Clinical Trials Register

Summary
EudraCT Number:	2016-002347-41
Sponsor's Protocol Code Number:	CA209-744
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:	2021-06-17
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

2016-002347-41

A.3

Full title of the trial

Risk-based, response-adapted, Phase II open-label trial of nivolumab + brentuximab vedotin (N + Bv) for children, adolescents, and young adults with relapsed/refractory (R/R) CD30 + classic Hodgkin lymphoma (cHL) after failure of first-line therapy, followed by brentuximab + bendamustine (Bv + B) for participants with a suboptimal response. CheckMate 744: CHECKpoint pathway and nivolumab clinical Trial Evaluation

Sperimentazione in aperto di Fase II, basata sul rischio, adattata alla risposta su nivolumab+brentuximab vedotin (N+Bv) seguita da brentuximab vedotin+bendamustina (Bv+B) per i partecipanti con risposta sub-ottimale, per bambini, adolescenti e giovani adulti con linfoma di Hodgkin classico (cHL) CD30+ recidivante/refrattario (R/R) dopo il fallimento della terapia di prima linea. (CheckMate 744: CHECKpoint pathway and nivolumab clinical Trial Evaluation)

A.3.1

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

A Study of Nivolumab + Brentuximab Vedotin in Children, Adolescents, and Young Adults With Classic Hodgkin Lymphoma (cHL) After Failure of First Line Therapy, Followed by Brentuximab Vedotin + Bendamustine for Participants With a Suboptimal Response (CheckMate 744)

Studio di nivolumab+brentuximab vedotin (N+Bv) seguita da brentuximab vedotin+bendamustina (Bv+B) per i partecipanti con risposta sub-ottimale, per bambini, adolescenti e giovani adulti con linfoma di Hodgkin classico (cHL) dopo il fallimento della terapia di prima linea. (CheckMate 744)

A.3.2

Name or abbreviated title of the trial where available

CheckMate 744

A.4.1

Sponsor's protocol code number

CA209-744

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02927769

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1183-3601

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/004/2017

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	0000000
B.5.5	Fax number	0000000
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
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	European Union
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 - 10 ml vial - clinico
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	BMS-936558, MDX1106, ONO-4538
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	Yes
D.2.1.1.1	Trade name	ADCETRIS
D.2.1.1.2	Name of the Marketing Authorisation holder	Seattle Genetics
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	NA
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	Powder 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	brentuximab vedotin
D.3.9.1	CAS number	914088-09-8
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	BRENTUXIMAB VEDOTIN
D.3.9.4	EV Substance Code	SUB32397
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	50
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: 3
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	Bendamustine HEXAL
D.2.1.1.2	Name of the Marketing Authorisation holder	Hexal AG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	NA
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	Powder 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	BENDAMUSTINE HYDROCHLORIDE
D.3.9.1	CAS number	3543-75-7
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	nd
D.3.9.4	EV Substance Code	SUB00696MIG
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.IMP: 4
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	ADCETRIS
D.2.1.1.2	Name of the Marketing Authorisation holder	Takeda Pharma A/S
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	NA
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	Powder 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	BRENTUXIMAB VEDOTIN
D.3.9.1	CAS number	914088-09-8
D.3.9.2	Current sponsor code	nd
D.3.9.3	Other descriptive name	BRENTUXIMAB VEDOTIN
D.3.9.4	EV Substance Code	SUB32397
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	50
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: 5
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	Bendamustine cell pharm
D.2.1.1.2	Name of the Marketing Authorisation holder	STADAPHARM GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	NA
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	Powder 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	bendamustina idrocloruro
D.3.9.1	CAS number	3543-75-7
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB00696MIG
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	2
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.IMP: 6
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 EEIG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	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.3.8	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	BMS-936558, MDX1106, ONO-4538
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.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 (R/R) CD30 + classic Hodgkin lymphoma (cHL)

linfoma di Hodgkin classico (cHL) CD30+ recidivante/refrattario (R/R)

E.1.1.1

Medical condition in easily understood language

Hodgkin Disease

Malattia di Hodgkin

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	HLGT
E.1.2	Classification code	10025319
E.1.2	Term	Lymphomas Hodgkin's disease
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

- R1 (Low Risk) Cohort: To describe event-free survival (EFS) rate at 3 years, as assessed by blinded independent central review (BICR).

