Clinical Trials Register

Summary
EudraCT Number:	2017-001338-24
Sponsor's Protocol Code Number:	MK-3475-669(INCB024360-304)
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:	2021-02-09
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

2017-001338-24

A.3

Full title of the trial

A Phase 3 Randomized, Open-Label Clinical Study to Evaluate the Efficacy and Safety of Pembrolizumab plus Epacadostat, Pembrolizumab Monotherapy, and the EXTREME Regimen as First line Treatment for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (KEYNOTE-669/ECHO-304)

Studio clinico di fase 3, randomizzato, condotto in aperto per valutare l¿efficacia e la sicurezza di Pembrolizumab pi¿ Epacadostat, di Pembrolizumab in monoterapia e del regime EXTREME come trattamento di prima linea per il carcinoma a cellule squamose di testa e collo ricorrente o metastatico (KEYNOTE-669/ECHO-304)

A.3.1

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

Pembrolizumab plus epacadostat, pembrolizumab monotherapy, and the EXTREME regimen as first line treatment for R/M HNSCC (KEYNOTE-669/ECHO-304)

Pembrolizumab pi¿ Epacadostat, Pembrolizumab in monoterapia e regime EXTREME come trattamento di prima linea per R/M HNSCC (KEYNOTE-669/ECHO-304)

A.3.2

Name or abbreviated title of the trial where available

Pembrolizumab plus epacadostat, and the EXTREME regimen as first line tre for R/M HNSCC

Pembrolizumab pi¿ epacadostat, e regime EXTREME come trattamento di prima linea per R/M HNSCC

A.4.1

Sponsor's protocol code number

MK-3475-669(INCB024360-304)

A.5.4

Other Identifiers

Name:

IND NUMBER

Number:

134,159

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	INCYTE CORPORATION
B.1.3.4	Country	United States
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	Incyte Corporation
B.4.2	Country	United States
B.4.1	Name of organisation providing support	Merck Sharp&Dohme Corp,sussidiaria di Merck&Co,Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	MSD Italia Srl
B.5.2	Functional name of contact point	Divisione Ricerca Clinica
B.5.3	Address:
B.5.3.1	Street Address	Via Vitorchiano, 151
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00189
B.5.3.4	Country	Italy
B.5.4	Telephone number	00636191371
B.5.5	Fax number	00636380371
B.5.6	E-mail	gcto.italy@merck.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	-
D.3.2	Product code	[-]
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	PEMBROLIZUMAB
D.3.9.1	CAS number	1374853-91-4
D.3.9.2	Current sponsor code	MK-3475
D.3.9.4	EV Substance Code	SUB167136
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	25
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)	Yes
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	Epacadostat
D.3.2	Product code	INCB024360
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	EPACADOSTAT
D.3.9.1	CAS number	1204669-58-8
D.3.9.2	Current sponsor code	INCB024360
D.3.9.4	EV Substance Code	SUB182018
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	100
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	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	Epacadostat
D.3.2	Product code	INCB024360
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	EPACADOSTAT
D.3.9.1	CAS number	1204669-58-8
D.3.9.2	Current sponsor code	INCB024360
D.3.9.4	EV Substance Code	SUB182018
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	25
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¿
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.3.1	Product name	-
D.3.2	Product code	[-]
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	-
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	Carboplatin-Actavis
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis Group PTC ehf.
D.2.1.2	Country which granted the Marketing Authorisation	Iceland
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	-
D.3.2	Product code	[-]
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	CARBOPLATINO
D.3.9.1	CAS number	41575-94-4
D.3.9.2	Current sponsor code	-
D.3.9.4	EV Substance Code	SUB06614MIG
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	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: 6
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	Fluorouracile-Teva
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Pharmacy Plc
D.2.1.2	Country which granted the Marketing Authorisation	Hungary
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	-
D.3.2	Product code	[-]
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	FLUOROURACILE
D.3.9.1	CAS number	51-21-8
D.3.9.2	Current sponsor code	-
D.3.9.4	EV Substance Code	SUB07721MIG
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	50
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: 7
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
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.3.1	Product name	-
D.3.2	Product code	[-]
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	-
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)	Yes
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: 8
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 Accord
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord healthcare S.L.U.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	-
D.3.2	Product code	[-]
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	-
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: 9
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	Fluorouracile
D.2.1.1.2	Name of the Marketing Authorisation holder	Hospira UK Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	-
D.3.2	Product code	[-]
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	FLUOROURACILE
D.3.9.1	CAS number	51-21-8
D.3.9.2	Current sponsor code	-
D.3.9.4	EV Substance Code	SUB07721MIG
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	50
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: 10
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	5-Fluorouracile "EBEWE"
D.2.1.1.2	Name of the Marketing Authorisation holder	EBEWE Pharma Ges.m.b.H. Nfg. KG
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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	-
D.3.2	Product code	[-]
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	FLUOROURACILE
D.3.9.1	CAS number	51-21-8
D.3.9.2	Current sponsor code	-
D.3.9.4	EV Substance Code	SUB07721MIG
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	50
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: 11
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	Carboplatino
D.2.1.1.2	Name of the Marketing Authorisation holder	Hospira UK Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	-
D.3.2	Product code	[-]
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	CARBOPLATINO
D.3.9.1	CAS number	41575-94-4
D.3.9.2	Current sponsor code	-
D.3.9.4	EV Substance Code	SUB06614MIG
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	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: 12
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	-
D.2.1.1.2	Name of the Marketing Authorisation holder	-
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	-
D.3.2	Product code	[-]
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	-
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: 13
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	-
D.2.1.1.2	Name of the Marketing Authorisation holder	-
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	-
D.3.2	Product code	[-]
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	FLUOROURACILE
D.3.9.1	CAS number	51-21-8
D.3.9.2	Current sponsor code	-
D.3.9.4	EV Substance Code	SUB07721MIG
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	50
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: 14
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	Carboplatino
D.2.1.1.2	Name of the Marketing Authorisation holder	-
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	-
D.3.2	Product code	[-]
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	CARBOPLATINO
D.3.9.1	CAS number	41575-94-4
D.3.9.2	Current sponsor code	-
D.3.9.3	Other descriptive name	Carboplatino
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	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.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Carcinoma a cellule squamose di testa e collo ricorrente o metastatico

