Clinical Trials Register

Summary
EudraCT Number:	2016-001491-29
Sponsor's Protocol Code Number:	UC-0110/1609
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:	2021-06-17
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

2016-001491-29

A.3

Full title of the trial

A Phase III, Randomised, international trial comparing mFOLFIRINOX triplet chemotherapy to mFOLFOX for highrisk stage III colon cancer in adjuvant setting

STUDIO INTERNAZIONALE DI FASE III RANDOMIZZATO DI TRATTAMENTO ADIUVANTE CON mFOLFIRINOX VERSO mFOLFOX6 IN PAZIENTI CON CARCINOMA COLORETTALE IN STADIO III AD ALTO RISCHIO.

A.3.1

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

Study on the post surgery treatment of patients with curative surgical resection due to colon rectal tumor.

Studio sul trattamento post operatorio di pazienti radicalmente operati per tumore del colonretto.

A.3.2

Name or abbreviated title of the trial where available

IROCAS

A.4.1

Sponsor's protocol code number

UC-0110/1609

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	UNICANCER
B.1.3.4	Country	France
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	GONO
B.4.2	Country
B.4.1	Name of organisation providing support	UNICANCER
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GONO
B.5.2	Functional name of contact point	Ufficio Sperimentazioni sede operat
B.5.3	Address:
B.5.3.1	Street Address	Via Roma, 67
B.5.3.2	Town/ city	PISA
B.5.3.3	Post code	56126
B.5.3.4	Country	Italy
B.5.4	Telephone number	050992192
B.5.5	Fax number	050992069
B.5.6	E-mail	irocas.italy@gmail.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	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 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	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 is a derivative of camptothecin. Camptothecins act as specific inhibitors of the enzyme DNA topoisomerase I.
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	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	Yes
D.3.11.13.1	Other medicinal product type	L’irinotecan è un derivato semisintetico della camptotecina

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

High-risk stage III colon cancer

Carcinoma colorettale in stadio III ad alto rischio

E.1.1.1

Medical condition in easily understood language

Operated colorectal cancer candidate for adjuvant therapy

Tumore al colon retto operato candidato a terapia adiuvante

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	10038098
E.1.2	Term	Rectosigmoid cancer stage III
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

Evaluate the efficacy comparing mFOLFIRINOX versus mFOLFOX 6 for patients with high-risk stage III colon cancer (pT4N1; pT1-4N2) in terms of 3-year Disease Free Survival rate with an expected gain in DFS of 9% at 3 years (74% versus 65%).

Valutare l’efficacia di mFOLFIRINOX verso mFOLFOX6 come trattamento adiuvante in pazienti con CCR in stadio III ad alto rischio in termini di tasso di pazienti liberi da malattia a 3 anni (3y -DFS) con un vantaggio del 9% a favore del braccio sperimentale (74% vs 65%).

E.2.2

Secondary objectives of the trial

• Evaluation of Efficacy: Disease-free-Survival at 2 years.
• Overall Survival (OS)
• Evaluation of Toxicity

Valutare l’efficacia e la sicurezza di mFOLFIRINOX confrontato con mFOLFOX6 in termini di:
• Sopravvienza libera da malattia a 2 anni [2y-DFS];
• Sopravvivenza globale (OS);
• Tasso di tossicità.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Pharmacogenetics
Version: 4.2
Date: 07/05/2018
Title: Pharmacogenetics of Fluoropyrimidines
Objectives: to study primarily the thymidylate synthase gene and the dihydropyrimidine dehydrogenase gene, which have been shown to be implicated in the occurrence of severe adverse drug toxicity and in the response

Other types of substudies
Specify title, date and version of each substudy with relative objectives: Pharmacogenetics of Oxaliplatin - version n°4.2 May 7th 2018. please see page 40-41 of the attached protocol.
Objective: Haplotype analyses will be performed using different databases (SNP500, NHIES, and HAPMAP) in order to determine the minimal set of tag SNP allowing the identification of the most frequent haplotypes in the Caucasian population.
Pharmacogenetics of Irinotecan - - version n°4.2 May 7th 2018. please see page 41 of the attached protocol.
Objective: Haplotype analyses will be performed using different databases (SNP500, NHIES, and HAPMAP) in order to determine the minimal set of tag SNP allowing the identification of the most frequent haplotypes in the Caucasian population.

