Clinical Trials Register

Summary
EudraCT Number:	2017-002676-87
Sponsor's Protocol Code Number:	CA209-9TM
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-11-04
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

2017-002676-87

A.3

Full title of the trial

A Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Nivolumab or Nivolumab plus Cisplatin, in Combination with Radiotherapy
in Participants with Cisplatin Ineligible and Cisplatin Eligible Locally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Studio di fase 3, randomizzato, in doppio cieco, controllato verso placebo di nivolumab o nivolumab pi¿ cisplatino, in combinazione con radioterapia in partecipanti idonei e non al cisplatino con carcinoma a cellule squamose della testa e del collo (SCCHN) localmente avanzato.

A.3.1

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

A Phase 3 Study of Nivolumab or Nivolumab plus Cisplatin, in Combination with Radiotherapy in Patients with Advanced Cancer of the Head and Neck

Studio di fase 3 di nivolumab o nivolumab pi¿ cisplatino, in combinazione con radioterapia in pazienti con carcinoma avanzato della testa e del collo

A.3.2

Name or abbreviated title of the trial where available

A Phase 3 Study of Nivolumab or Nivolumab plus Cisplatin, in Combination with Radiotherapy in Patien

Uno studio di fase 3 su Nivolumab o Nivolumab pi¿ cisplatino, in combinazione con radioterapia in pa

A.4.1

Sponsor's protocol code number

CA209-9TM

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	ristol-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	ristol-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	0
B.5.5	Fax number	0
B.5.6	E-mail	clinical.trials@bms.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	NIVOLUMAB - 10ml vial
D.3.2	Product code	BMS-936558
D.3.4	Pharmaceutical form	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.3.9.4	EV Substance Code	SUB122750
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	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	Cisplatin Neocorp 1 mg/ml (100 mg/ vials)
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.3.4	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	CISPLATINO
D.3.9.1	CAS number	15663-27-1
D.3.9.2	Current sponsor code	NA
D.3.9.4	EV Substance Code	SUB07483MIG
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	1
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: 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	Cisplatin-Ebewe
D.2.1.1.2	Name of the Marketing Authorisation holder	EBEWE Pharma
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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.3.4	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	CISPLATIN
D.3.9.1	CAS number	15663-27-1
D.3.9.2	Current sponsor code	NA
D.3.9.4	EV Substance Code	SUB07483MIG
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	1
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	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	Cisplatin TEVA, 1mg/ml concentrate for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA 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.3.4	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	CISPLATIN
D.3.9.1	CAS number	15663-27-1
D.3.9.2	Current sponsor code	NA
D.3.9.4	EV Substance Code	SUB07483MIG
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	1
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	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	ERBITUX - 5 MG/ML SOLUZIONE PER INFUSIONE - USO ENDOVENOSO- FLACONCINO (VETRO) 100 ML 1 FLACONCINO
D.2.1.1.2	Name of the Marketing Authorisation holder	MERCK KGAA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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.3.4	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	CETUXIMAB
D.3.9.1	CAS number	205923-56-4
D.3.9.2	Current sponsor code	NA
D.3.9.4	EV Substance Code	SUB01178MIG
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: 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 - 10 MG/ML- CONCENTRATO PER SOLUZIONE PER INFUSIONE- USO ENDOVENOSO- FLACONCINO (VETRO)- 10 ML- 1 FLACONCINO
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	Italy
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	NIVLUMAB - 10ml vial - COMMERCIAL
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.3.9.4	EV Substance Code	SUB122750
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)

carcinoma a cellule squamose della testa e del collo

E.1.1.1

Medical condition in easily understood language

Advanced cancer of the head and neck

Cancro avanzato della testa e del collo

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	PT
E.1.2	Classification code	10060121
E.1.2	Term	Squamous cell carcinoma of head and neck
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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

