Clinical Trials Register

Summary
EudraCT Number:	2014-002574-36
Sponsor's Protocol Code Number:	PRODIGE35
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-08-25
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

France - ANSM

A.2

EudraCT number

2014-002574-36

A.3

Full title of the trial

Phase II randomized study evaluation of FOLFIRINOX +/- LV5FU2 in maintenance and FIRGEM in 1rst line of metastatic pancreas cancer

Phase II randomisée dans le cancer pancréatique métastatique évaluant le FOLFIRINOX +/- LV5FU2 en entretien dans le cancer pancréatique métastatique

A.3.1

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

Evaluation of 3 treatments strategies (FOLFIRINOX +/- LV5FU2 and FIRGEM) in first line of treatment of chemotherapy in metastatic pancreas cancer

Évaluation de 3 stratégies de traitement FOLFIRINOX + /- LV5FU2 et FIRGEM en 1ière ligne de chimiothérapie dans le cancer pancréatique métastatique.

A.3.2

Name or abbreviated title of the trial where available

PANOPTIMOX

A.4.1

Sponsor's protocol code number

PRODIGE35

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	Fédération Francophone de Cancérologie Digestive
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	Fédération Francophone de Cancérologie Digestive
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	Fédération Francophone de Cancérologie Digestive
B.5.2	Functional name of contact point	Project manager
B.5.3	Address:
B.5.3.1	Street Address	7 bd Jeanne d'Arc BP 87900
B.5.3.2	Town/ city	DIJON
B.5.3.3	Post code	21079
B.5.3.4	Country	France
B.5.4	Telephone number	+33380393404
B.5.5	Fax number	+33380381841
B.5.6	E-mail	marie.moreau@u-bourgogne.fr

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	Campto
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER HODING FRANCE
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IRINOTECAN
D.3.9.1	CAS number	97682-44-5
D.3.9.4	EV Substance Code	SUB08295MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 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	Fluorouracile Ebewe
D.2.1.1.2	Name of the Marketing Authorisation holder	SANDOZ
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FLUOROURACIL
D.3.9.3	Other descriptive name	FLUOROURACIL
D.3.9.4	EV Substance Code	SUB07721MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	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 Ebewe
D.2.1.1.2	Name of the Marketing Authorisation holder	SANDOZ
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FLUOROURACIL
D.3.9.3	Other descriptive name	FLUOROURACIL
D.3.9.4	EV Substance Code	SUB07721MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	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	Elvorine
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER HODING FRANCE
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for 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	ELVORINE
D.3.9.3	Other descriptive name	CALCIUM LEVOFOLINATE
D.3.9.4	EV Substance Code	SUB06054MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 5
D.1.2 and D.1.3	IMP Role	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	GEMZAR
D.2.1.1.2	Name of the Marketing Authorisation holder	LILLY FRANCE S.A.S
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder for 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	GEMCITABINE
D.3.9.1	CAS number	95058-81-4
D.3.9.4	EV Substance Code	SUB07892MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 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	ELOXATINE
D.2.1.1.2	Name of the Marketing Authorisation holder	SANOFI-AVENTIS FRANCE
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	OXALIPLATIN
D.3.9.1	CAS number	61825-94-3
D.3.9.4	EV Substance Code	SUB09490MIG
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.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

metastatic pancreas adenocarcinoma

Adénocarcinome pancréatique métastatique

E.1.1.1

Medical condition in easily understood language

advanced pancras cancer

cancer avancé du pancréas

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10033575
E.1.2	Term	Pancreas cancer
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Main objective is to evaluate, in each arm, the patient rate in live and without radiological and or clinical progression at 6 months after randomization,

L'objectif principal est d'évaluer, dans chaque bras, le taux de patient vivant et sans progression radiologique (RECIST v1.1) et/ou clinique à 6 mois

E.2.2

Secondary objectives of the trial

Duration of desease control
Quality of live (QLQ-C30)
Toxicity (NCI-CTC V4.0)
Time to progression during the maintenance of treatment
Overall survival
Progression survival
Patient rate receiving 2de line of treatment
Evaluation of fragility geriatric factors predictif of treatment failure for > 65 years old patients

Durée de contrôle de la maladie
Qualité de vie (QLQ-C30)
Toxicité selon le NCI-CTC V4.0
Délai de progression pendant le traitement d'entretien
Survie globale
Survie sans progression
Taux de patients recevant une thérapie de 2ième ligne
Evaluer les facteurs gériatriques de fragilité prédictifs d'échec du traitement chez des patients de plus de 65 ans

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

A sub biological study will evaluate:
- germinal polymorphismes (UGT1A1, ERCC1, GSTT1, MTHFR, DPD, TS, ...) as predictive and prospective factors of treatments response
- research of predictif immunohistochemy biomarkers as response of treatment on tissus samples

