Clinical Trials Register

Summary
EudraCT Number:	2015-002505-11
Sponsor's Protocol Code Number:	CA009-002
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:	2021-02-11
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

2015-002505-11

A.3

Full title of the trial

A Phase 1/2a Dose Escalation and Cohort Expansion Study for Safety, Tolerability, and Efficacy of BMS-986156 Administered Alone and in Combination with Nivolumab (BMS-936558, anti-PD-1 Monoclonal Antibody) in Advanced Solid Tumors

Studio di fase 1/2a di incremento della dose e con espansione della coorte, per la sicurezza, la tollerabilità e l’efficacia dell’anticorpo monoclonale anti-GITR (BMS-986156) somministrato in monoterapia e in combinazione con Nivolumab (BMS-936558, anticorpo monoclonale anti PD-1) in tumori solidi in stadio avanzato

A.3.1

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

A Phase I/2a study of BMS-986156 given alone and in combination with nivolumab in subjects with advanced solid tumors

Studio di fase 1/2a di BMS-986156 somministrato da solo e in combinazione con Nivolumab in tumori solidi in stadio avanzato

A.3.2

Name or abbreviated title of the trial where available

.....

A.4.1

Sponsor's protocol code number

CA009-002

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02598960

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1170-8230

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	000000000000000
B.5.5	Fax number	0000000000000000000
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	BMS-986156
D.3.2	Product code	[BMS-986156]
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.3.9.2	Current sponsor code	BMS-986156
D.3.9.3	Other descriptive name	BMS986156
D.3.9.4	EV Substance Code	SUB180393
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	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: 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 (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-CLINICAL
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
D.3.9.3	Other descriptive name	BMS936558
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: 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	Opdivo (100mg/10ml)
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 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

Advanced Solid Tumors

Tumori solidi in stadio avanzato

E.1.1.1

Medical condition in easily understood language

Advanced Solid Tumors

Tumori solidi in stadio avanzato

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10065252
E.1.2	Term	Solid tumor
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 primary objective is to determine the safety, tolerability, dose limiting toxicities (DLTs), and MTD/MAD/alternate dose of BMS-986156 administered alone and in combination with nivolumab in subjects with advanced solid tumors.

L’obiettivo principale è determinare la sicurezza, la tollerabilità, le tossicità dose-limitanti (DLTs) e la dose MTD/MAD/alternativa di BMS-986156 somministrato da solo e in combinazione con Nivolumab in soggetti con tumori solidi in stadio avanzato.

E.2.2

Secondary objectives of the trial

• To investigate the preliminary anti-tumor activity of BMS-986156 administered alone and in combination with nivolumab in subjects with advanced solid tumors
• To characterize the PK of BMS-986156 administered alone and in combination with nivolumab
• To characterize the immunogenicity of BMS-986156 administered alone and in combination with nivolumab, and the immunogenicity of nivolumab administered with BMS-986156.

• Studiare l’attività antitumorale di BMS-986156 somministrato da solo e in combinazione con Nivolumab in soggetti con tumori solidi in stadio avanzato.
• Caratterizzare il profilo farmacocinetico di BMS-986156
• Caratterizzare il profilo di immunogenicità di BMS-986156 somministrato da solo e in combinazione con Nivolumab e l’immunogenicità di Nivolumab somministrato con BMS-986156.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

For Dose Escalation:
- Subjects with any previously treated advanced (metastatic or refractory) solid tumor
For Cohort Expansion:
- Subjects must have a previously treated advanced solid tumor to be eligible
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Willing and able to provide pre-treatment and on-treatment fresh tumor biopsy
- Women of child-bearing potential and men must use an acceptable method of contraception during treatment and for 23 weeks after treatment for women and 31 weeks for men

Per la coorte di espansione (l’Italia non partecipa alla coorte di dose escalation):
• Soggetti affetti da tumore solido in fase avanzata che abbia progredito o recidivato durante o dopo precedente trattamento con chemioterapia a base di platino.
• ECOG da 0 a 1
• Soggetti disponibili a fornire il consenso ad effettuare il prelievo bioptico del tessuto tumorale allo screening e una seconda volta in fase di trattamento
• Le donne potenzialmente fertili e gli uomini sessualmente attivi devono utilizzare un metodo contraccettivo accettabile per tutta la durata del trattamento e per le 23 settimane successive (nel caso delle donne) o per le 31 settimane succesive (nel caso degli uomini)

I criteri di eleggibilità completi sono specificati nel paragrafo 3.10.1 del protocollo.

