Clinical Trials Register

Summary
EudraCT Number:	2018-001423-40
Sponsor's Protocol Code Number:	CA045-001
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:	2021-06-08
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-001423-40

A.3

Full title of the trial

A Phase 3, Randomized, Open-label Study of NKTR-214 Combined with Nivolumab Versus Nivolumab in Participants with Previously Untreated Unresectable or Metastatic Melanoma

Studio di fase 3, randomizzato, in aperto, di NKTR-214 in combinazione con Nivolumab rispetto a Nivolumab in partecipanti affetti da melanoma metastatico o non resecabile, non precedentemente trattato

A.3.1

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

A Study of NKTR-214 Combined With Nivolumab vs Nivolumab Aone in
Participants With Previously Untreated Inoperable or Metastatic Melanoma

Studio di NKTR-214 combinato con Nivolumab vs Nivolumab Alone in Partecipanti affetti da melanoma metastatico o non resecabile, non precedentemente trattato.

A.3.2

Name or abbreviated title of the trial where available

17-214-08

A.4.1

Sponsor's protocol code number

CA045-001

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	BRISTOL-MYERS SQUIBB INTERNATIONAL CORPORATION
B.1.3.4	Country	Belgium
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	Bristol-Myers Squibb International Corporation
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Bristol-Myers Squibb International Corporation
B.5.2	Functional name of contact point	GCT-SU
B.5.3	Address:
B.5.3.1	Street Address	Parc de l'Alliance - Avenue de Finlande, 4
B.5.3.2	Town/ city	Braine-l'Alleud
B.5.3.3	Post code	1420
B.5.3.4	Country	Belgium
B.5.6	E-mail	clinical.trials@bms.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	Yes
D.2.1.1.1	Trade name	Opdivo (100 mg/ 10 ml)
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma
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 - 10ml vial - COMMERCIAL
D.3.2	Product code	[BMS-936558]
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	Nivolumab
D.3.9.1	CAS number	946414-94-4
D.3.9.2	Current sponsor code	BMS-936558
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB32944
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.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	NKTR-214 - 1 mg vial
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
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.3.9.1	CAS number	1939126-74-5
D.3.9.2	Current sponsor code	NKTR-214
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB192964
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	1
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

Untreated unresectable or metastatic melanoma

melanoma non resecabile o metastatico non precedentemente trattato

E.1.1.1

Medical condition in easily understood language

Untreated inoperable or metastatic melanoma

melanoma non operabile o metastatico non precedentemente trattato

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	10027481
E.1.2	Term	Metastatic melanoma
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 purpose of this study is to determine whether an investigational immunotherapy NKTR-214, when combined with nivolumab, is more effective than nivolumab by itself in participants with unresectable or metastatic melanoma that is previously untreated

Lo scopo di questo studio è di determinare se l’immunoterapia con NKTR-214, quando combinato con nivolumab, è più efficace di nivolumab da solo nei partecipanti con melanoma non resecabile o metastatico che non è stato precedentemente trattato

E.2.2

Secondary objectives of the trial

- To evaluate efficacy of NKTR-214 combined
with nivolumab and that of nivolumab
monotherapy
- To evaluate the association between PD-L1
tumor expression on tumor cells (= 1% or < 1%/indeterminate) and efficacy measures
including PFS and ORR by BICR and OS.
-To evaluate the safety and tolerability of
NKTR-214 combined with nivolumab and
that of nivolumab monotherapy

- Valutare l'efficacia di NKTR-214 combinato con nivolumab e quello di nivolumab in monoterapia
- Valutare l'associazione tra l’espressione tumorale del PD-L1 sulle cellule tumorali (= 1% o <1% / indeterminato) e le misure di efficacia compresi PFS e ORR tramite BICR e OS.
-Per valutare la sicurezza e la tollerabilità di NKTR-214 combinato con nivolumab e quello di Nivolumab in monoterapia