Une étude biologique évaluera
-les polymorphismes génétiques constitutionnels pouvant impacter l’efficacité des molécules de chimiothérapie (UGT1A1, ERCC1, GSTT1, MTHFR, DPD, TS ...).
- Une étude sur coupe de paraffine à la recherche de biomarqueurs immunohistochimiques prédictifs de réponse aux traitements

E.3

Principal inclusion criteria

Adénocarcinome of pancreas, histologically or cytologically proved
Metastatic disease
At least one mesurable lesion according to RECIST V1.1 criteria
No prior chemotherapy (excepted if there is at least on lestion out of the irradition area)
Age > 18 years. A favorable adviced by an onco geriatrician would be mandatory for inclusion of patients older than 75
Performance statut (WHO) 0-1
Polynyclear ≥ 1500/mm3
Bilirubine ≤ 1,5 fois la LSN, creatinin < 120μmol / L
Signed informed consent form

•Adénocarcinome du pancréas, histologiquement ou cytologiquement prouvé
•Maladie métastatique
•Au moins une lésion mesurable selon les critères RECIST v1.1
•Aucune chimiothérapie antérieure (chimiothérapie adjuvante par gemcitabine ou LV5FU2 autorisée si administré plus de 6 mois avant l'inclusion)
•Pas de radiothérapie précédente (sauf si au moins une lésion cible mesurable en dehors de la zone d'irradiation)
•Age > 18. Les patients de plus de 75 ans, jugés éligibles par l’investigateur, peuvent être éventuellement inclus après avis favorable d’un onco-gériatre
•Etat général : OMS 0-1
•PNN ≥ 1500/mm3, plaquettes ≥ 100 000/mm3
•Bilirubine ≤ 1,5 fois la LSN, créatinine < 120μmol / L
•Information du patient et signature du consentement éclairé

E.4

Principal exclusion criteria

Another type of pancreas tumor, as endocrine tumor ou with acinous cells
Ampulloma
Cerebral or meningeal metastasis
Gilbert disease
Neuropathie > or = grade 1
Study treatments contraindication
Uncontrolled diarrhoea or inflamatory disease of colon or rectum, or bowel obstruction or bowel sub-obstruction no resolved with specific treatment
Serious uncontrolled intercurrent infections or other serious uncontrolled concomitant disease prevent patient to receive study treatments
Cancer within the 5 years before inclusion, except for int situ cancer of the neck of the uterus or basal cell skin cancer
Significant previous cardiac and respiratory disease
Patient included in an other therapeutic study with experimental treatment
Pregnancy or breast feeding
Patient depreved of freedom or under gardianship
Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Autres types de tumeurs du pancréas, en particulier tumeur endocrine ou à cellules acineuses,
Ampullome
Présence de métastases cérébrales ou méningées,
Maladie de Gilbert
Présence de neuropathie > grade 1
Contre-indications spécifiques aux traitements étudiés
Antécédents de diarrhée chronique ou de maladie inflammatoire du côlon ou du rectum, ou d’occlusion ou de sub-occlusion non résolues sous traitement symptomatique,
Infection évolutive active ou autre pathologie grave sous-jacente susceptible d’empêcher le patient de recevoir le traitement
Autre cancer concomitant ou antécédents de cancer dans les 5 ans, à l'exception d'un carcinome in situ du col de l'utérus ou d’un carcinome basocellulaire ou épidermoïde, considérés comme guéri
Historique significatif de maladie cardiaque ou respiratoire
Patient déjà inclus dans un autre essai thérapeutique avec une molécule expérimentale,
Homme et femme en âge de procréer n’utilisant pas de contraception efficace
Femme enceinte ou susceptible de l’être ou en cours d'allaitement,
Personnes privées de liberté ou sous tutelle,
Impossibilité de se soumettre au suivi médical de l'essai pour des raisons géographiques, sociales ou psychiques.

E.5 End points

E.5.1

Primary end point(s)

Progression is defined as radiological (RECIST v1.1) and/or clinical according to the investigator. Progression or death (whatever the reason is) will be taking into account if the event occurs during the 6 first months of treatment.
Definition of disease-control duration: Disease -control duration in arm A (Folfirinox) is defined as the time between randomization and the first progression (radiological and/or clinical) or death (whatever the reason is) or the beginning of the next treatment line.
Disease -control duration in arm with maintenance (Arm B) is defined as:
• After the progression during the maintenance under LV5FU2 (PFS1), if the disease is not controlled after the re-introduction of folfirinox (PFS2) then the disease-control duration will be the time between the randomization and the progression before the re-introduction of folfirinox (PFS1)
• After the progression during the maintenance under LV5FU2 (PFS1), if the disease is adequately controlled after the re-introduction of folfirinox (Stability or objective response) then the disease-control duration will be the time between the randomization and the progression (PFS2) under folfirinox (PFS1 + PFS2).
Disease -control duration in FIRGEM arm (Arm C) is defined as:
If treatments' alternance (FOLFIRI.3/Gemcitabine) is stopped because of a progression (PFS1) then:
• if the disease is not controlled after the treatment switch then the disease-control duration will be the time between randomization and the progression (PFS1) before the switch.
• if the disease id adequately controlled (stability or objective response) the disease-control duration will be the time between randomization and the progression (PFS2) under treatment (PFS1+PFS2)
If treatments' alternance is stopped because of any other cause except progression (Toxicity, investigator's decision...) then the disease-control duration will be the time between randomization and the first progression (PFS1)
Patients will be censored at the date of last radiological evaluation or cut-off date.