- R2 (Standard Risk) Cohort: to describe the complete metabolic response (CMR) rate prior to HDCT/ASCT by BICR, using Lugano 2014 response criteria

- Coorte R1 (a basso rischio): descrivere il tasso di sopravvivenza libera da eventi (event-free survival, EFS) a 3 anni, in base alla valutazione del comitato centrale indipendente per la revisione in cieco (blinded independent central review, BICR).
- Coorte R2 (rischio standard): descrivere il tasso di risposta metabolica completa (CMR) prima dell’HDCT/ASCT in base alla valutazione del BICR, secondo i criteri di valutazione della risposta Lugano 2014.

E.2.2

Secondary objectives of the trial

- To assess overall response rate (ORR) (CMR + partial metabolic response [PMR]) using Lugano 2014 criteria of the low risk and standard risk cohorts following 4 cycles of nivolumab and brentuximab vedotin by BICR
- To assess PFS rate at 3 years by BICR using Lugano 2014 criteria
- Duration of Response (DOR) will be evaluated for those participants who achieved PMR or CMR by BICR as well as for those participants who achieved CMR by BICR prior to IFRT in the low risk cohort and for those participants who achieved CMR prior to HDCT/ASCT in the standard risk
cohort
- To describe the toxicity of nivolumab + brentuximab in combination in pediatric and young adult participants with relapsed or refractory classical Hodgkin's lymphoma (cHL) after failure of first-line treatment.
-To evaluate efficacy as assessed by investigators using LUGANO (2014) response criteria.

-Tasso di risposta globale (ORR) (CMR+ PMR) secondo i criteri Lugano 2014 per le coorti a basso rischio e a rischio standard dopo 4 cicli di nivo e brentuximab vedotin in base alla valutazione del BICR.
-Tasso di PFS a 3 anni in base alla valutazione del BICR secondo i criteri Lugano 2014.
-La durata della risposta (DOR) sarà valutata per quei partecipanti che hanno raggiunto una PMR o una CMR in base alla valutazione del BICR così come per quei partecipanti che hanno raggiunto una CMR in base alla valutazione del BICR prima della
IFRT nella coorte a basso rischio e per quei partecipanti che hanno raggiunto una CMR prima dell’HDCT/ASCT nella coorte a rischio standard.
-Valutare la tossicità della combinazione nivo+brentuximab nei partecipanti pediatrici e giovani adulti con cHL dopo il fallimento del trattamento di prima linea.
-Valutare l’efficacia in base alla valutazione degli sperimentatori utilizzando i criteri di valutazione della risposta Lugano 2014

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: N/A
Date: 23/09/2016
Title: N/A
Objectives: Retention of sample collection for additional research is mandatory for all participants, except where prohibited by local laws or regulations. This protocol will include residual sample storage for additional research.
For additional details, please refer to section 9.8.3 the original protocol dated 23-Sep-2016

Pharmacogenomics
Version: N/A
Date: 23/09/2016
Title: N/A
Objectives: Retention of sample collection for additional research is mandatory for all participants, except where prohibited by local laws or regulations. This protocol will include residual sample storage for additional research.
For additional details, please refer to section 9.8.3 the original protocol dated 23-Sep-2016

Farmacogenetica
Versione: N/A
Data: 23/09/2016
Titolo: N/A
Obiettivi: La riserva di raccolta di campioni per la ricerca addizionale è obbligatoria per tutti i pazienti eccetto dove sia proibita dalle leggi o dai regolamenti locali. Questo protocollo includerà la conservazione di campioni residui per la ricerca addizionale. Per maggiori dettagli per favore fare riferimento alla sezione 9.8.3 del protocollo originale datato 23 Settembre 2016

