Clinical Trials Register

Summary
EudraCT Number:	2017-003628-65
Sponsor's Protocol Code Number:	IMPROVE
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-10-06
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

2017-003628-65

A.3

Full title of the trial

Intermittent or continuous Panitumumab plus FOLFIRI for first-line treatment of patients with RAS/B-RAF wild-type metastatic colorectal cancer: a randomized phase 2 trial

A.3.1

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

Intermittent or continuous Panitumumab plus FOLFIRI for first-line treatment of patients with RAS/B-RAF wild-type metastatic colorectal cancer: a randomized phase 2 trial

Trattamento intermittente o continuo con Panitumumab + FOLFIRI in prima linea in pazienti affetti da tumore del colon-retto metastatico RAS/BRAF wild-type: studio randomizzato di fase 2

A.3.2

Name or abbreviated title of the trial where available

IMPROVE InterMittent Panitumumab plus folfiRi in metastatic cOlorectal cancer VErsus continuous trea

A.4.1

Sponsor's protocol code number

IMPROVE

A.5.4

Other Identifiers

Name:

IMPROVE

Number:

IMPROVE InterMittent Panitumumab plus folfiRi in m

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	ISTITUTO NAZIONALE TUMORI - IRCCS FONDAZIONE PASCALE
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AMGEN
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ISTITUTO NAZIONALE TUMORI - IRCCS FONDAZIONE PASCALE
B.5.2	Functional name of contact point	SC oncologia clinica sperimentale a
B.5.3	Address:
B.5.3.1	Street Address	Via M. Semmola
B.5.3.2	Town/ city	Napoli
B.5.3.3	Post code	80131
B.5.3.4	Country	Italy
B.5.4	Telephone number	0815903629
B.5.5	Fax number	0812140634
B.5.6	E-mail	a.avallone@istitutotumori.na.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	VECTIBIX - 20 MG/ML CONCENTRATO PER SOLUZIONE PER INFUSIONE - USO ENDOVENOSO 1 FLACONCINO (VETRO) 20 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	AMGEN EUROPE B.V.
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	PANITUMUMAB
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	PANITUMUMAB
D.3.9.1	CAS number	339177-26-3
D.3.9.2	Current sponsor code	PANITUMUMAB
D.3.9.3	Other descriptive name	PANITUMUMAB
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	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	IRINOTECAN HOSPIRA - 20MG/ML CONCENTRATO PER SOLUZIONE PER INFUSIONE 1 FLACONCINO IN VETRO DA 100MG/5ML
D.2.1.1.2	Name of the Marketing Authorisation holder	HOSPIRA ITALIA S.R.L.
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	irinotecan
D.3.2	Product code	irinotecan
D.3.4	Pharmaceutical form	Concentrate for solution for injection
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	IRINOTECAN CLORIDRATO TRIIDRATO
D.3.9.1	CAS number	100286-90-6
D.3.9.2	Current sponsor code	IRINOTECAN
D.3.9.3	Other descriptive name	IRINOTECAN
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	180
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	LEDERFOLIN - 175 MG POLVERE PER SOLUZIONE PER INFUSIONE 1 FLACONCINO
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER ITALIA S.R.L.
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	lederfolin
D.3.2	Product code	lederfolin
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
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	CALCIO LEVOFOLINATO
D.3.9.1	CAS number	80433-71-2
D.3.9.2	Current sponsor code	LEDERFOLIN
D.3.9.3	Other descriptive name	LEDERFOLIN
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	FLUOROURACILE TEVA - 5 G/100 ML SOLUZIONE PER INFUSIONE 1 FLACONCINO DA 100 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA ITALIA S.R.L.
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	fluorouracile
D.3.2	Product code	5-FU
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	5-FU
D.3.9.3	Other descriptive name	Fluorouracil
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2400
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	VECTIBIX - 20 MG/ML CONCENTRATO PER SOLUZIONE PER INFUSIONE - USO ENDOVENOSO 1 FLACONCINO (VETRO) 20 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	AMGEN EUROPE B.V.
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	panitumumab
D.3.2	Product code	panitumumab
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	PANITUMUMAB
D.3.9.1	CAS number	339177-26-3
D.3.9.2	Current sponsor code	Vectibix
D.3.9.3	Other descriptive name	Panitumumab
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	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	IRINOTECAN HOSPIRA - 20MG/ML CONCENTRATO PER SOLUZIONE PER INFUSIONE 1 FLACONCINO IN VETRO DA 100MG/5ML
D.2.1.1.2	Name of the Marketing Authorisation holder	HOSPIRA ITALIA S.R.L.
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	IRINOTECAN
D.3.2	Product code	IRINOTECAN
D.3.4	Pharmaceutical form	Concentrate for solution for injection
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	IRINOTECAN CLORIDRATO TRIIDRATO
D.3.9.1	CAS number	100286-90-6
D.3.9.2	Current sponsor code	IRINOTECAN
D.3.9.3	Other descriptive name	IRINOTECAN
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	180
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	LEDERFOLIN - 175 MG POLVERE PER SOLUZIONE PER INFUSIONE 1 FLACONCINO
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER ITALIA S.R.L.
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	LEDERFOLIN
D.3.2	Product code	LEDERFOLIN
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
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	CALCIO LEVOFOLINATO
D.3.9.2	Current sponsor code	lederfolin
D.3.9.3	Other descriptive name	lederfolin
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 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	FLUOROURACILE TEVA - 5 G/100 ML SOLUZIONE PER INFUSIONE 1 FLACONCINO DA 100 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA ITALIA S.R.L.
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	FLUOROURACILE
D.3.2	Product code	5-FU
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	5-FU
D.3.9.3	Other descriptive name	FLUOROURACIL
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2400
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	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	FLUOROURACILE TEVA - 5 G/100 ML SOLUZIONE PER INFUSIONE 1 FLACONCINO DA 100 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA ITALIA S.R.L.
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	fluorouracile
D.3.2	Product code	fluorouracile
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
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	5-FU
D.3.9.3	Other descriptive name	FLUOROURACIL
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	400
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	FLUOROURACILE TEVA - 5 G/100 ML SOLUZIONE PER INFUSIONE 1 FLACONCINO DA 100 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA ITALIA S.R.L.
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	FLUOROURACILE
D.3.2	Product code	5-FU
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
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	5-FU
D.3.9.3	Other descriptive name	FLUOROURACIL
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	400
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

