Clinical Trials Register

Summary
EudraCT Number:	2016-000373-21
Sponsor's Protocol Code Number:	IRX-22015A
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:	2018-02-22
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

2016-000373-21

A.3

Full title of the trial

A Randomized Phase 2 Trial of Neoadjuvant and Adjuvant Therapy with the
IRX-2 Regimen in Patients with Newly Diagnosed Stage II, III or IVA Squamous Cell Carcinoma of the Oral Cavity

Studio di fase 2 randomizzato della terapia neoadiuvante e adiuvante con il regime IRX 2, in pazienti con carcinoma squamocellulare del cavo orale in stadio II, III o IVA di nuova diagnosi

A.3.1

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

A Randomized Phase-2 Trial to Evaluate the Effects of the IRX-2 Regimen before Surgery and after Chemotherapy or Radiation in Newly Diagnosed Patients with Stage II, III or IVA Squamous Cell Cancer of the Oral Cavity

Studio di fase 2 randomizzato per valutare gli effetti con il regime IRX 2, in pazienti con carcinoma squamocellulare del cavo orale in stadio II, III o IVA di nuova diagnosi

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

IRX-22015A

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02609386

A.5.4

Other Identifiers

Name:

Number:

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	IRX THERAPEUTICS, INC.
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	IRX Therapeutics, 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	Pivotal S.L.
B.5.2	Functional name of contact point	Pivotal Medical Department
B.5.3	Address:
B.5.3.1	Street Address	Calle Gobelas 19
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28023
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34 91 7081 250
B.5.5	Fax number	+34 91 7081 301
B.5.6	E-mail	vanesa.pons@pivotal.es

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	IRX-2
D.3.2	Product code	NA
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	IRX-2
D.3.9.3	Other descriptive name	Primary Cytokine Components: IL-2, IL-1β, IFN-γ and TNF-α.
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	115
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	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	ENDOXAN BAXTER - 500 MG POLVERE PER SOLUZIONE INIETTABILE 1 FLACONE
D.2.1.1.2	Name of the Marketing Authorisation holder	BAXTER S.P.A.
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	CICLOFOSFAMIDE
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CICLOFOSFAMIDE
D.3.9.1	CAS number	50-18-0
D.3.9.2	Current sponsor code	NA
D.3.9.4	EV Substance Code	SUB06859MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	500 to 1000
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	Yes
D.2.1.1.1	Trade name	INDOXEN - 25 MG CAPSULE RIGIDE 25 CAPSULE
D.2.1.1.2	Name of the Marketing Authorisation holder	SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE SPA
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	INDOMETACINA
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INDOMETACINA
D.3.9.2	Current sponsor code	na
D.3.9.3	Other descriptive name	INDOMETACINA
D.3.9.4	EV Substance Code	SUB08180MIG
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	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	OMEPRAZOLO DOC GENERICI - 20 MG CAPSULE RIGIDE GASTRORESISTENTI 5 CAPSULE IN FLACONE HDPE
D.2.1.1.2	Name of the Marketing Authorisation holder	DOC GENERICI SRL
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	OMEPRAZOLO
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	OMEPRAZOLO
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	OMEPRAZOLO
D.3.9.4	EV Substance Code	SUB09439MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 5
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Forceval
D.2.1.1.2	Name of the Marketing Authorisation holder	Alliance Pharmaceuticals Ltd
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	zinco contenente multivitamine
D.3.2	Product code	NA
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ZINCO SOLFATO
D.3.9.1	CAS number	7733-02-0
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	ZINCO SOLFATO
D.3.9.4	EV Substance Code	SUB12619MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	15 to 30
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Multivitamine e minerali
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	Multivitamine e minerali
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	15 to 30
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	ENDOXAN BAXTER - 500 MG POLVERE PER SOLUZIONE INIETTABILE 1 FLACONE
D.2.1.1.2	Name of the Marketing Authorisation holder	BAXTER S.P.A.
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	CICLOFOSFAMIDE
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CICLOFOSFAMIDE
D.3.9.1	CAS number	50-18-0
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	CICLOFOSFAMIDE
D.3.9.4	EV Substance Code	SUB06859MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	500 to 1000
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	INDOXEN - 25 MG CAPSULE RIGIDE 25 CAPSULE
D.2.1.1.2	Name of the Marketing Authorisation holder	SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE SPA
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	INDOMETACINA
D.3.2	Product code	NA
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INDOMETACINA
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	INDOMETACINA
D.3.9.4	EV Substance Code	SUB08180MIG
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: 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	OMEPRAZOLO DOC GENERICI - 20 MG CAPSULE RIGIDE GASTRORESISTENTI 5 CAPSULE IN FLACONE HDPE
D.2.1.1.2	Name of the Marketing Authorisation holder	DOC GENERICI SRL
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	OMEPRAZOLO
D.3.2	Product code	NA
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	OMEPRAZOLO
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	OMEPRAZOLO
D.3.9.4	EV Substance Code	SUB09439MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 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	Forceval
D.2.1.1.2	Name of the Marketing Authorisation holder	Alliance Pharmaceuticals Ltd
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	zinco contenente multivitamine
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	solfato di zinco
D.3.9.1	CAS number	7733-02-0
D.3.9.2	Current sponsor code	na
D.3.9.3	Other descriptive name	zinco
D.3.9.4	EV Substance Code	SUB12619MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	15 to 30
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Multivitamine e minerali
D.3.9.2	Current sponsor code	na
D.3.9.3	Other descriptive name	multivitamine
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	15 to 30
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