Farmacogenomica
Versione: N/A
Data: 23/09/2016
Titolo: N/A
Obiettivi: La riserva di raccolta di campioni per la ricerca addizionale è obbligatoria per tutti i pazienti eccetto dove sia proibita dalle leggi o dai regolamenti locali. Questo protocollo includerà la conservazione di campioni residui per la ricerca addizionale. Per maggiori dettagli per favore fare riferimento alla sezione 9.8.3 del protocollo originale datato 23 Settembre 2016

E.3

Principal inclusion criteria

• Classic Hodgkin Lymphoma (cHL), relapsed or refractory
• Minimal limitation on activities of daily living as measured by Karnofsky = 50 for participants > 16 years of age or Lansky = 50 for participants = 16 years of age.
• One prior anti-cancer therapy that did not work

- linfoma di Hodgkin classico (cHL) recidivante o refrattario
- limitazioni minime nello svolgimento delle attività quotidiane misurate, per il pazienti > 16 anni, secondo la scala Karnofsky (punteggio maggiore /= 50) e per i pazienti minore/= 16 anni 50 secondo la scala Lansky (punteggio maggiore/= 50)
- fallimento di una prima linea di trattamento

E.4

Principal exclusion criteria

• Active, known, or suspected autoimmune disease or infection
• Active cerebral/meningeal disease related to the underlying malignancy
• More than one line of anti-cancer therapy or no treatment at all
• Received a stem cell transplant for Hodgkin Lymphoma and/or a solid organ transplant
• Prior treatment with any drug that targets T cell co-stimulation pathways (such as checkpoint inhibitors)

• Malattia autoimmune o infezione attiva, nota o sospetta
• Malattia cerebrale/meningeale attiva correlata con la patologia in studio
• Più di una linea di terapia anti-cancro o nessun trattamento precedente
• Precedente trapianto di cellule staminali per il Linfoma di Hodgkin e/o trapianto d’organo
• Precedente trattamento con qualsiasi farmaco che abbia come target i meccanismi di costimolazione delle cellule T (come gli inibitori dei checkpoint)

E.5 End points

E.5.1

Primary end point(s)

- Event Free Survival (EFS) ; Low Risk Group. Based on blinded
independent central review (BICR)
- Complete Metabolic Response (CMR) prior to RT; Low Risk Group. The
CMR rate is defined as the proportion of all response-evaluable
participants who, assessed by the BICR, achieve best response of CMR
using Lugano 2014 criteria.
- Complete Metabolic Response (CMR) Rate; Standard Risk Group. This is
the rate prior to high-dose chemotherapy followed by autologous stem
cell transplant (HDCT/ASCT) based on the blinded independent central
review (BICR).

- Coorte R1 (a basso rischio): Tasso di sopravvivenza libera da eventi (event-free survival, EFS) in
base alla valutazione del comitato centrale indipendente per la revisione in cieco (blinded independent central review, BICR).
- Coorte R1 (a basso rischio): Tasso di risposta metabolica completa (CMR) precedente alla RT. Il tasso di CMR è definito come la
porzione di tutti i pazienti con risposta valutabile che raggiungano come miglior risposta la CMR valutata dal BICR utilizzando i
criteri di valutazione della risposta Lugano 2014.
- Coorte R2 (rischio standard): Tasso di Risposta Metabolica Completa (CMR) prima della chemioterapia ad alto dosaggio seguita
da trapianto di cellule staminali autologhe (HDCT/ASCT) in base alla valutazione del BICR, secondo i criteri di valutazione della
risposta Lugano 2014.

