Clinical Trials Register

Summary
EudraCT Number:	2012-001514-42
Sponsor's Protocol Code Number:	CA209-040
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

2012-001514-42

A.3

Full title of the trial

A Phase 1/2, Dose-escalation, Open-label Study of Nivolumab or
Nivolumab in Combination with Other Agents in Advanced Hepatocellular
Carcinoma Subjects with or without Chronic Viral Hepatitis

Studio clinico di Fase I/II, in aperto, di aumento della dose, di Nivolumab o Nivolumab in combinazione con altri agenti in pazienti con carcinoma epatocellulare in stadio avanzato con o senza epatite virale cronica.

A.3.1

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

Study to evaluate the effectiveness, safety and tolerability of nivolumab
and the combination nivolumab plus other agents in subjects with
advanced liver cancer.

Studio clinico per valutare l'efficacia, la sicurezza e la tollerabilità di Nivolumab e la combinazione di Nivolumab con altri agenti in pazienti con carcinoma epatocellulare in stadio avanzato.

A.3.2

Name or abbreviated title of the trial where available

Anti-PD-1 HCC

A.4.1

Sponsor's protocol code number

CA209-040

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01658878

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	Global Submission Management-Clinic
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	000000
B.5.5	Fax number	000000
B.5.6	E-mail	mg-gsm-ct@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 10 ml - CLINICAL
D.3.2	Product code	[BMS-936558]
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Nivolumab
D.3.9.1	CAS number	946414-94-4
D.3.9.2	Current sponsor code	BMS-936558-01
D.3.9.3	Other descriptive name	Anti-PD-1 Human Monoclonal Antibody; MDX-1106
D.3.9.4	EV Substance Code	SUB32944
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Ipilimumab
D.3.2	Product code	[BMS-734016]
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ipilimumab
D.3.9.1	CAS number	477202-00-9
D.3.9.2	Current sponsor code	BMS-734016
D.3.9.3	Other descriptive name	BMS-734016
D.3.9.4	EV Substance Code	SUB22577
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	5
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	Comparator
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	Nexavar
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
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	Yes
D.2.5.1	Orphan drug designation number	ORPHA131367
D.3 Description of the IMP
D.3.1	Product name	Nexavar
D.3.2	Product code	[ooo]
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SORAFENIB
D.3.9.1	CAS number	284461-73-0
D.3.9.2	Current sponsor code	ooo
D.3.9.4	EV Substance Code	SUB23139
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	200
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	Cabometyx
D.2.1.1.2	Name of the Marketing Authorisation holder	Ipsen 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	Cabozantinib
D.3.2	Product code	[XL184]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cabozantinib
D.3.9.1	CAS number	1140909-48-1
D.3.9.2	Current sponsor code	XL184
D.3.9.3	Other descriptive name	CABOZANTINIB S-MALATE
D.3.9.4	EV Substance Code	SUB176318
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	20
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: 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	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- 10ml -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-936558-01
D.3.9.3	Other descriptive name	Anti-PD-1 Human Monoclonal Antibody; MDX-1106
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

Hepatocellular carcinoma

carcinoma epatocellulare

E.1.1.1

Medical condition in easily understood language

Hepatocellular carcinoma

carcinoma epatocellulare

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	10019829
E.1.2	Term	Hepatocellular carcinoma recurrent
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	10019828
E.1.2	Term	Hepatocellular carcinoma non-resectable
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	10019830
E.1.2	Term	Hepatocellular carcinoma resectable
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 first part of the study is the Dose Escalation Phase designed to
establish the safety of nivolumab at different dose levels for each of the
three cohorts (uninfected HCC subjects, HCV-infected HCC subjects, and
HBV-infected subjects). The second part of the study is the Expansion
Phase designed to generate additional clinical data at specified doses for
each of the 3 cohorts. A third cohort has been added in this study to
compare the efficacy of nivolumab and sorafenib in the treatment of
Advanced HCC. A fourth cohort will generate data on the safety and
efficacy of the combination nivolumab plus ipilimumab in the treatment
of Advanced HCC.In the fifth cohort, additional clinical data will be
generated for Child Pugh B subjects.A sixth cohort has been added to
establish the safety and tolerability of nivo combined with cabozantinib
and nivo and ipi combined with cabozantinib in subjects with advanced
HCC who are naive to sorafenib or have been previously treated with
sorafenib.