E.1.1.1

Medical condition in easily understood language

Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Carcinoma a cellule squamose di testa e collo ricorrente o metastatico

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

E.2 Objective of the trial

E.2.1

Main objective of the trial

To estimate ORR of pembrolizumab + epacadostat, pembrolizumab monotherapy, and the EXTREME regimen based on RECIST 1.1 by investigator determination.

Stimare l'ORR di pembrolizumab + epacadostat, pembrolizumab in monoterapia e il regime EXTREME basato su RECIST 1.1 in seguito a determinazione da parte dell'investigatore.

E.2.2

Secondary objectives of the trial

To evaluate the safety and tolerability of the 3 treatment groups.

Valutare la sicurezza e la tollerabilità dei 3 gruppi di trattamento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically or cytologically-confirmed R/M HNSCC that is considered incurable by local therapies will be enrolled in this study.
2. A male participant must agree to use contraception as detailed in Appendix 5 of this protocol during the treatment period and for at least 120 days after the last dose of pembrolizumab and epacadostat, or pembrolizumab alone, and for at least 180 days after the last dose of the EXTREME regimen, whichever is longer. He must also refrain from donating sperm during this period. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participant.
3. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 OR
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the treatment period and for at least 120 days after the last dose of pembrolizumab and epacadostat, or pembrolizumab alone, and for at least 180 days after last dose of the EXTREME regimen, whichever is longer. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participant.
4. The participant (or legally acceptable representative if applicable) provides written informed consent for the study.
5. Have measurable disease by CT or MRI based on RECIST 1.1 as determined by site radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions following radiation therapy.
6. Have an ECOG PS of 0 or 1 within 7 days prior to randomization.
7. Have adequate organ function as defined in the protocol. Specimens must be collected within =10 days prior to the start of study treatment.
8. Have documentation of results from testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using CINtec® p16 Histology assay and a 70% cutoff point. If HPV status was previously tested using this method, no additional testing is required.
9. Have a baseline archival tumor specimen available or is willing to undergo a pre-study treatment tumor core or excisional biopsy of a tumor lesion not previously irradiated, to obtain the specimen. Fine needle aspirate (FNA) and bone metastases samples are not acceptable.