Newly Diagnosed Stage II, III or IVA Squamous Cell Carcinoma of the
Oral Cavity.

pazienti con carcinoma squamocellulare del cavo orale in stadio II, III o IVA di nuova diagnosi

E.1.1.1

Medical condition in easily understood language

You have recently been found to have advanced cancer in your oral cavity, called squamous cell cancer of the oral cavity.

E' stato recentemente diagnosticato un cancro avanzato nella cavità orale chiamato carcinoma squamocellulare del cavo orale

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	10041857
E.1.2	Term	Squamous cell carcinoma of the oral cavity
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

The primary objective is to determine if the event-free survival (EFS) of subjects treated with Regimen 1 (IRX-2 Regimen with cyclophosphamide, indomethacin, zinc, omeprazole and IRX-2)
is longer than for subjects treated with Regimen 2 (Regimen 1 with cyclophosphamide, indomethacin, zinc, omeprazole but without IRX-2). Key exploratory objectives for the detection of biological activity, prognostic and predictive factors, and clinical-pathologic-immunologic correlates, are included and defined in the protocol. The key exploratory endpoints will be analysed separately from, and not affect the primary endpoint analysis.

stabilire se la sopravvivenza libera da eventi (EFS) dei soggetti trattati con il Regime 1 sia più lunga di quella dei soggetti trattati con il Regime 2.

E.2.2

Secondary objectives of the trial

1. to determine if OS of subjects treated with Regimen 1 is longer than for subjects treated with Regimen 2;
2. to compare the safety of each Regimen;
3. to compare the feasibility of each Booster Regimen.

1) stabilire se la sopravvivenza globale (OS) dei soggetti trattati con il Regime 1 sia più lunga di quella dei soggetti trattati con il Regime 2;
2) confrontare la sicurezza di ciascun Regime;
3) confrontare la fattibilità di ciascun Regime booster.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Pathologically confirmed diagnosis of Stage II, III or IVA squamous cell cancer of the oral cavity (excluding the lip).
2. Subjects: males or females at least 18 years of age at study entry.
3. Disease is surgically resectable with a curative intent.
4. Karnofsky Performance Status ≥ 70%.
5. Haematological, Hepatic and Renal functions are adequate for surgical intervention.

6. Females of child-bearing potential must have negative urine/serum pregnancy test and agree to used a highly effective form of birth control.
7. Subjects are able to give Informed Consent and adhere to the protocol treatment plan.