Prima parte: aumento della dose, per stabilire la sicurezza di nivolumab a diversi livelli di dose per ciascuna delle tre coorti (soggetti con HCC non infetti, soggetti con HCC infetti con HCV e soggetti con HCC infetti con HBV).
Seconda parte: espansione, per ottenere ulteriori dati clinici a dosi specifiche per ciascuna delle 3 coorti.
Terza coorte: confrontare l'efficacia di nivolumab e Sorafenib nel trattamento dell’ HCC avanzato.
Quarta coorte: dati sulla sicurezza ed efficacia del nivolumab in combinazione con ipilimumab per il trattamento dell’HCC in stadio avanzato.
Quinta coorte: ulteriori dati clinici per i soggetti Chils Pugh B.
Sesta coorte: determinare la sicurezza e la tollerabilità di Nivolumab in combinazione con Cabozantinib e Nivolumab più Ipilimumab combinato con Cabozantinib in pazienti con epatocarcinoma in stadio avanzato che sono naive al Sorafenib o sono stati trattati precedentemente con Sorafenib.
.

E.2.2

Secondary objectives of the trial

In all cohorts, duration of response (DOR), TTP (time to response),
progression free survival (PFS), overall survival (OS), and PD-L1
expression. In the dose escalation phase, pharmacokinetic parameters

In tutte le coorti, durata della risposta (DOR), TTP (tempo di risposta), sopravvivenza libera da progressione (PFS), la sopravvivenza globale (OS) ed espressione del PD-L1. Nella fase di aumento della dose, i parametri farmacocinetici.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Subjects of 18 years or older (men and women) with histologically
confirmed advanced hepatocellular carcinoma, not eligible for surgical
and/or locoregional therapies; or progressive disease after surgical and
/or locoregional therapies
-Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to
1
-Dose Escalation Phase: Child-Pugh score of 7 points or less. Cohort 5:
Child-Pugh Class B (B7 to B8). For all other cohorts Child-Pugh score of 6
points or less

•Uomini e donne di età > = 18 anni con carcinoma epatocellulare avanzato istologicamente confermato, non possono beneficiare di terapie chirurgiche e/o locoregionali o con progressione di malattia dopo terapie chirurgiche e / o locoregionali
•ECOG Performance Status inferiore o uguale a 1.
•Fase di aumento della dose: punteggio di Child-Pugh di 7 punti o meno. Coorte 5 punteggio di Child-Pugh classe B (B7-B8) Per tutte le altre coorti punteggio di Child-Pugh di 6 punti o meno

E.4

Principal exclusion criteria

-History of autoimmune disease
-Any prior or current clinically significant ascites

•Storia di malattia autoimmune
•Qualsiasi ascite clinicamente significativa precedente o attuale

E.5 End points

E.5.1

Primary end point(s)

Dose Escalation Cohort: Safety, tolerability, dose limiting toxicity, and
maximum tolerated dose of
Nivoumab
Expansion Cohort: Objective Response Rate (ORR)
Nivolumab vs. Sorafenib cohort: ORR
Nivolumab plus ipilimumab combination cohort: safety & tolerability of
combination and ORR
Child Pugh B Cohort 5: Objective Response Rate (ORR)
Cabozantinib Combination Cohort: safety & tolerability of combination
and ORR

•coorte di aumento della dose: sicurezza, tollerabilità, la tossicità dose limitante e
massima dose tollerata di Nivolumab
•Coorte Espansione: Percentuale di Risposta Obiettiva (ORR)
•coorte Nivolumab vs Sorafenib: ORR
•coorte di combinazione Nivolumab più Ipilimumab: sicurezza e la tollerabilità della combinazione e ORR
•coorte 5 Child Pugh B: ORR
• Coorte di combinazione con Cabozantinib: sicurezza e tollerabilità della combinazione ed ORR

E.5.1.1

Timepoint(s) of evaluation of this end point

Dose Escalation Cohort (1-2Q 2016) and Nivolumab plus Ipilimumab
combination cohort (2Q 2017): safety assessments (adverse events,
discontinuations, lab abnormalities) will be performed until 100 days
after last dose.
Expansion cohort, Nivolumab vs. Sorafenib cohort, Nivolumab plus
Ipilimumab combination cohort and Cohort 5: best overall response will
be determined approximately 6 months after accrual period for each
cohort (1-2Q 2016 for dose escalation and expansion cohorts; 2Q 2017
nivolumab vs. sorafenib cohort and nivolumab plus ipilimumab
combination cohort; 3Q 2017 for Cohort 5).
Cabozantinib Combination Cohort: minimum 6 months of follow-up