patients with RAS/B-RAF wild-type metastatic colorectal cancer

pazienti affetti da tumore del colon-retto
metastatico RAS/BRAF wild-type

E.1.1.1

Medical condition in easily understood language

patients with RAS/B-RAF wild-type metastatic colorectal cancer

pazienti affetti da tumore del colon-retto
metastatico RAS/BRAF wild-type

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	10052360
E.1.2	Term	Colorectal adenocarcinoma
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 investigate whether experimental intermittent treatment of Panitumumab + FOLFIRI (given until progression during treatment or cumulative toxicity) results in a Progression Free Survival on treatment (PFSOT) similar to that obtained with standard continuous treatment of Panitumumab + FOLFIRI (given until progression or cumulative toxicity).

Valutare se il trattamento sperimentale intermittente con
Panitumumab + FOLFIRI (somministrato fino a progressione
durante il trattamento o tossicit¿ cumulativa) riporti un tempo libero da progressione durante il trattamento (PFSOT) simile a quello ottenuto con un trattamento continuo in modalit¿ standard (somministrato fino a progressione o tossicit¿ cumulativa).

E.2.2

Secondary objectives of the trial

To explore potential biomarkers of primary and secondary
resistance as well as to monitor treatment activity by
analyzing circulating tumor DNA (cfDNA) mutational
status, using next generation sequencing (NGS), from blood
samples (¿liquid biopsy¿) collected at baseline, at week 8,
16 and thereafter every 8 weeks, concomitantly with tumor
assessment, and at progression of disease
¿ To explore the prognostic and predictive value as well as the
potential to monitor treatment activity, of Metabolomic
profiling in peripheral blood at baseline and during treatment
(every 8 weeks and at progression of disease) evaluated by
NMR Spectrometer (600 MHz).
¿ To explore the prognostic and predictive value of tumor
DNA mutational profiling, evaluated by NGS on archived
tumor samples or on newly obtained biopsies.