Cohort 1: cisplatin-ineligible participants
¿ To compare the event free survival (EFS) of nivolumab in combination
with radiotherapy (RT) to that of cetuximab in combination with RT in
participants with locally advanced squamous cell carcinoma of the head
and neck (SCCHN) who are ineligible for cisplatin based
chemoradiotherapy (CRT)
Cohort 2: cisplatin-eligible participants
¿ To compare the EFS of nivolumab plus cisplatin in combination with RT
to that of cisplatin alone in combination with RT, in participants with
locally advanced SCCHN who are eligible for cisplatin based CRT

Coorte 1: partecipanti non idonei a cisplatino
- Confrontare la sopravvivenza libera da eventi (EFS) di nivolumab in combinazione con radioterapia (RT) a quella di cetuximab in combinazione con RT in partecipanti con carcinoma a cellule squamose della testa e del collo (SCCHN) localmente avanzato che non sono idonei a chemio-radioterapia (CRT) a base di cisplatino
Coorte 2: partecipanti idonei a cisplatino
- Confrontare la EFS di nivolumab pi¿ cisplatino in combinazione con RT rispetto a quella di cisplatino in monoterapia in combinazione con RT in partecipanti con SCCHN localmente avanzato che sono idonei a CRT a base di cisplatino

E.2.2

Secondary objectives of the trial

Cohort 1: cisplatin-ineligible participants
¿ To compare the duration of loco-regional control (DLRC) of nivolumab
in combination with RT to that of cetuximab in combination with RT
¿ To compare the overall survival (OS) of nivolumab in combination with
RT to that of cetuximab in combination with RT
¿ To compare the proportion without meaningful symptom deterioration
of nivolumab in combination with RT to that of cetuximab in combination
with RT

Cohort 2: cisplatin-eligible participants
¿ To compare the DLRC of nivolumab plus cisplatin in combination with
RT to that of cisplatin alone in combination with RT
¿ To compare the OS of nivolumab plus cisplatin in combination with RT
to that of cisplatin alone in combination with RT
¿ To compare the proportion without meaningful symptom deterioration
of nivolumab plus cisplatin in combination with RT to that of cisplatin
alone in combination with RT

Coorte 1:
- Confrontare la durata del controllo loco-regionale (¿duration of loco-regional control¿, DLRC) di nivolumab in combinazione con RT a quella di cetuximab in combinazione con RT
- Confrontare la dur-ata della sopravvivenza globale (OS) di nivolumab in combinazione con RT a quella di cetuximab in combinazione con RT
- Confrontare la proporzione senza significativo deterioramento dei sintomi di nivolumab in combinazione con RT a quella di cetuximab in combinazione con RT

Coorte 2:
- Confrontare la DLRC di nivolumab pi¿ cisplatino in combinazione con RT a quella di cisplatino in monoterapia in combinazione con RT
- Confrontare la OS di nivolumab pi¿ cisplatino in combinazione con RT a quella di cisplatino in monoterapia in combinazione con RT
- Confrontare la proporzione senza deterioramento significativo dei sintomi di nivolumab pi¿ cisplatino in combinazione con RT a quella di cisplatino in monoterapia in combinazione con RT

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Histologically proven SCCHN from one of the following primary sites:
oral cavity, oropharynx, hypopharynx, and larynx
• Locally advanced disease which is un-resectable, or resectable but
suitable for an organ sparing approach
• No previous radiotherapy or systemic treatment for SCCHN
• Eastern cooperative oncology group (ECOG) score of 0-1
• Age = 18 years or age of majority
• Measurable disease by RECIST 1.1 criteria, and tumor assessment
performed prior to randomization
• Sufficient sample of fresh or archival (< 3 months from informed
consent date) formalin-fixed, paraffin-embedded (FFPE) tissue block, or
unstained tumor tissue sections, with an associated pathology report,
must be submitted for biomarker evaluation for PD-L1 status. Central lab
must provide Interactive Response Technology (IRT) with confirmation
of receipt of evaluable tumor tissue prior to randomization. Biopsy
should be excisional, incisional or core needle. Fine needle or aspiration
is unacceptable for submission. PD-L1 status must be available prior to
randomization.
• HPV p16 test result available (performed locally or centrally) for
participants with oropharyngeal disease
•Patients must be of intermediate or high risk categories*:
• High risk:
• Oral cavity, hypopharynx, larynx, oropharynx (p16 negative): Stage
III/ IV
• Oropharynx (p16 positive): Stage III (T4 any N or T1-3 N3) -
irrespective of smoking status.
• Intermediate risk:
• Oropharynx (p16 positive): T3 N0-2 or T1-3 N2 disease if smoking >
20 pack year history
*TNM clinical staging according to AJCC version 8