- Coorte di aumento della dose (1-2Q 2016) e coorte di combinazione
Nivolumab più Ipilimumab (2Q 2017): valutazioni di sicurezza (eventi avversi, interruzioni del trattamento, anomalie di laboratorio) verranno eseguite fino a 100 giorni dopo l'ultima dose.
- Coorte di espansione, coorte Nivolumab vs Sorafenib e coorte di combinazione Nivolumab più Ipilimumab: la migliore risposta complessiva sarà determinata circa 6 mesi dopo il periodo di accrual per ogni coorte (1-2Q 2016 per le coorti di aumento della dose e di espansione; 2Q 2017 per la coorte nivolumab vs sorafenib e la coorte di combinazione nivolumab più ipilimumab). 3Q 2017 per la coorte 5.
- Coorte di combinazione con Cabozantinib: minimo 6 mesi di follow-up

E.5.2

Secondary end point(s)

In all cohorts, CR, DCR, DOR, TTR, TTP, TTP Rate, PFS, OS, OSR and PDL1
expression. In the dose escalation phase, pharmacokinetic
parameters

In tutte le coorti, risposta completa (CR), tasso di controllo della malattia (DCR), durata della risposta (DOR), tempo di risposta (TTR), tempo di progressione (TTP), tasso del tempo di progressione (TTP Rate), sopravvivenza libera da progressione (PFS), la sopravvivenza globale (OS), tasso di sopravvivenza globale (OSR) ed espressione del PD-L1. Nella fase di aumento della dose, i parametri farmacocinetici

E.5.2.1

Timepoint(s) of evaluation of this end point

accrual period for each cohort (1-2Q 2016 for dose escalation and
expansion cohorts; 2Q 2017 nivolumab vs. sorafenib cohort and
nivolumab plus ipilimumab combination cohort; 3Q 2017 for cohort 5).

Gli endpoint secondari saranno determinati circa 6 mesi dopo il periodo di accrual per ogni coorte (1-2Q 2016 per coorti di aumento della dose e di espansione; 2Q 2017 per la coorte nivolumab vs sorafenib e la coorte di combinazione nivolumab più ipilimumab). 3Q 2017 per la coorte 5

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

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Exploratory Biomarker Assessments

Valutazione dei biomarcatori esplorativi

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 escalation, and multidose study of BMS-936558

Aumento della dose e studio multidose di BMS-936558

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

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Sorafenib (nella coorte Nivolumab vs Sorafenib in prima linea)

Sorafenib (in the 1L Nivolumab vs Sorafenib cohort)

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

Hong Kong

Japan

Korea, Republic of

Singapore

Taiwan

United States

Germany

Italy

Spain

United Kingdom

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 study will end when survival follow-up collection has concluded.
The last visit will be defined as the latest survival visit included in the
final analysis of OS (ie. the latest subject death, loss to follow up, or
withdrawal of consent).

Lo studio si concluder¿ quando la raccolta dei dati di sopravvivenza sar¿ conclusa.
L'ultima visita sar¿ definita come l'ultima visita di sopravvivenza inclusa nell¿analisi finale della sopravvivenza complessiva (es. L¿ultimo soggetto deceduto, perso al follow-up o che ha ritirato il consenso).

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:

372

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

248

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

250

F.4.2.2

In the whole clinical trial

620

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 study end subjects who continue to demonstrate clinical benefit will
be eligible to receive BMS supplied study drug. Study drug will be
provided via study extension, rollover study or another mechanism.BMS
can terminate access to study drug if:a) marketing application rejected
by responsible HA;b) study terminated due to safety concerns;c)subject
can obtain medication from a government sponsored or private health
program; or d) therapeutic alternatives become available in local
market

Il farmaco potrebbe essere fornito mediante studio di estensione, di roll-over o altro. L'accesso potrebbe essere interrotto se: a) il farmaco non viene approvato nel paese; o b) lo studio viene interrotto per problemi di sicurezza; o c) il soggetto può ottenere il farmaco attraverso un sistema sanitario privato o finanziato dal governo; o d) altre opzioni di trattamento diventano disponibili nel paese

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

2015-06-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-05-11

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

Select Country:	Select Age Range:
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Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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