Valutare potenziali biomarcatori di resistenza primaria e
secondaria come pure il monitoraggio dell¿attivit¿ del
trattamento attraverso l¿analisi mutazionale del DNA
circolante, utilizzando la tecnica del ¿next generation
sequencing¿ (NGS), da campioni di sangue (¿biopsia
liquida) raccolti in basale, alle settimana 8, 16 e di seguito
ogni 8 settimane, concomitantemente con la valutazione
strumentale del tumore, e a progressione di malattia
¿ Valutare il significato prognostico e predittivo del profilo
metabolomico ricavato da sangue periferico in basale e
durante il trattamento (ogni 8 settimane e a progressione di
malattia) valutato attraverso uno spettrometro di risonanza
magnetica nucleare (600MHz).
¿ Valutare il valore prognostico e predittivo del profilo
mutazionale del DNA tumorale valutato attraverso NGS su
biopsie tumorali archiviate o su nuove biopsie.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1)Written informed consent to study procedures and to molecular
analyses;
2) Histologically proven diagnosis of colorectal cancer with wildtype
RAS and BRAF status in certified laboratories;
3) Initially unresectable metastatic colorectal cancer not previously
treated with chemotherapy for metastatic disease;
4) At least one measurable lesion according to RECIST1.1 criteria;
5) Availability of a tumor sample (primary and/or metastatic sites)
for exploratory research;
6) Age = 18 years;
7) ECOG PS = 2;
8) Life expectancy of at least 12 weeks;
9) Previous adjuvant chemotherapy allowed only if more than 6
months elapsed between the end of adjuvant and first relapse;
10) Neutrophils = 1.5 x 109/L, Platelets =100 x 109/L, Hgb = 9 g/dl;
11) Total bilirubin =1.5 time the upper-normal limits (UNL) of the
normal values and ASAT (SGOT) and/or ALAT (SGPT) = 2.5 x
UNL (or < 5 x UNL in case of liver metastases) alkaline
phosphatase = 2.5 x UNL (or < 5 x UNL in case of liver
metastases);
12) Creatinine clearance =50 mL/min or serum creatinine = 1.5 x
UNL;
13) Female with a childbearing potential and male subjects must be
willing to use adequate contraception (barrier contraceptive
measure, oral contraception, intrauterine device);
14) Will and ability to comply with the protocol.

1) Consenso informato scritto per le procedure dello studio e per le
analisi molecolari;
2) Diagnosi istologica di adenocarcinoma colorettale, con analisi
RAS e BRAF wild-type, effettuata in laboratori certificati;
3) Tumore del colon-retto metastatico, inizialmente non resecabile,
non trattato precedentemente con chemioterapia per malattia
metastatica;
4) Almeno una lesione misurabile in accordo ai criteri RECIST 1.1;
5) Disponibilità di reperto bioptico tumorale (primario e/o del sito di
metastasi) per indagini di ricerca;
6) Età = 18 anni;
7) ECOG PS = 2;
8) Aspettativa di vita di almeno 12 settimane;
9) Un precedente trattamento chemioterapico adiuvante è consentito
solo se trascorsi più di 6 mesi tra la fine del trattamento e la
comparsa della prima recidiva;
10) Neutrofili = 1.5 x 109/L, Piastrine=100 x 109/L, Hgb = 9 g/dl;
11) Bilirubina totale = 1.5 volte del normale valore del limite
superiore di normalità (LSN) e ASAT (SGOT) e/o ALAT (SGPT) =
2.5 LSN (o < 5 x LSN in caso di metastasi epatiche); Fosfatasi
alcalina = 2.5 x LSN (o < 5 x LSN in caso di metastasi epatiche);
12) Clearance della creatinina = 50 mL/min o creatinina sierica =
1.5 x LSN;
13) Uomini e donne potenzialmente fertili devono essere d’accordo
all’uso di un adeguato contraccettivo (metodo di barriera,
contraccettivo orale, dispositivo intrauterino);
14) Volontà e capacità di rispettare le indicazioni del protocollo
clinico.

E.4

Principal exclusion criteria

1) Previous treatment for metastatic disease;
2) Radiotherapy to any site within 4 weeks before the study;
3) Any contraindication to use Panitumumab, Irinotecan, 5-FU or
folinic acid
4) Known or clinically suspected brain metastases.
5) History or evidence upon physical examination of CNS disease
unless adequately treated.
6) Ascites, pleural effusion or pericardial fluid requiring drainage in
last 4 weeks.
7) Diagnosis of interstitial pneumonitis or pulmonary fibrosis;
8) Active uncontrolled infections or other clinically relevant
concomitant illness contraindicating chemotherapy administration
or which, in the investigating physician's opinion, rules out the
patient's participation in the study;
9) Clinically significant (i.e. active) cardiovascular disease for
example cerebrovascular accidents (=6 months), myocardial
infarction (=6 months), unstable angina, New York Heart
Association (NYHA) grade II or greater congestive heart failure
(CHF), serious cardiac arrhythmia requiring medication;
10) Treatment with any investigational drug within 30 days prior to
enrolment;
11) Other co-existing malignancies or malignancies diagnosed
within the last 5 years with the exception of localized basal and
squamous cell carcinoma or cervical cancer in situ;
12) Lack of physical integrity of the gastrointestinal tract or history
of acute or sub-acute intestinal occlusion or chronic inflammatory
bowel disease or chronic diarrhea.
13) Disease that is deemed potentially resectable.
14) Known hypersensitivity to trial drugs or hypersensitivity to any
other component of the trial drugs.
15) Any concomitant drugs contraindicated for use with the trial
drugs according to the product information of the pharmaceutical
companies.
16) Breastfeeding

