Clinical Trials Register

Summary
EudraCT Number:	2017-002676-87
Sponsor's Protocol Code Number:	CA209-9TM
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-01-04
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

Spain - AEMPS

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)

Estudio en fase III, aleatorizado, con doble enmascaramiento y controlado con placebo, de Nivolumab o Nivolumab con cisplatino, en combinación con radioterapia en participantes con Carcinoma de Células Escamosas de Cabeza y Cuello (CCECC) localmente avanzado elegibles o no para recibir tratamiento con cisplatino.

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

Estudio en fase III de Nivolumab o Nivolumab con cisplatino, en combinación con radioterapia en participantes con Carcinoma de Cabeza y Cuello

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	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.5.6	E-mail	clinical.trials@bms.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Opdivo (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
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	BMS-936558, MDX1106, ONO-4538
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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	CISPLATIN
D.3.9.1	CAS number	15663-27-1
D.3.9.3	Other descriptive name	CISPLATIN
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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.3.9.3	Other descriptive name	CISPLATIN
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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.3.9.3	Other descriptive name	CISPLATIN
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck KGaA
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.3.4	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.3.9.3	Other descriptive name	CETUXIMAB
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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/infusion
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/infusion
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 de células escamosas de cabeza y cuello (CCECC) en estadio avanzado

E.1.1.1

Medical condition in easily understood language

Advanced cancer of the head and neck

Cáncer de cabeza y cuello en estadio avanzado

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	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

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

Cohorte 1: participantes no elegibles para cisplatino
• Comparar la supervivencia sin acontecimientos (SSA) de nivolumab en combinación con radioterapia (RT) a la de cetuximab en combinación con RT en participantes con carcinoma de células escamosas de cabeza y cuello (CCECC) localmente avanzado que no reúnen los requisitos para la quimiorradioterapia (QRT) basada en cisplatino
Cohorte 2: participantes elegibles para cisplatino
• Comparar la SSA de nivolumab con cisplatino en combinación con RT frente a la SSA de cisplatino en monoterapia en combinación con RT, en participantes con CCECC localmente avanzado que son elegibles para recibir QRT basada en 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

Cohorte 1: participantes no elegibles para cisplatino
• Comparar la duración del control locorregional (DCLR) de nivolumab en combinación con RT frente a la de cetuximab en combinación con RT
• Comparar la supervivencia general (SG) de nivolumab en combinación con RT frente a la de cetuximab en combinación con RT
• Comparar la proporción sin deterioro significativo de los síntomas de nivolumab en combinación con RT frente a la de cetuximab en combinación con RT
Cohorte 2: participantes elegibles para cisplatino
• Comparar la DCLR de nivolumab con cisplatino en combinación con RT frente a la de cisplatino en monoterapia en combinación con RT
• Comparar la SG de nivolumab con cisplatino en combinación con RT frente a la de cisplatino en monoterapia en combinación con RT
• Comparar la proporción sin deterioro significativo de los síntomas de nivolumab con cisplatino en combinación con RT frente a la de cisplatino en monoterapia en combinación 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 N0-2or T1-3 N2 disease if smoking > 20 pack year history
*TNM 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.

• CCECC probado histológicamente en una de las siguientes ubicaciones primarias: cavidad bucal, orofaringe, hipofaringe y laringe.
• Enfermedad localmente avanzada no resecable, o resecable pero adecuada para un enfoque de conservación del órgano.
• Sin radioterapia ni tratamiento sistémico previos para el CCECC.
• Puntuación del Grupo Oncológico Cooperativo del Este (ECOG) de 0-1.
• Edad >18 años o mayoría de edad.
• Enfermedad medible por los criterios RECIST 1.1 y evaluación del tumor realizada antes de la aleatorización.
• Se deben enviar muestras suficientes de secciones del tejido tumoral en bloques fijados en formol e incluidos en parafina (FFIP) o sin marcar, nuevas o de archivo (<3 meses desde la fecha del consentimiento informado), con un informe patológico asociado, para la evaluación de los biomarcadores con el objetivo de determinar el estado PD-L1. El laboratorio central debe proporcionar una tecnología de respuesta interactiva (IRT) con confirmación de recepción del tejido tumoral evaluable antes de la aleatorización. La biopsia debe ser por escisión o incisión o con aguja gruesa. La aguja fina o la aspiración no son aceptables para su envío. El estado PD-L1 debe estar disponible antes de la aleatorización.
• Resultado de la prueba del VPH p16 disponible (realizada de forma local o central) para participantes con enfermedad orofaríngea.
• Los pacientes deben estar en las categorías de riesgo intermedio o alto*:
• Riesgo alto:
• Cavidad oral, hipofaringe, laringe, orofaringe (negativo para p16): Estadio III/IV
• Orofaringe (positivo para p16): Estadio III (T4 cualquier N o t1-3 N3 ); independientemente del estado de tabaquismo.
• Riesgo intermedio:
• Orofaringe (positivo para p16): T3 N0-2 o T1-3 N2 si el índice de consumo de cigarrillos es de >1 cajetilla diaria durante 20 años o equivalente.
* Estadificación tumor, ganglios, metástasis (TNM) según la versión 8 del Comité Americano Conjunto sobre Cáncer (AJCC).

