OMS
* Cambiamenti del marker di proliferazione Ki67 tra il basale e l'intervento chirurgico
* Sicurezza e tollerabilità documentate secondo NCI-CTCAE V5.0
* Sopravvivenza libera da eventi e sopravvivenza globale su un periodo di 3 anni

E.5.2.1

Timepoint(s) of evaluation of this end point

* At surgery
* At surgery
* At surgery
* At surgery
* At surgery
* At surgery
* Adverse events documented from the time of informed consent to 100 days after the last dose of Nivolumab or 30 days after the last dose of neoadjuvant chemotherapy, whichever is later
* Time from randomisation to time of an invasive breast cancer event, assessed for up to 3 years post-randomisation

* All'intervento chirurgico
* All'intervento chirurgico
* All'intervento chirurgico
* All'intervento chirurgico
* All'intervento chirurgico
* All'intervento chirurgico
* Eventi avversi documentati dal momento del consenso informato fino a 100 giorni dopo l'ultima dose di Nivolumab o 30 giorni dopo l'ultima dose di chemioterapia neoadiuvante, a seconda di quale sia la più recente
* Tempo dalla randomizzazione al momento di un evento invasivo di cancro al seno, valutato fino a 3 anni dopo la randomizzazione

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

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

Nivolujmab monoterapia piombo in "finestra" o l'inizio di nivolumab in concomitanza con la chemioter

Nivolujmab monotherapy lead in "window" or commencement of nivolumab concurrently with chemotherapy

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

Information not present in EudraCT

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

Australia

Belgium

Italy

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

A participant is considered to have completed the study if he/she has completed all phases of the study including the End of Treatment Visit and Survival Follow up data has been collected.

Si considera che un partecipante abbia completato lo studio se ha completato tutte le fasi dello studio, compresa la visita di fine trattamento e se sono stati raccolti i dati di follow-up della sopravvivenza.

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

108

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 care as discussed with doctor.

Il trattamento sarà alla discrezione del medico curante.

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

2021-10-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-09-22

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

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