Clinical Trials Register

Summary
EudraCT Number:	2016-000894-19
Sponsor's Protocol Code Number:	CA209-647
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-12-16
Trial results	View 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

2016-000894-19

A.3

Full title of the trial

A Phase 2, Open-label, Single-arm, Two-cohort Study of Nivolumab in
Relapsed/Refractory Primary Central Nervous System Lymphoma (PCNSL)
or Relapsed/Refractory Primary Testicular Lymphoma (PTL)

Studio di Fase II, in Aperto, a Singolo Braccio, 2 Coorti, di Nivolumab nel Linfoma Primitivo del Sistema Nervoso Centrale (PCNSL) Recidivo/Refrattario o nel Linfoma Primitivo Testicolare (PTL) Recidivo/Refrattario

A.3.1

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

Efficay and safety study of Nivolumab in subjects with Primary Central
Nervous System Lymphoma (PCNSL) or Primary Testicular Lymphoma
(PTL)

Studio di sicurezza ed efficacia di Nivolumab in soggetti con Linfoma Primitivo del Sistema Nervoso Centrale (PCNSL) o Linfoma Primitivo Testicolare

A.3.2

Name or abbreviated title of the trial where available

CheckMate 647

A.4.1

Sponsor's protocol code number

CA209-647

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1180-0996

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.5.4	Telephone number	00000000000
B.5.5	Fax number	000000000000
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	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	NIVOLUMAB - 10ml vial
D.3.2	Product code	BMS-936558
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	NIVOLUMAB
D.3.9.1	CAS number	946414-94-4
D.3.9.2	Current sponsor code	BMS-936558-01
D.3.9.3	Other descriptive name	MDX1106, ONO-4538
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.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	NIVOLUMAB - 4ml vial
D.3.2	Product code	BMS-936558
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	NIVOLUMAB
D.3.9.1	CAS number	946414-94-4
D.3.9.2	Current sponsor code	BMS-936558-01
D.3.9.3	Other descriptive name	MDX1106, ONO-4538
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

Relapsed/Refractory Primary Central Nervous System Lymphoma
(PCNSL) or Relapsed/Refractory Primary Testicular Lymphoma (PTL)

Linfoma Primitivo del Sistema Nervoso Centrale (PCNSL) Recidivo/Refrattario o Linfoma Primitivo Testicolare (PTL) Recidivo/Refrattario

E.1.1.1

Medical condition in easily understood language

Central Nervous System Cancer or Testicular Cancer

Cancro del Sistema Nervoso Centrale o Cancro Testicolare

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10043302
E.1.2	Term	Testicular cancer
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10036685
E.1.2	Term	Primary central nervous system lymphoma
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

To assess the clinical benefit of nivolumab in subjects with
relapsed/refractory PCNSL or relapsed/refractory PTL as measured by
ORR by blinded Independent Central Review (BICR)

Valutare il beneficio clinico di nivolumab in soggetti affetti da PCNSL recidivo/refrattario o PTL recidivo/refrattario misurato in base al tasso di risposta globale (Overall Response Rate, ORR) valutato da una Commissione Indipendente in cieco (BICR)

E.2.2

Secondary objectives of the trial

- To assess PFS based on BICR assessment for PCNSL or PTL,
respectively
- To assess ORR and DOR based on investigator assessment for PCNSL
or PTL, respectively
- To assess overall survival (OS) for PCNSL or PTL, respectively

- Valutare la sopravvivenza libera da progressione (Progression Free Survival, PFS) sulla base della valutazione BICR rispettivamente per PCNSL o PTL.
- Valutare l¿ORR e la durata della risposta (Duration Of Response, DOR) sulla base della valutazione dello sperimentatore rispettivamente per PCNSL o PTL.
- Valutare la sopravvivenza globale (Overall Survival, OS) rispettivamente per PCNSL o PTL

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

a) Men and women, age of more than 18 years old at the time of
screening
b) Subjects with pathologically confirmed PCNSL or PTL who progressed
after or did not respond to at least 1 line of systemic therapy (PCNSL
prior therapy may include: high-dose methotrexate [HD-MTX], HD-MTX
based regimen, high dose cytarabine, radiation therapy alone as
treatment or as part of consolidation therapy, high-dose therapy with
autologous stem cell transplant as part of consolidation therapy, and/or
intraocular MTX alone or as part of consolidation therapy; PTL prior
therapy may include: chemoimmunotherapy such as CHOP-R or any
other regimens, with/without prophylactic radiation to contralateral
testis or orchiectomy or intrathecal chemotherapy)
c) Radiologically measurable disease within 28 days of first dose
d) Karnofsky performance status of 70 or higher

a) Uomini e donne, di età maggiore di 18 anni al momento dello screening
b) Soggetti affetti da PCNSL o PTL patologicamente confermato che hanno registrato una progressione o non hanno risposto ad almeno 1 linea di terapia sistemica (la terapia precedente per PCNSL può includere: metotressato ad alta dose [High-Dose Methotrexate, HD MTX], regime a base di HD-MTX, citarabina ad alta dose, radioterapia da sola come trattamento o come parte della terapia di consolidamento, terapia ad alta dose con trapianto autologo di cellule staminali come parte della terapia di consolidamento e/o MTX intraoculare da solo o come parte della terapia di consolidamento; la precedente terapia per PTL può includere: chemioimmunoterapia come CHOP-R o qualsiasi altro regime, con/senza radiazione profilattica del testicolo controlaterale o chemioterapia intratecale)
c) Malattia radiologicamente misurabile entro 28 giorni dalla prima dose
d) Performance Status di Karnofsky di 70 o superiore