Criterios de inclusión específicos (grupo A y grupo B) para la cohorte 1 (participantes no elegibles para cisplatino)
• El médico considera al participante no elegible para el tratamiento con quimiorradioterapia (QRT) basada en platino. Esto debe ser por una o más de las siguientes razones:
• Edad de ≥70 años en el momento de la inclusión.
• Aclaramiento de creatinina <60 ml/min y >30 ml/min (mediante la fórmula Cockcroft-Gault; véase a continuación**).
• Pérdida de audición grave (umbral de audición mínimo de 80 dB o más en cualquiera de los oídos).
Criterios de inclusión específicos (grupo C y grupo D) para la cohorte 2 (participantes elegibles para cisplatino)
• Función renal adecuada en los 28 días previos a la aleatorización, como sigue:
• Aclaramiento de creatinina ≥60 ml/min determinado por la recogida a las 24 horas o estimado según la fórmula de Cockcroft-Gault:
Aclaramiento de creatinina = (140 - edad) x (peso en kg)/Creatinina sérica mg/dl × 72**

** Los participantes de ≥70 años de edad pueden entrar en la cohorte 1 o 2, dependiendo de si la evaluación del médico es que
el participante es elegible para cisplatino (cohorte 2) o no elegible para cisplatino (cohorte 1) en función de su edad. Se prevé que, en la mayoría de los casos, los pacientes de ≥70 años de edad se considerarán no elegibles para cisplatino y entrarán en la cohorte 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.

• Carcinoma que tenga origen en la nasofaringe o en los senos paranasales, carcinoma de células escamosas que se originó en la piel y en las glándulas salivales o histología no escamosa (p. ej., melanoma de mucosas) y carcinoma de células escamosas de origen primario desconocido.
• Indicios clínicos o radiológicos de enfermedad metastásica.
• Radioterapia previa que se solape con campos de radiación.
• Cualquier trastorno médico grave o no controlado que, en opinión del investigador, pueda aumentar el riesgo asociado con la participación en el estudio o la administración del fármaco del estudio, afectar a la capacidad del participante para recibir el tratamiento del protocolo, o interferir con la interpretación de los resultados del estudio.
• Angina inestable activa y/o insuficiencia cardíaca congestiva.
• Infarto de miocardio en los 6 meses previos a la aleatorización.
• Los participantes que tengan una pérdida de peso de >10 % de peso corporal entre la selección y la aleatorización se eliminarán del estudio.
• Participantes con enfermedad autoinmunitaria activa, conocida o sospechada. Se permite la inclusión de participantes con diabetes mellitus de tipo I, hipotiroidismo que solo requiera sustitución hormonal, trastornos cutáneos (como vitíligo, psoriasis o alopecia) que no requieran tratamiento sistémico, o enfermedades que no se espera que vuelvan a ocurrir en ausencia de un desencadenante externo.
• Participantes con una afección que requiera tratamiento sistémico con corticosteroides (>10 mg diarios de prednisona o equivalente) u otro inmunosupresor durante los 14 días previos a la aleatorización. Se permiten los esteroides inhalados o tópicos y esteroides de sustitución suprarrenal a dosis equivalentes a >10 mg diarios de prednisona, en ausencia de enfermedad autoinmunitaria activa.

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.

El criterio de valoración principal de ambas cohortes es la SSA. La SSA se define como el tiempo desde la aleatorización hasta la progresión radiográfica, según lo determinado por una revisión central independiente enmascarada (RCIE) mediante RECIST 1.1 o, para los participantes que no tengan progresión radiológica, el tiempo desde la aleatorización hasta la muerte.

E.5.1.1

Timepoint(s) of evaluation of this end point

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

Se comparará formalmente la SSA entre los grupos en cada cohorte. Consulte la sección 10.3 del protocolo.

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 diseaserelated symptom score derived from items included in the EORTC QLQC30 and QLQQ-H&N35, at 24 weeks following treatment completion.

• La DCLR se define como el tiempo desde la aleatorización hasta la recaída locorregional.
• La SG se define como el tiempo desde la aleatorización hasta la muerte por cualquier causa.
• La proporción sin deterioro significativo de los síntomas se define como la proporción sin empeoramiento significativo en una puntuación de síntomas relacionados con la enfermedad, derivada de los elementos incluidos en los cuestionarios de calidad de vida EORTC QLQ-C30 y QLQQ-H&N35, 24 semanas después de la finalización del tratamiento.

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

Se evalúa a lo largo del estudio. Consulte la sección 10.3 del protocolo.

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

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, 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

UVUP

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

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

Representantes legales (según la legislación del país) pueden firmar el consentimiento en diversas situaciones

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.

Al final del estudio, los participantes que muestren beneficio clínico serán elegibles para recibir el tratamiento del estudio suministrado por BMS durante la duración máxima del tratamiento especificada en la Sección 7.1 del protocolo. El tratamiento del estudio se proporcionará a través de una extensión del estudio, un estudio de renovación que requiere aprobación de la autoridad Competente de salud y el comité de ética o mediante otro mecanismo a discreción de 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

2018-02-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-02-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-10-14

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