1. In questo studio saranno arruolati partecipanti di sesso maschile/femminile che abbiano compiuto 18 anni di età alla data della firma del consenso
informato, affetti da HNSCC R/M confermato istologicamente o citologicamente
e considerato incurabile con le terapie locali.
2. I partecipanti di sesso maschile devono accettare di impiegare uno dei metodi contraccettivi descritti nell’Appendice 5 del protocollo durante il
periodo di trattamento e per almeno 120 giorni dopo l’ultima dose di pembrolizumab ed epacadostat o di pembrolizumab da solo e per almeno 180 giorni dopo l’ultima dose del regime EXTREME, a seconda del periodo più lungo. Devono inoltre evitare di donare lo sperma durante questo periodo.
Nota: l’astinenza è accettabile se si tratta dello stile di vita abituale e del metodo contraccettivo preferito dal partecipante.
3. Una partecipante di sesso femminile è idonea alla partecipazione qualora non sia in stato di gravidanza, non stia allattando al seno e
soddisfi almeno una delle condizioni che seguono:
a.) Non sia donna in età fertile (WOCBP) secondo la definizione riportata nell’Appendice 5
OPPURE
b.) Sia una WOCBP che accetta di attenersi ai metodi contraccettivi dell’Appendice 5 durante il periodo di trattamento e per almeno 120 giorni dopo
l’ultima dose di pembrolizumab ed epacadostat o di pembrolizumab da solo e per almeno 180 giorni dopo l’ultima dose del regime EXTREME, a seconda del periodo più lungo.
Nota: l’astinenza è accettabile se si tratta dello stile di vita abituale e del metodo contraccettivo preferito dalla partecipante.
4. Il partecipante (o il rappresentante legale, ove applicabile) fornisce il consenso informato allo studio.
5. Presentare una malattia misurabile tramite TC o RMI in base ai criteri RECIST 1.1, in base ai risultati della revisione radiologica effettuata dal centro.
Le lesioni localizzate in una zona già sottoposta a radiazioni sono considerate misurabili se ne è stata dimostrata la progressione dopo la radioterapia.
6. Presentare un PS ECOG di 0 o 1 nei 7 giorni precedenti la randomizzazione.
7. Presentare una funzionalità d’organo adeguata come definito nel protocollo. I campioni devono essere prelevati entro =10 giorni dall’inizio del trattamento dello studio.
8. Avere la documentazione dei risultati del test dello stato dell’HPV per il tumore orofaringeo definito come test IHC per p16 utilizzando l’esame istologico
CINtec® per p16 e un punto di cut-off del 70%. Se lo stato dell’HPV è stato testato in precedenza utilizzando questo metodo, non è richiesto alcun test
aggiuntivo.
9. Disporre di un campione di tumore basale in archivio o essere disponibile a sottoporsi ad agobiopsia o biopsia escissionale del tumore pre-trattamento dello studio di una lesione tumorale non precedentemente irradiata al fine di ottenere
tale campione. I campioni di ago aspirato con ago sottile (FNA) e di metastasi ossee non sono accettabili.