1) Un precedente trattamento per malattia metastatica;
2) Trattamento radioterapico su qualsiasi sede entro 4 settimane
dall’inizio dello studio;
3) Qualsiasi controindicazione all’uso di Panitumumab, Irinotecan,
5-FU o acido folico;
4) Metastasi cerebrali note o clinicamente sospette;
5) Storia clinica o evidenza, tramite esame fisico, di malattia a
carico del SNC se non adeguatamente trattata;
6) Storia di ascite, versamento pleurico o pericardico richiedenti un
drenaggio nelle ultime 4 settimane;
7) Diagnosi di polmonite interstiziale o fibrosi polmonare;
8) Infezioni attive non controllate o altre malattie concomitanti,
clinicamente rilevanti, che controindichino l’assunzione di
chemioterapia o che, a giudizio del medico ricercatore, escludano la partecipazione allo studio del paziente;
9) Malattie cardiovascolari (i.e. attive) clinicamente significative,
ad esempio episodi cerebrovascolari (= 6 mesi), infarto miocardico
(= 6 mesi), angina instabile, insufficienza cardiaca congestizia
(ICC), secondo la New York Heart Association (NYHA), di grado II
o superiore, grave aritmia cardiaca richiedente trattamento
farmacologico;
10) Trattamento con qualsiasi farmaco sperimentale entro 30 giorni
dall’arruolamento;
11) Altri tumori concomitanti o tumori diagnosticati entro gli ultimi
5 anni eccetto basalioma e carcinoma a cellule squamose o cancro al collo dell’utero in situ;
12) Mancanza di integrità fisica del tratto gastrointestinale o
precedenti di un’occlusione o sub occlusione intestinale o malattia
infiammatoria cronica intestinale o diarrea cronica
13) Malattia ritenuta potenzialmente resecabile;
14) Nota ipersensibilità ai farmaci dello studio o ipersensibilità a
qualsiasi altro componente dei farmaci dello studio;
15) Qualsiasi farmaco concomitante controindicato all’uso con i
farmaci dello studio in accordo alle informazioni delle aziende
farmaceutiche sul prodotto;
16) Allattamento
17) Uomini e donne (fertili) sessualmente attivi non disposti all’uso
di contraccettivi (orali o metodo di barriere) durante lo studio e fino
a 6 mesi dopo l’ultimo trattamento dello studio.

E.5 End points

E.5.1

Primary end point(s)

PFSot is defined as the time from randomization to the first
objective disease progression documented in patients undergoing treatment cycle (objective disease progression during treatment free intervals are excluded) or death due to any cause, whichever occurs first.

PFSOT è definita come il tempo dalla randomizzazione alla prima progressione obiettiva di malattia documentata in quei pazienti che
si stanno sottoponendo a trattamento (escludendo gli intervalli di progressione di malattia che avvengono durante le pause di trattamento) oppure a morte dovuta a qualsiasi causa.

E.5.1.1

Timepoint(s) of evaluation of this end point

8 weeks

8 settimane

E.5.2

Secondary end point(s)

¿ Safety and tolerability
¿ Quality of life (QoL)
¿ Overall response rate (ORR)
¿ Duration of response (DoR)
¿ Early Tumor Shrinkage (ETS)
¿ Deepness of response (DpR)
¿ Overall Survival (OS)

¿ Profilo di sicurrezza e tollerabilit¿
¿ Qualit¿ di vita (QoL)
¿ Tassi di risposta obiettiva (ORR)
¿ Durata della risposta (DoR)
¿ Risposta tumorale precoce(ETS)
¿ Profondit¿ della risposta (DpR)
¿ Risposta globale (OS)

E.5.2.1

Timepoint(s) of evaluation of this end point

8 weeks

8 settimane

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

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

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)

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

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

diversa modalit¿ di somministrazione: continuo versus intermittente

different drug administration: continous versus intermittent

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

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:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

136

F.4.2

For a multinational trial

F.4.2.1

In the EEA

136

F.4.2.2

In the whole clinical trial

136

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)

normal practice

normale pratica clinica

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

2018-01-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-12-20

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

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Orphan Designation Number:
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