Farmacogenetica
Versione: 4.2
Data: 07/05/2018
Titolo: Farmagenetica delle fluoropirimidine
Obiettivi: valutare il coinvolgimento della timidilato sintetasi e della diidropirimidina deidrogenasi nella tossicità e nella risposta al trattamento

Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Farmacogenetica dell'Oxaliplatino - versione 4.2 del 07/05/2018. Vedere paragrafo 9.3.2 del protocollo allegato
obiettivo: studiare i polimorfismi del Glutatione-S-transferasi nella popolazione caucasica per valutare il possibile impatto predittivo sull’insorgenza della neurotisscità.
Farmacogenetica dell Irinotecan - - versione 4.2 del 07/05/2018. Vedere paragrafo 9.3.3 del protocollo allegato
studiare i polimorfismi della glucuronosiltransferasi UGT nella popolazione caucasica per valutare il possibile impatto predittivo di efficacia e tossicità.

E.3

Principal inclusion criteria

• Patient =18 years and < 71years
• Patient with ECOG =1
• Pathologically confirmed high-risk stage III colon adenocarcinoma, restricted to pT4N1 or pT1-4N2 tumor.
• Curative R0 surgical resection within 42 days before randomization.
• Patients who have undergone surgery for colon cancer, defined as a tumor location >12 cm from the anal verge by endoscopy and/or above the peritoneal reflection at surgery (high rectum), without gross or microscopic evidence of residual disease after surgery with curative intent
• Start of study drug treatment has to be performed less than 56 days after surgery.
• No prior chemotherapy.
• No prior abdominal or pelvic irradiation.
• Patient with adequate organ function.
• Adequate contraception if applicable.
• Patient able and willing to comply with study procedures as per protocol
• Patient able to understand and willing to sign and date the written voluntary informed consent form at screening visit prior to any protocol-specific procedures
• Public or private health insurance coverage
• Life expectancy of > or = at 5 years

• Pazienti di età compresa tra 18-71 anni.
• Pazienti con ECOG PS =1.
• Diagnosi confermata istologicamente di adenocarcinoma del colon-retto in stadio III ad alto rischio, definito pT4N1 o pT1-4N2.
• Malattia sottoposta a resezione con intento curativo R0.
• Pazienti sottoposti a intervento chirurgico per carcinoma del colon, con lesione tumorale localizzata a una disanza dal margine anale >12 cm all’endoscopia e/o al di sopra del riflessione peritoneale alla descrizione dell’intervento (retto alto), senza evidenza macroscopica o patologica di malattia residua dopo chirurgia con intento curativo.
• Inizio del trattamento in studio entro 56 giorni dalla data della chirurgia.
• Non permesso precedente trattamento chemioterapico.
• Non permesso precedente trattamento radioterapico in ambito addominale o pelvico.
• Adeguata funzione d’organo:
• Uso di adeguati metodi contraccettivi.
• Paziente in grado e disposto a rispettare le procedure di studio come da protocollo.
• Paziente in grado di comprendere, firmare e datare il modulo di consenso informato scritto alla visita di screening prima di qualsiasi procedura specifica del protocollo.
• Paziente affiliato a un regime di sicurezza sociale.
• Aspettativa di vita = 5 anni

E.4

Principal exclusion criteria

• Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to study treatment start. Incompletely healed wounds or anticipation of the need for major surgical procedure during the course of the study
• Metastatic disease
• Presence of inflammatory bowel disease and/or ileus
• Known hypersensitivity reaction to any of the components of study treatments.
• Pregnancy (absence to be confirmed by ß-hCG test) or breast-feeding period
• Clinically relevant coronary artery disease or history of myocardial infarction in the last 12 months, or high risk of uncontrolled arrhythmia (for men: QT/QTc =450 msec, for women: QT/QTc =470 msec)
• Previous malignancy in the last 5 years except curative treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix
• Medical, geographical, sociological, psychological or legal conditions that would not permit the patient to complete the study or sign informed consent
• History or current evidence on physical examination of central nervous system disease or peripheral neuropathy = grade 1 Common Toxicity Criteria for Adverse Events (CTCAE) v4.03.
• Any significant disease which, in the investigator’s opinion, would exclude the patient from the study.
• Known DPD deficiency or UGT1A1 homozygous 7/7
• Patients already included in another therapeutic trial involving an experimental drug

