Clinical Trials Register

Summary
EudraCT Number:	2021-000493-29
Sponsor's Protocol Code Number:	CA224-069
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2022-02-10
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

2021-000493-29

A.3

Full title of the trial

A Phase 1/2 Study of the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Relatlimab Plus Nivolumab in Pediatric and Young Adult Participants with Recurrent or Refractory Classical Hodgkin
Lymphoma and Non-Hodgkin Lymphoma

Studio di fase I/II sulla sicurezza, tollerabilità, farmacocinetica ed efficacia preliminare di relatlimab più nivolumab in partecipanti pediatrici e giovani adulti affetti da linfoma di Hodgkin classico e linfoma non Hodgkin ricorrente o refrattario

A.3.1

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

Relatlimab + Nivolumab in Pediatric and Young Adult Lymphomas

Relatlimab + nivolumab nei linfomi nella popolazione pediatrica e nei giovani adulti

A.3.2

Name or abbreviated title of the trial where available

RELATIVITY-069

A.4.1

Sponsor's protocol code number

CA224-069

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1264-4062

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	GSM-CT
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	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	Anti-LAG-3
D.3.2	Product code	[BMS-986016]
D.3.4	Pharmaceutical form	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	relatlimab
D.3.9.2	Current sponsor code	BMS-986016
D.3.9.4	EV Substance Code	SUB168199
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	Opdivo
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma
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
D.3.2	Product code	[BMS-936558]
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.3.9.1	CAS number	946414-94-4
D.3.9.2	Current sponsor code	BMS-936558
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

Recurrent or Refractory Classical Hodgkin Lymphoma and Non-Hodgkin Lymphoma

Linfoma di Hodgkin classico e Linfoma Non-Hodgkin ricorrente o refrattario

E.1.1.1

Medical condition in easily understood language

Hodgkin Lymphoma and Non-Hodgkin Lymphoma

Linfoma di Hodgkin e Linfoma Non-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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10080208
E.1.2	Term	Classical Hodgkin lymphoma
E.1.2	System Organ Class	100000004864

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	10025322
E.1.2	Term	Lymphomas non-Hodgkin's unspecified histology
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

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	10025320
E.1.2	Term	Lymphomas non-Hodgkin's B-cell
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

Part A: To characterize the safety, tolerability, and define the MTD or RP2D for the combination of relatlimab + nivolumab in pediatric participants less than 18 years of age with R/R cHL and NHL.
Part A: To characterize the PK of relatlimab for the combination of relatlimab + nivolumab in pediatric participants less than 18 years of age with R/R cHL and NHL.
Part B: To assess the preliminary efficacy of relatlimab + nivolumab based on the RP2D from part A in participants less than or equal to 30 years old with cHL (Cohort 1).

Parte A: caratterizzare la sicurezza e la tollerabilità, nonché definire la MTD o la RP2D per la combinazione di relatlimab + nivolumab in partecipanti pediatrici di età inferiore a 18 anni con cHL e LNH R/R.
Parte A: caratterizzare la PK di relatlimab per la combinazione di relatlimab + nivolumab in partecipanti pediatrici di età inferiore a 18 anni con cHL e LNH R/R.
Parte B: valutare l’efficacia preliminare di relatlimab + nivolumab in base alla RP2D della Parte A in partecipanti di età inferiore o uguale a 30 anni con cHL (Coorte 1).

E.2.2

Secondary objectives of the trial

Part B: To assess the safety of relatlimab + nivolumab in R/R cHL (Cohort 1) and NHL (Cohort2)
Part B: To evaluate the ORR of relatlimab + nivolumab in participants <= 30 years of age with cHL (Cohort 1)

Parte B: valutare la sicurezza di relatlimab + nivolumab nel cHL (Coorte 1) e LNH (Coorte 2) R/R.
Parte B: valutare l’ORR di relatlimab + nivolumab in partecipanti di età <= 30 anni con cHL (Coorte 1).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male and female participants less than 18 years of age (Part A), and less than or equal to 30 years of age (Part B) with Recurrent or Refractory Classical Hodgkin Lymphoma (R/R cHL) (Cohort 1) and Non
Hodgkin Lymphoma (NHL) (Cohort 2).
• Participants with pathologically confirmed high-risk R/R cHL, after non-response to or failure of first-line standard therapy prior to HDCT/ASCT.
• Participants with pathologically confirmed high-risk, R/R NHL after failure or non-response to first-line therapy
• Participants must have measurable FDG-PET-CT positive disease in both cHL and NHL cohorts.

• Partecipanti di sesso maschile e femminile di età inferiore a 18 anni (Parte A) e di età pari o inferiore a 30 anni (Parte B) con cHL (Coorte 1) e LNH (Coorte 2) R/R.
• Partecipanti con cHL R/R ad alto rischio confermato patologicamente, dopo mancata risposta o fallimento della terapia standard di prima linea prima di HDCT/ASCT.
• Partecipanti con LNH R/R ad alto rischio confermato patologicamente dopo fallimento o mancata risposta alla terapia di prima linea
• I partecipanti devono presentare malattia positiva alla FDG-PET-TC misurabile in entrambe le coorti cHL e LNH.