Cohort 1 (cisplatin-ineligible participants) Specific Inclusion Criteria
(Arm A and Arm B)
• Physician assesses participant to be non-eligible for treatment with
platinum based combined CRT. This must be for one or more of the
following reasons:
• Age = 70 years at enrolment
• Creatinine clearance < 60mL/min and > 30mL/min (using the
Cockcroft and Gault formula– see below**)
• Severe hearing loss (minimal hearing threshold of 80 dB or more in
either ear)
Cohort 2 (cisplatin-eligible participants) Specific Inclusion Criteria (Arm
C and Arm D)
• Adequate renal function within 28 days prior to randomization as
follows:
• Creatinine clearance = 60 mL/min. as determined by 24 hour collection
or estimated by Cockcroft-Gault formula:
Creatinine Clearance = [(140 - age) x (wt in kg)/Serum Cr mg/dL x
72**

**Participants aged = 70 years may enter either Cohort 1 or 2
dependent on whether the physician's assessment is that
the participant is eligible for cisplatin (Cohort 2) or ineligible for
cisplatin (Cohort 1) based on their age. It is anticipated that in the
majority of cases, patients aged = 70 years will be considered ineligible
for cisplatin and enter cohort 1.

• SCCHN istologicamente comprovato da uno dei seguenti siti primari: cavo orale, orofaringe, ipofaringe e laringe
Malattia localmente avanzata non resecabile o resecabile, ma idonea per un approccio di conservazione dell’organo
• Nessuna precedente radioterapia o trattamento sistemico per il SCCHN
Punteggio ECOG (Eastern Cooperative Oncology Group) di 0-1
• Età = 18 anni o maggiorenne
• Malattia misurabile tramite i criteri RECIST 1.1 e valutazione del tumore effettuata prima della randomizzazione
• Per la valutazione dei biomarcatori per lo stato PD-L1 deve essere inviato un campione sufficiente di blocco di tessuto fresco o archiviato (< 3 mesi dalla data del consenso informato) fissato in formalina e incluso in paraffina (FFPE), oppure sezioni di tessuto tumorale non colorate, con associato un referto di patologia. Il laboratorio centrale deve fornire la tecnologia di risposta interattiva (IRT, Interactive Response Technology) con conferma di ricezione del tessuto tumorale valutabile prima della randomizzazione. La biopsia deve essere di recisione, di incisione o percutanea. Non sono ammesse biopsie tramite ago aspirato. Lo stato PD-L1 deve essere disponibile prima della randomizzazione.
• Disponibilità del risultato del test HPV p16 (eseguito localmente o a livello centrale) per i soggetti con malattia orofaringea
• I pazienti devono appartenere alla categoria di rischio intermedia o elevata*:
• Rischio elevato:
• Cavo orale, ipofaringe, laringe, orofaringe (p16 negativo): Stadio III/ IV
• Orofaringe (p16 positivo): Stadio III (T4 qualsiasi N o T1-3 N3) - indipendentemente dallo stato o meno di fumatore.
• Rischio intermedio:
• Orofaringe (p16 positivo): T3 N0-2, T1-3 N2 se fumatore anamnesi annuale > 20 pacchetti
*Stadiazione clinica TNM in conformità con AJCC versione 8