E.4

Principal exclusion criteria

- Known central nervous system metastases or central nervous system as the only source of disease
- Other concomitant malignancies (with some exceptions per protocol)
- Active, known or suspected autoimmune disease
- Uncontrolled or significant cardiovascular disease
- History of chronic hepatitis
- History of active hepatitis (B or C)
- Impaired liver or bone marrow function
- Major surgery less than 1 month before start of the study

Per la coorte di espansione (l’Italia non partecipa alla coorte di dose escalation):
• Soggetti con metastasi cerebrali non trattate o per i quali il sistema nervoso centrale è l’unica sede di malattia
• Presenza di neoplasie concomitanti
• Soggetti con malattie autoimmuni attive, note o sospette
• Patologie cardiovascolari significative o non controllate
• Storia clinica di epatite cronica
• Storia clinica di epatite B o C attive
• Funzione epatica o del midollo osseo danneggiate
• Chirurgia principale eseguita meno di 1 mese prima dell’inizio del trattamento

I criteri di eleggibilità completi sono specificati nel paragrafo 3.10.2 del protocollo

E.5 End points

E.5.1

Primary end point(s)

The assessment of safety will be based on the incidence of AEs, SAEs, adverse events leading to discontinuation, and deaths. In addition clinical laboratory test abnormalities will be examined.

La valutazione della sicurezza sarà basata sull’incidenza degli eventi avversi, seri e non seri, delle reazioni avverse che hanno condotto alla discontinuazione del farmaco e dei decessi. Inoltre saranno esaminate anche le anomalie di laboratorio.

E.5.1.1

Timepoint(s) of evaluation of this end point

Non-serious AEs/SAEs will be collected starting with the first dose of study medication and through 100 days after discontinuation of dosing.

I dati relativi agli eventi avversi, sia seri che non seri, saranno raccolti a partire dal primo giorno di dose del farmaco in studio e fino a 100 giorni dopo la discontinuazione del trattamento

E.5.2

Secondary end point(s)

1. ORR, duration of response, and progression free survival rate (PFSR)
2. Selected BMS-986156 parameters, such as Cmax, Tmax, AUC-(TAU), AUC (0-T) will be assessed, if feasible, from concentration-time data
3. Frequency of positivex ADA to BMS-986156 and or nivolumab

1. Percentuale di risposta obiettiva (ORR), durata della risposta, e percentuale di sopravvivenza libera da progressione (PFSR)
2. Per BMS-986156 saranno valutati dei parametri selezionati quali Cmax, Tmax, AUC-(TAU), AUC (0-T) dai dati di concentrazione-tempo
3. Frequenza della positività degli anticorpi anti-farmaco al BMS-986156 e/o Nivolumab

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Every 8 weeks during treatment, response and survival follow-up periods
2. During Cycle 1 and Cycle 3
3. During Cycle 1, Cycle 2 and Cycle 3

1. Ogni 8 settimane durante il periodo di trattamento, di risposta e di follow up per la sopravvivenza
2. Durante il Ciclo 1 e 3
3. Durante il Ciclo,1, Ciclo 2 e Ciclo3

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

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

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

Australia

Canada

Belgium

France

Germany

Italy

Netherlands

Spain

Switzerland

United Kingdom

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

L’ultima visita di follow up dell’ultimo paziente

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:

304

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

190

F.4.2.2

In the whole clinical trial

300

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 may be eligible to receive study drug. Study drug would 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. Please refer to
Section 3.9 Post Study Access to Therapy of the Protocol CA009-002.

Alla fine dello studio, i soggetti che continuano a dimostrare un beneficio clinico dal farmaco potrebbero essere idonei per continuare a ricevere la terapia. Il farmaco verrebbe fornito tramite una estensione dello studio, uno studio di rollover che richiederà approvazione dell’autorità competente e del comitato etico o attraverso un meccanismo alternativo a discrezione di BMS. Fare riferimento alla sezione 3.9 del protocollo.

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

2016-09-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-07-21

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

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