E.4

Principal exclusion criteria

1Hs carcin of nasopharynx,salivary gland,unknown primary origin,or nonsquamous histologies as primary tumors2Hs disease progresswithin6months of completion of curatively intended syst treat for locoregionally advancHNSCC3Hs life expectancy of less than3months and hs rapidly progressing disease(tumor bleeding,unctrltumor pain)in opinion of treating investigator 4Hs hist ofbleeding requiring a medical intervent(embolizat procedure,RBCtransfusion,or hospitalizat)within30dys ofstud enrollment5Hs a hist of peripheral neuropathy=Grade2for pt who may receive cisplatin6Hs hist ofdihydropyrimidine dehydrogenase(DPD)defic(homozygous orheterozygous mutat)7Hs hist of any contraindication or hs a severe hypersensitivity to any components of epacadostat,pembro(=Grade3),cisplatin or carboplatin,cetux,5FU8Had allogenic tissue/solidorgantransplant9Hs a hist of gastrointestinal condition or procedure that may affect drug absorption10Any hist of Serotonin Syndr after receiving serotonergic drugs11WOCBP who hs positive urine pregnancy test within72hours before first dose of stud treat(App5)If urine test cannt be confirmed negative,serum pregnancy test is required.in such cases,participant must be excluded from participation if serum pregnancy result is positive12Hs received prior syst therapy(as part of multimodal treat)forHNSCCadministered in recurrent and/or metastatic setting for incurable disease13Hs nt fully recovered(=Grade1or a baseline)fromAEs due to a previously administer treat14Hs received prior palliative radioth within2wks of start of stud treat.Pt must have recover from all radiation-related toxicities,nt require corticosteroids,nt have had radiation pneumonitis15Hs receiv prior therapy with epacadostat or anyIDO1inhib,antiPD1,antiPDL1,antiPDL2agent,or any agent directed to anther stimulatory or coinhibTcellR(CTLA4,OX40,CD137)16Hs received live vaccine within30dys prior to the first dose ofstud treat17Hs received therapy with anMAOI,melatonin supplement,UGT1A9inhibitor within21dys prior to starting treat,or anticipates requiring one of thse prohibited medicats during treat phse18Current use of any prohibited medicat as described inSect7.7.3of protocol19Is currently pt in orhs participated in a stud of aninvestigational agent or hs used an investigational device within4wks prior to first dose of stud treat20Hs a diagnosis of immunodefic or is receiving chronic syst steroid therapy(dosing exceeding10mg daily of prednisone orequivalent)or any other form of immunosuppressive therapy within7dys prior to first dose of stud treat.Corticosteroid use as premedicat for allergic react(IVcontrast)is permitted21Hs a known additional malignancy that’s progressing or hs required active syst treat within past3years22Hs known active central nervous syst metastases or carcintous meningitis23Hs active autoimm disease that hs required syst treat in past2years24Hs hist of(noninfectious)pneumonitis that required steroids orhs current pneumonitis25Hs active infection requiring syst therapy26Hs known hist of human immunodefic virus(HIV)infection.NoHIVtesting is required unless mandated by local health authority27Hs known hist of or ispositive for active hepatitisB(defined as hepatitisBsurface antig[HBsAg]reactive)or hepatitisC(defined asHCVRNAis detected)28Hs known psychiatric or substance abuse disorders that would interfere with cooperating with requirements of stud29Hs hist orcurrent evidence ofanycondition,therapy or lab abnormality that might confound the results of stud,interfere with participant’s participation for full duration of the stud,or isnt in the best interest of the participant to participate,in opinion of treating investigator.30Is pregnant or breastfeeding,or expecting to conceive or father children within projected duration of the stud,starting with Screen Visit through120dys after last dose of pembro and epacadostat or pembro montherapy and up to180dys after last dose ofEXTREMEregimen31Screen correctQT(QTc)interval>480ms is excluded