E.4

Principal exclusion criteria

• Prior treatment with an anti-cytotoxic T-lymphocyte-associated protein 4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways, with the exception of anti-PD(L)-1
targeted therapies.
• Prior treatment with LAG-3-targeted agents.
• Participants with prior autologous stem cell transplantation (HDCT/ASCT).
• Participants with a history of allogeneic bone marrow transplantation and with active graft versus host disease (GVHD) and prior history of Grade > 2 GVHD.
• Participants with clinically significant systemic illnesses unrelated to the cancer as judged by the investigators, which would compromise the participant's ability to tolerate the study treatment.
• Participants with autoimmune disease.

• Precedente trattamento con un anticorpo anti-proteina 4 associata ai linfociti T citotossici o qualsiasi altro anticorpo o farmaco specificamente mirato alla co-stimolazione delle cellule T o ai pathway del checkpoint, ad eccezione delle terapie mirate anti-PD(L)-1.
• Precedente trattamento con agenti mirati a LAG-3.
• Partecipanti con precedente trapianto autologo di cellule staminali (HDCT/ASCT).
• Partecipanti con anamnesi di trapianto allogenico di midollo osseo e con malattia del trapianto contro l’ospite (GVHD) attiva e anamnesi pregressa di GVHD di grado >2.
• Partecipanti con malattie sistemiche clinicamente significative non correlate al tumore secondo il giudizio degli sperimentatori, che comprometterebbero la capacità del partecipante di tollerare il trattamento dello studio.
• Partecipanti con malattia autoimmune.

E.5 End points

E.5.1

Primary end point(s)

1/Part A- Dose-limiting toxicities (DLTs), Maximum Tolerated Dose/Recommended Phase 2 Dose; (MTD/RP2D), and incidences of Adverse Events (AEs), Serious Adverse Events (SAEs), AEs leading to
discontinuation, deaths and laboratory abnormalities
2/Part A- maximum observed serum concentration (Cmax), trough observed concentration (Ctrough), time to maximum concentration (Tmax), and area under the curve within a dosing interval (AUC(TAU))
for relatlimab
3/Part B- Complete Metabolic Response (CMR) rate

1/ Parte A: tossicità dose-limitante (DLT), Dose Massima Tollerata/Dose raccomandata per la Fase 2 (MTD/RP2D) e incidenze di Eventi Avversi (EA), Eventi avversi gravi (SAE) ed EA che portano all’interruzione del trattamento, al decesso e ad anomalie di laboratorio
2/ Parte A: concentrazione sierica massima osservatao(Cmax), Concentrazione minima osservata (Cmin), tempo alla concentrazione massima (Tmax) es area sotto la curva entro l'intervallo di dosaggio AUC(TAU) per relatlimab
3/ Parte B: Tasso di Risposta metabolica completa (RMC)

E.5.1.1

Timepoint(s) of evaluation of this end point

1/Up to 100 days after the last dose of study Treatment
2/At specified timepoints in Section 9.5 of the protocol
3/Up to 32 weeks from last patient first treatment

1/ Fino a 100 giorni dopo l'ultima dose di trattamento in studio
2/ Agli specifici tempi come nella sezione 9.5 del protocollo
3/ Fino a 32 settimane dopo il primo trattamento dell'ultimo paziente

E.5.2

Secondary end point(s)

1/Part B: Incidences of AEs, SAEs, AEs leading to discontinuation, deaths, and laboratory abnormalities
2/Part B: Overall Response Rate (ORR)

1/ Parte B: incidenze di Eventi Avversi (EA), Eventi avversi gravi (SAE) ed EA che portano all’interruzione del trattamento, al decesso e ad anomalie di laboratorio
2/ Parte B: Tasso di risposta totale

E.5.2.1

Timepoint(s) of evaluation of this end point

1/Up to 100 days after the last dose of study Treatment
2/Up to 2 years after LPFT

1/ Fino a 100 giorni dopo l'ultima dose di trattamento in studio
2/ Fino a 2 anni dopo il primo trattamento dell'ultimo paziente

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

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

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

Tollerabilità

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Dose-finding cohort by age/weight group

individuazione della dose per coorte di età/peso

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

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)

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

France

Germany

Italy

Netherlands

Spain

United Kingdom

United States

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

The last participant last visit in the survival follow-up period

LVLS nel periodo di follow-up di 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

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

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 conclusion of the study, if the study treatment is not available as an approved treatment in the local country, participants who continue to demonstrate clinical benefit may be eligible to receive BMS-supplied
study treatment for maximum of 2 years treatment duration as specified in Section 7.1. If the study treatment is not available as an approved and available treatment, study intervention may be provided via compassionate use or single named patient access requiring approval

Alla conclusione dello studio, se il trattamento in studio non sarà disponibile come autorizzato, i partecipanti che continueranno a dimostrare beneficio clinico potranno essere eleggibili a ricevere il trattamento in studio fornito da BMS per un massimo di 2 anni di trattamento, come specificato nella sezione 7.1. Se il trattamento in studio non sarà disponibile come trattamento autorizzato, esso potrebbe essere fornito per uso compassionevole o per singolo paziente in seguito ad approvazione.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	ECMC Paediatric Network
G.4.3.4	Network Country	United Kingdom

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-05-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-03-28

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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IMP with orphan designation in the indication
Orphan Designation Number:
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