• Chirurgia maggiore, biopsia aperta o gravi traumi nei 28 giorni precedenti l’inizio del trattamento in studio. Ferite incompletemente guarite o prevista necessità di una procedura chirurgica maggiore durante il corso dello studio.
• Malattia metastatica.
• Malattia infiammatorie dell’intestino e/o ileo.
• Nota ipersensibilità o allergia a uno qualsiasi dei farmaci previsti dallo studio.
• Donne in gravidanza o in allattamento. Le donne in età fertile con un test positivo di gravidanza o che non hanno effettuato un test di gravidanza alla visita basale.
• Malattia cardiovascolare clinicamente significativa o storia di infarto miocardico negli ultimi 12 mesi, o alto rischio di aritmia incontrollata (per gli uomini: QTc =450 msec, per le donne: QTc =470 msec).
• Altri tumori maligni coesistenti o diagnosticati nei 5 anni precedenti, fatta eccezione per il basalioma, il carcinoma squamocellu della cute e il carcinoma in situ della cervice uterina.
• Condizioni mediche, geografiche, sociali, psicologiche o legali che non consentono al paziente di completare lo studio o di firmare il consenso informato.
• Metastasi del SNC attive o non trattate e neuropatia periferica sintomatica di grado > 1 secondo i criteri NCI-CTC, v 4.03.
• Qualsiasi malattia significativa che, secondo il parere dello sperimentatore, escluderebbe il paziente dallo studio.
• Paziente con deficit di DPD o con omozigosi (7/7) per UGT1A1; il test deve essere eseguito per tutti i pazienti prima della somministrazione di 5-FU, secondo la comunicazione ANSM in merito alla raccomandazione sull'alto rischio di non sottoporre a test DPD in paziente prima della somministrazione di 5-FU.
• Trattamenti con qualsiasi altro farmaco sperimentale.

E.5 End points

E.5.1

Primary end point(s)

The primary end-point is the Disease Free Survival (DFS) at 3 years, defined as the time from the date of randomization up to the date of:
- first local, regional or distant relapse;
- second colorectal cancer;
- death from any cause included treatment-related death.
Other primary cancer (except second primary colorectal) will be ignored. Second primary cancer will be recorded to have the opportunity of evaluating other definition of DFS.

Sopravvivenza libera da malattia a tre anni (3y-DFS) è definita come il tempo dalla randomizzazione fino alla data di:
- prima evidenza di ripresa di malattia a livello locale, regionale o a distanza;
- insorgenza di un secondo tumore colorettale;
- morte per qualsiasi causa.
Altri tumori primitivi (eccetto l’isorgenza di un secondo tumore colorettale) saranno ignorati. Il secondo tumore primitivo verrà registrato per avere l'opportunità di valutare un'altra definizione di DFS.

E.5.1.1

Timepoint(s) of evaluation of this end point

3 years

3 anni

E.5.2

Secondary end point(s)

Disease Free Survival at 2 years, defined as the time from the date of randomization up to the date of:
- first local, regional or distant relapse
- second colorectal cancer
- death from any cause included treatment-related death.
Other primary cancer (except second primary colorectal) will be ignored. Second primary cancer will be recorded to have the opportunity of evaluating other definition of DFS; Overall Survival (OS) is defined as the time from the date of randomization to the date of documented death from any cause.

Sopravvivenza libera da malattia a due anni (2y-DFS) è definita come il tempo dalla randomizzazione fino alla data di:
- prima evidenza di ripresa di malattia a livello locale, regionale o a distanza;
- insorgenza di un secondo tumore colorettale;
- morte per qualsiasi causa.
Altri tumori primitivi (eccetto l’isorgenza di un secondo tumore colorettale) saranno ignorati. Il secondo tumore primitivo verrà registrato per avere l'opportunità di valutare un'altra definizione di DFS.; Sopravvivenza globale definita come il tempo dalla randomizzazione alla data di morte per qualsiasi causa.

E.5.2.1

Timepoint(s) of evaluation of this end point

2 years; 9 YEARS AND 6 MONTHS

2 anni; 9 anni e 6 mesi

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

nel braccio sperimentale un chemioterapico in più (Irinotecano)

Experimental Arm additional of third chemotherapy agent (Irinotecan)

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

Canada

France

Italy

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

DURATION UNTIL PRIMARY ENDPOINT EVALUATION: 3 YEARS (estimated date March 2024)
OVERALL TRIAL DURATION (INCLUDING FOLLOW-UP): 9 YEARS AND 6 MONTHS (estimated date March 2026)

Durata dello studio fino alla valutazione dell endpoint primario: 3 anni (data stimata Marzo 2024)
Durata complessiva dello studio che include l'endopint della Sopravvivenz: 5 anni (data stimata Marzo 2026)

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:

640

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

213

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

150

F.4.2

For a multinational trial

F.4.2.1

In the EEA

490

F.4.2.2

In the whole clinical trial

640

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)

Follow-up assessment will be performed every 24 weeks for the first 2 years after the end of the last cycle of adjuvant chemotherapy, then every year for the following 3 years.

Follow-up ogni 24 settimane per i primi 2 anni dopo la fine dell'ultimo ciclo di chemioterapia adiuvante, a seguire ogni anno per i successivi 3 anni.

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

2019-07-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-06-13

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

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