1Cancro della nasof,delle ghiand saliv,di orig prim scon o con istol n squam come tum prim
2Progres della mal entro6m dal compl di un trat sistem con int curat per HNSCCavanzato a liv lochgio
3 Aspett di vita infer a3mesi e/o mal in rapida progres(sang della massa tumor,dol incontroll sede del tumor)sec l’opin dello sper resp del trat
4Anamn di sang che richiede interv med(proced di embolizzaz,trasfus di glo rossi o ricovero)entro30g dall’arrl nello stu
5Per i pt che pos assum cisplatino:anamn di neurop perif=Grado2
6Anamn di defic dell’enzimDPD(mut omoz o eteroz)
7Anamn di qls controind o ipersens grav a qls comp di epacadostat,pembrolizumab(=Grado3)cisplatino o carboplatino,cetuximab e5FU
8Trapianto di org solid/tess allog
9Anamn di pat o proced gastr che può influenzare assorb del f
10Qls anamn di sindr da seroton suc all’assunz di fi serotoninerg
11WOCBP con test di gravid sulle urin posit nelle72hpreced la1dose del trat dello stu(App5).In caso n sia possib conf la negativ test urin,è rich test di gravid sul siero.In tali casi,la pt deve ess esclusa dalla partecip se il risultato del test di gravid sul siero è posit
12Terap sistem preced(come parte del trat multim)perHNSCCsomministr in amb ricor e/o metast per mal incurab
13Ristabiliz n raggiun o incompl(vale a dire=Grado1o basale)da AEs dovuti a un trat somminis prec
14Radiot pall nelle2set preced inizio del trat dello stu.I pt devono esser guariti da tutte le toss correl alla radiot,n necessit di corticoster e n present polmonit da radiaz
15Terap prec con epacadostat o qls inib diIDO1 un agente antiPD1,antiPDL1 o antiPDL2 o con qls agentdiret contro altro recett stimol o coinib delle cellT(CTLA4,OX40,CD137)
16Somm di un vacc viv nei30gprec la1dose del trat dello stu
17Terap con unIMAO,un integrat della melat o un inib diUGT1A9nei21g preced l’inizio del trat o event prevista neces di uno di questi fi n consentiti durante la fase di trat
18Assunz in cor di un f n consent,come descrit nella Sez7.7.3
19Part in corso o pregres a uno stu condot su un agent sperim o utiliz di un dispos sperim nelle4set preced la1dose del trat dello stu.Nota:i pt che sono entr nella fas di followup posttrat di uno stu spe pos partecip a condiz che siano passat4sett dall’ultima dos dell’agent sper preced
20Diagnosi di immunodef o assunz di una terap steroidea sistem cronica(a un dosag sup a10mg al giorno di prednisone o equivalente)o qls altra forma di ter immunosop nei7g preced la1dose del trat dello stu.L’uso dei corticoster come prefar per le reaz allerge(al mezzo di contrasto EV)è cons
21Presenza di ulter malignità nota che è progredit o ha richiesto trat sistem attiv negli ultimi3anni
22Presenza di metast attive note al SNCe/o mening carc
23Malattia autoim in fase attiv che ha richiest un trat per via sistem negli ultimi2anni
24Anamn di polm(n infett)che ha richiesto uso di steroidi o polmon in cor
25Inf att che richied una terap per via sistem
26Anamn nota di infezione da HIV.Il test per l’HIV n è nec,a meno che n venga richiesto dall’autorità sanit loc
27Anamn nota o posit per l’epatBattiva(definita come reattiva all’antigene di superf dell’epatiteB [HbsAg])o epatiteCattiva(definita come HCV RNA[qualitativa])rilevata
28Disturbi noti di natura psichiatrica o di abuso di sostan che potreb interfer con la collab e con i requ dello stu
29Anamn o prova ricorre di qls condiz,terap o valori di lab anomali che potrebb inficiare i risult dello stu, interferire con la partecip del sog per tutta la durat dello stu o far consider che n è nel miglior interes del sog parteciparvi,secondo l’op dello sperim respons del trat
30Gravid o allat al seno,o intenz di conc o gener figli nell’arco della durat stimata dello stu,a partire dalla visita di screening fino a120g dopo l’ultima dose di pembrolizumab ed epacadostat o pembrolizumab in monot e fino a180g dopo ultima dose del regimeEXTREME
31Il QTc allo screening>480millisec costit criterio di escl

E.5 End points

E.5.1

Primary end point(s)

ORR is defined as the proportion of participants in the analysis population who have a best response of CR or PR.

L'ORR è definito come la proporzione di partecipanti all'analisi popolazione che ha una migliore risposta di CR o PR.

E.5.1.1

Timepoint(s) of evaluation of this end point

Once the last patient has a week 9 scan (first imaging timepoint post randomization) completed or discontinues, ORR for preliminary efficacy evaluation can be performed.

Una volta che l'ultimo paziente ha una scansione alla settimana 9 (primo imaging timepoint post randomizzazione) completato o interrotto, ORR per la valutazione dell'efficacia preliminare può essere eseguita.

E.5.2

Secondary end point(s)

Objective Response Rate (ORR) - per RECIST 1.1 by BICR

Il tasso di risposta obiettiva (ORR), basato sulla BICR utilizzando i criteri RECIST 1.1

E.5.2.1

Timepoint(s) of evaluation of this end point

Every Three week post randomization up to 35 visits, post treatment follow up visits and survival visits

Ogni 3 settimane dopo la randomizzazione fino a 35 visite, dopo le visite di followup e dopo le visite di sopravvivenza

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

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

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

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Brazil

Canada

Japan

Korea, Republic of

Mexico

Taiwan

Turkey

United States

Austria

France

Germany

Hungary

Italy

Poland

Portugal

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

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:

437

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

188

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

Nessuno

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

2018-02-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-29

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

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Orphan Designation Number:
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