1. Carcinoma squamocellulare del cavo orale (escluso il labbro) in stadio clinico II, III o IVA confermato da esame patologico

2. Maschi e femmine con almeno 18 anni di età
3. Malattia chirurgicamente resecabile con intento curativo

4. Performance Status di Karnofsky (KPS) ≥70%
5. Funzioni ematologiche, epatice e renali adeguate per l'intervento chirurgico
6. Le donne in età fertile devono avere i test di gravidanza urine/siero negative e accettare di usare un metodo contraccettivo altamente efficace
7. Disposti a e in grado di fornire il consenso informato e aderire alla terapia del protocollo

E.4

Principal exclusion criteria

1. Prior surgery, radiation or chemotherapy (excluding biopsy or any procedure required for supportive care).
2. Tumour of the oropharynx.
3. Tumour involvement likely to be associated with T4b cancer.
4. Distant metastased (M1 disease).
5. Diagnosis of another invasive cancer which is currently not in remission and has required treatment within the last 5 years.
6. Known infection with hepatitis B, C or HIV.
7. Use of any Investigational agent within 30 days of randomization.
8. Symptomatic cardiopulmonary disease which are not clinical stable.
9. Myocardial infarction within the last 3 months.
10. Stroke or other cerebral vascular insufficiency within last 3 months.
11. Daily use systemic immunosuppressive therapy or corticosteroids
(except for hormone deficiency) 30 days prior to randomization.
12. Known allergies to ciprofloxacin(or other quinolones) acetylsalicylic acid or indomethacin.

1. Precedente intervento chirurgico, radioterapia o chemioterapia diversi da biopsia o procedura di emergenza richiesta per la cura di supporto di questo tumore del cavo orale
2. Tumore dell’orofaringe
3. Coinvolgimento tumorale dei seguenti siti o uno qualsiasi di questi segni o sintomi verosimilmente associati a cancro T4b
4. Metastasi distanti (malattia M1)
5. Diagnosi pregressa di tumore invasivo dal quale il soggetto NON è libero da malattia E che ha richiesto il trattamento negli ultimi 5 anni
6. Infezione nota da epatite B, epatite C o HIV
7. Qualsiasi agente sperimentale nei 30 giorni precedenti
8. Malattia cardiopolmonare sintomatica non clinicamente stabile
9. Infarto del miocardio negli ultimi 3 mesi
10. Ictus o altri sintomi di insufficienza vascolare cerebrale negli ultimi 3 mesi
11. Somministrazione giornaliera di terapia immunosoppressiva sistemica o corticosteroidi (eccetto a dosi fisiologiche per deficit ormonale) nel corso dei 30 giorni precedenti
12. Allergia alla ciprofloxacina (o altri chinolonici), acido acetilsalicilico o indometacina

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is event-free survival (EFS).
Progression prior to surgical resection will not be considered an Event, but failure to resect tumor that was apparent at randomization for any reason or the presence of gross residual disease at surgery will be considered an Event. Progression after resection should be confirmed by biopsy, but in the absence of biopsy confirmation, unequivocal clinical evidence of progression in the primary or nodal sites or distant metastatic disease using RECIST v1.1 criteria will be accepted as progression. Scans (CT, MRI or PET) should be performed to restage disease and establish patterns of relapse. The date of progression will be the date on which the decision not to resect tumor that was apparent at randomization is made or the date upon which the Investigator first observes recurrent locoregional or metastatic disease by physical or radiologic examination. Death for any cause will also be considered an Event. Diagnosis of a second malignancy will not be considered an Event, but date of diagnosis, site and histology will be collected.

L’EFS sarà valutata attraverso un esame obiettivo nelle visite di follow-up di routine ogni 3 mesi dopo l’intervento chirurgico, per i primi due anni, e poi ogni 6 mesi durante gli anni 3 e 4 e mediante TC toraciche eseguite una volta all'anno per 4 anni. La progressione prima della resezione chirurgica non sarà considerata un Evento, ma l'insuccesso nella resezione di un tumore evidente alla randomizzazione per qualsiasi motivo sarà considerato un Evento. La progressione dopo la resezione deve essere confermata mediante biopsia; dovranno essere eseguiti esami (TC, RM o PET) per la ristadiazione della malattia e la definizione dei modelli di recidiva. La data di progressione sarà la data in cui viene presa la decisione di non asportare il tumore evidente alla randomizzazione, o in cui lo Sperimentatore osserva per la prima volta recidiva loco-regionale o malattia metastatica, mediante esame obiettivo o radiologico. Anche la morte per qualsiasi causa sarà considerata un Evento. La diagnosi di secondo tumore maligno non sarà considerata un Evento; tuttavia, saranno registrati data della diagnosi, sito e istologia.