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Pharmacogenetics
Version: 1
Date: 24/05/2018
Title: A Phase 3, Randomized, Open-label Study of NKTR-214 Combined with Nivolumab Versus Nivolumab in Participants with Previously Untreated Unresectable or Metastatic Melanoma
Objectives: Ricerca addizionale facoltativa – vedere sez 9.8.1 del protocollo: questo protocollo includerà la conservazione dei campioni residui per la ricerca addizionale (AR) La ricerca addizionale è facoltativa per tutti i partecipanti allo studio, salvo dove la conservazione e / o la raccolta dei campioni siano vietate da leggi o regolamenti locali, dai Comitati etici o dai requisiti istituzionali. Questa raccolta per la ricerca addizionale ha lo scopo di espandere la capacità traslazionale di ricerca e sviluppo di Bristol-Myers Squibb e supporterà scopi di ricerca non ancora definiti che miglioreranno la comprensione delle malattie e delle opzioni per il trattamento. Potrebbe anche essere utilizzata per sostenere le richieste dell'autorità sanitaria per l'analisi e l'avanzamento dello sviluppo farmacodiagnostico, al fine di meglio identificare i farmaci migliori per i giusti pazienti. Questo può anche includere l'esplorazione genetica / genomica finalizzata ad esplorare i percorsi della malattia, la progressione e la risposta al trattamento - Eastern Cooperative Oncology Group (ECOG) performance status of </=1 (adults 18 years or older)/ Lansky Performance Score >/= 80% (minors ages 12-17 only) - Histologically confirmed stage III (unresectable) or stage IV melenoma - Treatment-naive participants (ie, no prior systemic anticancer therapy for unresectable or metastatic melanoma) with the exception of prior adjuvant treatment E.

Farmacogenetica
Versione: 1
Data: 24/05/2018
Titolo: Studio di fase 3, randomizzato, in aperto, di NKTR-214 in combinazione con Nivolumab rispetto a Nivolumab in partecipanti affetti da melanoma metastatico o non resecabile, non precedentemente trattato
Obiettivi: Ricerca addizionale facoltativa – vedere sez 9.8.1 del protocollo: questo protocollo includerà la conservazione dei campioni residui per la ricerca addizionale (AR) La ricerca addizionale è facoltativa per tutti i partecipanti allo studio, salvo dove la conservazione e / o la raccolta dei campioni siano vietate da leggi o regolamenti locali, dai Comitati etici o dai requisiti istituzionali. Questa raccolta per la ricerca addizionale ha lo scopo di espandere la capacità traslazionale di ricerca e sviluppo di Bristol-Myers Squibb e supporterà scopi di ricerca non ancora definiti che miglioreranno la comprensione delle malattie e delle opzioni per il trattamento. Potrebbe anche essere utilizzata per sostenere le richieste dell'autorità sanitaria per l'analisi e l'avanzamento dello sviluppo farmacodiagnostico, al fine di meglio identificare i farmaci migliori per i giusti pazienti. Questo può anche includere l'esplorazione genetica / genomica finalizzata ad esplorare i percorsi della malattia, la progressione e la risposta al trattamento

E.3

Principal inclusion criteria

- Eastern Cooperative Oncology Group (ECOG) performance status of
</=1 (adults 18 years or older)/ Lansky Performance Score >/= 80%
(minors ages 12-17 only)
- Histologically confirmed stage III (unresectable) or stage IV melenoma
- Treatment-naive participants (ie, no prior systemic anticancer therapy
for unresectable or metastatic melanoma) with the exception of prior
adjuvant and/or neoadjuvant treatment for melanoma with approved
agents

- Stato delle prestazioni del gruppo di oncologia della cooperativa orientale (ECOG)
</ = 1 (adulti dai 18 anni in su) / Punteggio delle prestazioni di Lansky> / = 80%
(solo minori di età compresa tra 12 e 17 anni)
- Melanoma stadio III (non resecabile) o stadio IV confermato istologicamente
- Partecipanti naive al trattamento (cioè nessuna precedente terapia antitumorale sistemica
per melanoma non resecabile o metastatico) ad eccezione del precedente
trattamento adiuvante e / o neoadiuvante per il melanoma con agenti approvati