Criteri di inclusione specifici (Braccio A e Braccio B) coorte 1 (partecipanti non idonei al cisplatino)
• Il medico valuta che il/la partecipante non sia idoneo/a al trattamento combinato con CRT a base di platino. La non idoneità deve essere per uno o più dei seguenti motivi:
• Età = 70 anni all’arruolamento
Clearance della creatinina < 60 mL/min e > 30 mL/min (mediante formula di Cockcroft-Gault, vedere di seguito**)
• Grave perdita dell’udito (soglia minima dell’udito di 80 dB o più per ogni orecchio)
Criteri di inclusione specifici (Braccio C e Braccio D) coorte 2 (partecipanti idonei al cisplatino)
• Idonea funzione renale entro 28 giorni prima della randomizzazione come segue:
• Clearance della creatinina = 60 mL/min determinata con raccolta nelle 24 ore o stimata mediante formula di Cockroft-Gault:
Clearance della creatinina = [(140 - età) x (peso in kg)/Cr sierica mg/dL x 72**

** I partecipanti di età = 70 anni possono essere arruolati nella Coorte 1 o 2 in base alla valutazione del medico di idoneità al
cisplatino (Coorte 2) o non idoneità al cisplatino (Coorte 1) del/della partecipante sulla base dell’età. Si prevede che nella maggior parte dei casi i pazienti di età = 70 anni saranno considerati non idonei al cisplatino e saranno quindi assegnati alla coorte 1.

E.4

Principal exclusion criteria

• Carcinoma originating in the nasopharynx or paranasal sinus,
squamous cell carcinoma that originated from the skin and salivary
gland or non-squamous histology (eg, mucosal melanoma), squamous
cell carcinoma of unknown primary
• Clinical or radiological evidence of metastatic disease
• Prior radiotherapy that overlaps with radiation fields
• Any serious or uncontrolled medical disorder that, in the opinion of the
investigator, may increase the risk associated with study participation or
study drug administration, impair the ability of the participant to receive
protocol therapy, or interfere with the interpretation of study results
• Active unstable angina and/or congestive heart failure
• Myocardial infarction within 6 months prior to randomization
• Participants who have a weight loss of > 10% of body weight between
screening and randomization will be removed from the study
• Participants with an active, known or suspected autoimmune disease.
Participants with type I diabetes mellitus, hypothyroidism only requiring
hormone replacement, skin disorders (such as vitiligo, psoriasis, or
alopecia) not requiring systemic treatment, or conditions not expected
to recur in the absence of an external trigger are permitted to enroll.
• Participants with a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalent) or other
immunosuppressive medications within 14 days of randomization.
Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Participants with active interstitial lung disease (ILD) / pneumonitis or with a history of ILD /pneumonitis requiring steroids.

• Carcinoma con origine nella nasofaringe o seno paranasale, carcinoma a cellule squamose con origine cutanea e nelle ghiandole salivari oppure con istologia non squamosa (ad es. melanoma mucosale), carcinoma a cellule squamose con origine primaria sconosciuta
• Evidenza clinica o radiologica di malattia metastatica
• Precedente radioterapia che si sovrappone ai campi di radiazione
• Qualsiasi disturbo medico grave o non controllato che, nell’opinione dello sperimentatore, potrebbe aumentare il rischio associato alla partecipazione allo studio o alla somministrazione del farmaco in studio, compromettere la capacità del partecipante di ricevere la terapia del protocollo oppure interferire con l’interpretazione dei risultati dello studio
• Angina instabile attiva e/o insufficienza cardiaca congestizia
• Infarto miocardico nei 6 mesi precedenti la randomizzazione
• I partecipanti che presenteranno una perdita di peso > 10% del peso corporeo tra lo screening e la randomizzazione saranno rimossi dallo studio
• Partecipanti con una malattia autoimmune attiva, nota o sospetta. È concesso l’arruolamento di partecipanti con diabete mellito di tipo I, ipotiroidismo che richiede solo terapia ormonale sostitutiva, malattie cutanee (quali vitiligine, psoriasi o alopecia) che non richiedono trattamento sistemico o condizioni che si prevede non ricorrano in assenza di un elemento scatenante esterno.
• Partecipanti con una condizione che richiede trattamento sistemico con corticosteroidi (> 10 mg al giorno di prednisone o equivalente) o altri medicinali immunosoppressori entro 14 giorni dalla randomizzazione. Steroidi inalati o topici e dosi di steroidi per la terapia sostitutiva adrenergica > 10 mg al giorno di prednisone o equivalente sono concessi in assenza di malattia autoimmune attiva.
• Partecipanti che siano affetti da malattia polmonare interstiziale (ILD) attiva/polmonite o con un'anamnesi di ILD/polmonite richiedente steroidi.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint in both cohorts is EFS. EFS is defined as the time
from randomization to radiographic progression, as determined by a
Blinded Independent Central Review (BICR) using RECIST 1.1 or, for
participants who do not have radiographic progression, the time from
randomization to death.