E.5.1.1

Timepoint(s) of evaluation of this end point

EFS will be assessed by physical examination at routine follow-up visits every 3 months after surgery for the first two years and every 6 months during years 3 and 4 and by chest CT scans performed yearly x 4 years.

EFS valutati nelle visite di routine otni 3 mesi dopo l'intervento per i primi 2 anni, ed ogni 6 mesi durante il 3 e 4 anno e attraverso TAC torace annuali per i primi 4 anni

E.5.2

Secondary end point(s)

The secondary endpoints are overall survival (OS) and safety and feasibility.
Survival data will be collected in all subjects (phone contact after progression will be sufficient). When the subject comes to clinic and/or is contacted by phone, the date of that contact is to be reported as an update of the subject's survival.
Safety of each Regimen and feasibility of the Booster Regimens will be assessed by the incidence and severity of AEs, SAEs, and subject discontinuations.

I dati di sopravvivenza saranno raccolti in tutti i soggetti (sarà sufficiente il contatto telefonico dopo la progressione). La sicurezza di ciascun Regime e la fattibilità dei Regimi booster saranno valutate attraverso l'incidenza e la severità degli eventi avversi, gli eventi aversi seri e le interruzioni del trattamento da parte dei soggetti (come definito nel Protocollo).

E.5.2.1

Timepoint(s) of evaluation of this end point

Survival data will be collected at each study visit after surgery at 3, 6, 9,
12, 15, 18, 21, 24, 30, 36, 42, and 48 months with telephone calls for survival status to occur every 3 months if subject is not seen in follow- up until data collection ceases.
All subjects will be assessed for AEs as detailed in the study schedule. AEs will be measured from day of randomisation until 30 days post- surgery and subsequently from the first day of each booster Regimen until 30 days after the completion. SAEs will be measured from day of randomization until the subject ends the trial.

Dati di sopravvivenza raccolti ad ogni visita dopo l'intervento a 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, e 48 mesi con telefonate per verificare la sopravvivenza dei soggetti ogni 3 mesi se non si presentato al followup fino al termine della raccolta.
Tutti i soggetti saranno monitorati per le AE con da tempistica dello studio. AE sanno misurati dal giorno della randomizzazione fino a 30 giorni dopo l'intervento e successivamente dal primo giorno di ciascun regime booster fino a 30 giorni dal completamento. SAE saranno misurati dal giorno della randomizzazione fino alla conclusione dello studio da parte del soggetto.

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

E.6.7

Pharmacodynamic

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

Yes

E.6.13.1

Other scope of the trial description

Key exploratory objectives:
- changes in tumor size from baseline to surgery;
- lymphocyte infiltrates in the pre-treatment tumor biopsy, the surgical specimen and changes between these two samples.
Additional exploratory objectives:
- surgical pathology;
- prognostic and predictive factors and clinical-pathologic-immunologic correlates;
- Human papilloma virus (HPV) status;
- the peripheral T cell receptor profile;
- RNA expression profiling of immune-inflammatory markers.

Obiettivi esplorativi chiave:

1variazioni delle dimensioni del tumore dal basale all'intervento chirurgico
2infiltrati linfocitari nella biopsia tumorale pre-trattamento, nel campione chirurgico e le variazioni tra questi due campioni
3patologia chirurgica
4fattori prognostici e predittivi e fattori correlati clinici-patologici-immunologici
5 stato del papillomavirus umano HPV
6profilo dei recettori dei linfociti T periferici
7profiling dell'espressione dell’RNA dei marker immunoinfiammatori

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Il confronto è con il regime di trattamento con gli stessi componenti eccetto IRX-2

The comparator treatment regimen, has the same components except for
IRX-2.

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

Brazil

Canada

Germany

Italy

Spain

Switzerland

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

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

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

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

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

Yes

F.3.3.2

Women of child-bearing potential using contraception

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

200

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)

There are no plans for treatment or care after the subject has ended his/her participation in the trial other than standard of care.

Non sono previsti programmi per il trattamento dopo il termine dello studio.

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-10-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-09-22

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

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