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to 5 years

Fino a 5 anni

E.5.2

Secondary end point(s)

• Overall Response Rate (ORR)
Based on blinded independent central review (BICR)
• Progression Free Survival Rate (PFSR)
Based on the blinded independent central review (BICR)
• Duration of Response (DOR)
Based on the blinded independent central review (BICR)
• Incidence of serious and non-serious adverse events of nivolumab
(BMS-936558) and brentuximab when given in combination
• Incidence of clinically significant abnormalities in general laboratory
tests of nivolumab (BMS-936558) and brentuximab when given in
combination. Hematology, Chemistry and Urinalysis
• Incidence of clinically significant vital sign measurements of
nivolumab (BMS-936558) and brentuximab when given in combination.
Temperature, Blood Pressure and Heart Rate
•Complete Metabolic Response (CMR)
•Complete Metabolic Response (CMR) rate at any time prior to radiation
therapy
•EFS: Low Risk Group. Based on investigator assessments
•ORR: All participants, based on investigator assessments, after 4 cycles
of nivolumab + brentuximab vedotin treatment
•PFSR:All participants, based on investigator assessments
•DOR: All participants, based on investigator assessments

- Tasso di risposta globale (overall response rate ORR) in base alla valutazione del comitato
centrale indipendente per la revisione in cieco (blinded independent central review, BICR)
- Tasso di sopravvivenza libera da progressione (Progression Free Survival Rate, PFSR) in base alla valutazione del comitato
centrale indipendente per la revisione in cieco (blinded independent central review, BICR)
- Durata della risposta (duration of response, DOR) in base alla valutazione del comitato centrale indipendente per la revisione in
cieco (blinded independent central review, BICR)
- Incidenza di Eventi Avversi seri o non seri per Nivolumab (BMS-936558) e Brentuximab vedotin quando somministrati in
combinazione.
- Incidenza di anormalità clinicamente significative nei test di laboratorio generali per Nivolumab (BMS-936558) e Brentuximab
vedotin quando somministrati in combinazione.
- Incidenza di rilevazioni clinicamente significative dei parametri vitali per Nivolumab (BMS-936558) e Brentuximab vedotin quando
somministrati in combinazione. Temperatura Pressione Sanguigna e Frequenza Cardiaca.
- Risposta metabolica completa (CMR)
- Tasso di Risposta metabolica completa (CMR) in qualsiasi momento prima della radioterapia
- EFS: gruppo a basso rischio. Secondo la valutazione dello sperimentatore
- ORR: tutti i partecipanti, secondo la valutazione dello sperimentatore, dopo 4 cicli di trattamento con nivolumab+brentuximab vedotin
- PFSR: tutti i partecipanti, secondo la valutazione dello sperimentatore
- DOR: tutti i partecipanti, secondo la valutazione dello sperimentatore

E.5.2.1

Timepoint(s) of evaluation of this end point

- ORR: Up to 12 weeks
- Others: Up to 5 years

-ORR: Fino a 12 settimane
- Gli altri: Fino a 5 anni

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

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

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

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

Canada

United States

France

Germany

Ireland

Italy

Netherlands

Poland

Spain

United Kingdom

Czechia

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 (Once participants reach the survival follow-up phase, either in-person visits or documented telephone calls/email correspondence to assess the participant’s status are acceptable)

La conclusione della sperimentazione è definita come l’ultima procedura effettuata per l’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)

Yes

F.1.1.5.1

Number of subjects for this age range:

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:

F.1.3

Elderly (>=65 years)

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

Assents are allowed since this is a pediatric study

Gli assensi sono permessi considerando che si tratta di uno studio pediatrico

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)

At the end of the study, BMS will not continue to provide BMS-supplied study treatment to participants/investigators unless BMS chooses to extend the study. The investigator should ensure that the participant receives appropriate standard of care.

Al termine dello studio BMS non continuerà a fornire i trattamenti di studio ai soggetti partecipanti/sperimentatori a meno che BMS decida di estendere lo studio. Lo sperimentatore dovrà assicurarsi che i soggetti partecipanti ricevano terapia standard appropriata.

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

2017-03-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-01-31

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

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Orphan Designation Number:
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