L'endpoint primario in entrambe le coorti è l’EFS. Si definisce EFS il tempo dalla randomizzazione alla progressione radiografica, determinato da una Revisione centralizzata indipendente in cieco (BICR) mediante RECIST 1.1 o, per i partecipanti senza progressione radiografica, il tempo dalla randomizzazione al decesso.

E.5.1.1

Timepoint(s) of evaluation of this end point

L’EFS verrà confrontata formalmente tra bracci di ciascuna coorte, si prega di fare riferimento alla sezione 10.3 del protocollo

EFS will be compared formally between arms in each cohort, please refer
to section 10.3 of the protocol

E.5.2

Secondary end point(s)

¿ DLRC is defined as the time from randomization to loco-regional
relapse.
¿ OS is defined as time from randomization until death from any cause.
¿ Proportion without meaningful symptom deterioration is defined as the
proportion with no meaningful worsening in a disease-related symptom
score derived from items included in the EORTC QLQC30 and QLQH&
N35, at 24 weeks following treatment completion.

¿ Si definisce DLRC il tempo compreso dalla randomizzazione alla recidiva loco-regionale.
¿ La OS ¿ definita come il tempo intercorso tra la randomizzazione ed il decesso per una qualsiasi causa.
¿ Si definisce proporzione senza significativo deterioramento dei sintomi la proporzione senza significativo peggioramento in un punteggio di sintomi correlati alla malattia derivato da elementi inclusi nei QLQC30 e QLQQ-H&N35 di EORTC, dopo 24 settimane dal completamento del trattamento.

E.5.2.1

Timepoint(s) of evaluation of this end point

Evaluated throughout the study, please refer to section 10.3 of the
protocol

Valutata nel corso dello studio, si prega di fare riferimento alla sezione 10.3 del protocollo

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

Yes

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

Argentina

Australia

Belgium

Brazil

Canada

China

Colombia

France

Germany

Italy

Japan

Korea, Democratic People's Republic of

Mexico

Poland

Romania

Russian Federation

Spain

Taiwan

Turkey

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

291

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

755

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

Legally acceptable representatives (as per country guidelines) may provide consent in certain situations

Rappresentati legali accettabili (da linee guida nazionali) possono fornire il consenso in determinate situazioni

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

341

F.4.2.2

In the whole clinical trial

1046

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, participants who continue to
demonstrate clinical benefit will be eligible to receive BMS supplied
study treatment for the maximum treatment duration specified in
protocol Section 7.1. Study treatment will 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.

A conclusione dello studio, i partecipanti che continuano a
dimostrare un beneficio clinico saranno idonei a ricevere il trattamento in studio fornito da BMS per la massima durata del trattamento specificata nel protocollo nella sezione 7.1. Il trattamento in studio sar¿ fornito tramite un¿estensione dello studio, uno studio di rollover che richiede l¿approvazione dell¿autorit¿ sanitaria responsabile e del comitato etico, o attraverso un altro meccanismo a discrezione di BMS.

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-03-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-02-28

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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Orphan Designation Number:
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