E.4

Principal exclusion criteria

a) Intraocular PCNSL without evidence of brain disease. Patients with
prior history of intraocular
involvement treated only with intraocular methotrexate and no prior
systemic therapy are excluded.
b) PCNSL with systemic disease
c) PCNSL patients who cannot undergo magnetic resonance imaging
assessments
d) Patients with brain stem lesions
e) Active, known, or suspected autoimmune disease
f) Known history of positive test for human immunodeficiency virus or
known acquired immunodeficiency
syndrome
g) Prior treatment with an anti-programmed death ligand (PD)-1, anti-
PD-L1, anti-PD-L2, anti-CD137, or
anti-CTLA-4 antibody, or any other antibody or drug specifically
targeting T-cell co-stimulation or
checkpoint pathways

a) PCNSL intraoculare senza evidenza di malattia cerebrale. Pazienti con storia precedente di coinvolgimento intraoculare trattati solo con metotressato e senza precedenti trattamenti sistemici sono esclusi
b) Pazienti affetti da PCNSL con malattia sistemica
c) Pazienti affetti da PCNSL che non possono essere sottoposti a valutazioni tramite risonanza magnetica
d) Pazienti con lesioni al peduncolo encefalico
e) Pazienti con malattia autoimmune attiva, nota o sospetta
f) Anamnesi nota di test positivo per il virus dell’immunodeficienza umana o sindrome da immunodeficienza acquisita nota
g) Precedente trattamento con un anticorpo anti-proteina del ligando della morte programmata (Programmed Death, PD)-1, anti-PD-L1, anti-PD-L2, anti-CD137 o anti-CTLA-4 o con qualsiasi altro anticorpo o farmaco mirato specificamente contro la co-stimolazione delle cellule T o i percorsi di controllo

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is BICR-assessed ORR. It is defined as the best response designation recorded between the date of first study drug dose and the date of initial objectively documented progression per criteria or the date of subsequent therapy, whichever
occurs first.
The BICR-assessed objective response will be further characterized by the DOR. DOR is defined as the time from first response (partial response [PR] or complete response [CR]) to the date of initial objectively documented progression as determined using the
International Primary CNS Lymphoma Collaborative Group (IPCG) criteria for PCNSL and Lugano 2014 response evaluation for PTL, as determined by BICR, or death due to any cause, whichever occurs first.

ORR valutato secondo BICR. È definita come la migliore classificazione della risposta registrata tra la data della prima dose del farmaco in studio e la data della progressione iniziale oggettivamente documentata in accordo ai criteri o la data della terapia successiva, quale delle due si sia verificata per prima.
La risposta obiettiva valutata dal BICR sarà ulteriormente caratterizzata dalla DOR. La DOR è definita come il tempo intercorso dalla prima risposta (risposta parziale [PR] o risposta completa [CR]) alla data della iniziale progressione oggettivamente documentata come determinato utilizzando il Criteri dell’International Primary CNS Lymphoma Collaborative Group (IPCG) per PCNSL e Lugano 2014 valutazione della risposta per PTL, come determinato dal BICR, o al decesso dovuto a qualsiasi causa, quale delle due si sia verificata per prima.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary endpoint will be analyzed 6 months after last patient first
treatment in each cohort. All treated subjects will be evaluated.

6 mesi dopo la LPFT in caiscuna coorte. Tutti i soggetti saranno valutati.

E.5.2

Secondary end point(s)

The secondary endpoints are PFS based on BICR assessment, ORR and
DOR based on investigator assessment, and OS

PFS valutato secondo BICR, ORR e DOR secondo valutazione degli Sperimentatori e OS

E.5.2.1

Timepoint(s) of evaluation of this end point

Tumor assessments for PCNSL will occur every 2 months for 2 years,
then every 6 months until disease progression.
Tumor assessments for PTL will occur every 2 months for 6 months, then
every 3 months for 1.5 years, then every 6 months until disease
progression

PCNSL: valutazione tumorale ogni 2 mesi per 2 anni, poi ogni 6 mesi fino a progressione di malattia. PTL: valutazione tumorale ogni 2 mesi per 6 mesi, poi ogni 3 mesi per 1,5 anni, poi ogni 6 mesi fino a progressione di malattia

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

Yes

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

Yes

E.8.1.7.1

Other trial design description

in aperto

open

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

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

Czechia

France

Hong Kong

Hungary

Israel

Italy

Russian Federation

Singapore

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

100

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, subjects who continue to demonstrate
clinical benefit will be eligible to receive BMS supplied study drug
provided via an extension of the study, a rollover study requiring
approval by responsible HA and EC, or through another mechanism at
the discretion of BMS

Alla conclusione dello Studio, i soggetti che continueranno a dimostrare beneficio clinico saranno eleggibili per ricevere farmaco fornito da BMS (nivolumab) tramite un¿estensione dello Studio, uno Studio di roll over tramite richiesta di approvazione delle autorit¿ competenti e comitati etici o attraverso altri meccanismi 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

2016-10-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-10-06

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
Orphan Designation Number:
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