E.4

Principal exclusion criteria

- Active brain metastases or leptomeningeal metastases
- Uveal melanoma
- Participants with an active, known or suspected autoimmune disease

- Metastasi cerebrali attive o metastasi leptomeningee
- Melanoma uveale
- Partecipanti con una malattia autoimmune attiva, nota o sospetta

E.5 End points

E.5.1

Primary end point(s)

1- Overall response rate (ORR) by Blinded Independent central review (BICR)
2- Progression-free survival (PFS) by BICR
3- Overall survival (OS)

- Tasso di risposta generale (ORR) per revisione centrale indipendente in cieco (BICR)
- Sopravvivenza libera da progressione (PFS) secondo BICR
- Sopravvivenza globale (OS)

E.5.1.1

Timepoint(s) of evaluation of this end point

1- Approximately 16 months
2- Approximately 22 months
3- Up to 59 months

1- Circa 16 mesi
2- Circa 22 mesi
3- Fino a 59 mesi

E.5.2

Secondary end point(s)

1- Clinical Benefit Rate (CBR)
2- Duration of Response (DoR)
3- Time To Response (TTR)
4- ORR by investigator and in biomarker population
5- PFS by investigator and in biomarker population
6- OS in biomarker population
7- Incidence of participants with non-serious Adverse Events (AEs)
8- Incidence of participants with Serious Adverse Events (SAEs)
9- Incidence of treatment-related AEs
10- Incidence of treatment-related SAEs
11- Incidence of laboratory abnormalities in blood, blood serum and
urine

1- Tasso di beneficio clinico (CBR)
2- Durata della risposta (DoR)
3- Tempo alla risposta (TTR)
4- ORR da parte dello sperimentatore e nella popolazione di biomarcatori
5- PFS da parte dello sperimentatore e nella popolazione di biomarcatori
6- OS nella popolazione di biomarcatori
7- Incidenza dì partecipanti con eventi avversi non gravi (eventi avversi)
8- Incidenza di partecipanti con eventi avversi gravi (SAE)
9- Incidenza di eventi avversi correlati al trattamento
10- Incidenza di eventi avversi non gravi correlati al trattamento
11- Incidenza di anomalie di laboratorio nel sangue, siero di sangue e
urine

E.5.2.1

Timepoint(s) of evaluation of this end point

1-4 Approximately 16 months
5 - Approximately 22 months
6 - Up to 59 months
7-11 Up to 5 years

1-4 Approssimativamente 16 months
5 – Approssimativamente 22 months
6 – superiore a 59 months
7-11 superiore a 5 years

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

Yes

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

Yes

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

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

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

Brazil

Canada

Israel

New Zealand

Russian Federation

United States

Austria

Belgium

France

Germany

Greece

Ireland

Italy

Netherlands

Poland

Romania

Spain

Switzerland

United Kingdom

Czechia

Argentina

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

LVLS

LVLS (ultima visita dell’ultimo soggetto)

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

Yes

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

561

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

408

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Minors (adolescents) will be included in this study where locally permitted

I minori (adolescenti) saranno inclusi in questo studio dove consentito dalle leggi locali

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

710

F.4.2.2

In the whole clinical trial

1020

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)

At the conclusion of the study, participants who continue to demonstrate clinical benefit will be
eligible to receive BMS supplied study treatment for the maximum treatment duration in Protocol
Section 7.1. Study treatment will be provided via an extension of the study, a rollover study
requiring approval by responsible health authority and ethics committee or through another
mechanism at the discretion of BMS.

Alla conclusione dello studio, i partecipanti che continuano a dimostrare beneficio clinico saranno idonei a ricevere il trattamento di studio fornito da BMS per la massima durata del trattamento specificato nella sezione 7.1 del protocollo. Il trattamento di studio sarà fornito tramite un'estensione dello studio, uno studio di rollover che richiederà approvazione da parte dell'autorità sanitaria responsabile e del comitato etico, o attraverso un altro meccanismo a discrezione di BMS.

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

2018-10-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-10-15

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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