La progression est définie comme une progression radiologique selon les critères RECIST v1.1 et/ou clinique selon l'investigateur. La progression ou le décès (quelle qu’en soit la raison) seront pris en compte si l'événement se produit au cours des 6 premiers mois de traitement
Définition de la durée de contrôle de la maladie:
- La durée de contrôle de la maladie dans le bras A (Folfirinox) est définie comme le temps entre la date de randomisation et la date de la progression sous traitement (clinique et/ou radiologique) ou du décès (toute cause et quel que soit le moment) ou la date de changement de ligne.
- La durée de contrôle de la maladie dans le bras avec entretien (bras B) est définie comme suit:
• Après progression pendant l'entretien par LV5FU2 (SSP1), si la maladie n'est pas contrôlée après réintroduction du folfirinox (SSP2) alors la durée de contrôle de la maladie sera égale au temps entre la randomisation et la progression avant la réintroduction du folfirinox (SSP1).
• Après progression pendant l'entretien sous LV5FU2 (SSP1), si la maladie est de nouveau contrôlée après réintroduction du folfirinox alors la durée de contrôle (stabilité, RO) de la maladie sera égale au temps entre la randomisation et la progression (SSP2) sous folfirinox (SSP1 + SSP2).

- La durée de contrôle de la maladie dans le bras FIRGEM (bras C) est définie comme suit:
Si l'arrêt de l'alternance des traitements (FOLFIRI.3/Gemcitabine) est dû à une progression (SSP1) alors:
• Si la maladie n'est pas contrôlée après changement de traitement alors la durée de contrôle de la maladie sera égale au temps entre la randomisation et la progression avant changement de traitement (SSP1).
• Si la maladie est de nouveau contrôlée après changement de traitement alors la durée de contrôle (stabilité, RO) de la maladie sera égale au temps entre la randomisation et la progression (SSP2) sous traitement (SSP1+ SSP2)
Si l'arrêt de l'alternance des traitements est dû à une autre cause que la progression (toxicité, décision de l'investigateur ...) alors la durée de contrôle de la maladie sera le temps jusqu'à la première progression (SSP1).
Les patients sans événements seront censurés à la date de dernière évaluation radiologique ou la date de point.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months after randomization of each patient

6 mois après la randomisation de chaque patient

E.5.2

Secondary end point(s)

Progression-free survival will be calculated as the time between randomization date and the date of the first progression (local, metastatic or clinical) or the date of death (whatever the reason is). Patients alive without any progression will be censored at the date of last news.
Time until progression during the maintenance= delay between the end of induction's treatment (Folfirinox or Folfiri.3) and the date of radiological progression during maintenance.
Duration of maintenance (Arm B) = delay between the last folfirinox cure and the date of the progression involving folfirinox restart.
Efficacy = Percentage of objective response according to RECIST V1.1 at 2,4 and 6 months
Best treatment response during the six first months will be derived.
Overall survival = delay between randomization and death (whatever the reason is). Patients alive will be censored at the date of last news.

La survie sans progression sera calculée comme le délai entre la date de randomisation et la date de première progression (locale, métastatique) ou la progression clinique, la date de décès (toutes causes confondues). ). Les patients vivants et sans progression seront censurés à la date de leur dernières nouvelles.
- Temps jusqu'à de progression durant l’entretien = délai entre la fin du traitement d'induction (FOLFIRINOX ou FOLFIRI3) et la date de progression radiologique pendant la période d'entretien
- La durée du traitement d’entretien (bras B) = délai entre la dernière cure de folfirinox et la date de progression entrainant la reprise du folfirinox.
- L’efficacité = taux de réponse objective selon les critères RECIST 1.1 à 2, 4 et 6 mois
- La meilleure réponse au traitement durant les 6 premiers mois sera dérivée.
- La survie globale = délai entre la date de randomisation et la date du décès (toutes causes confondues). Les patients vivants seront censurés à la date de leur dernières nouvelles.

E.5.2.1

Timepoint(s) of evaluation of this end point

the secondary objectives will be calculated 2 years after the last patient included

Les objectifs secondaires seront déterminés 2 ans après le dernier patient inclus

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)

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

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

The end of the trial is the last visit of the last subject undergoing the trial

La fin de l'étude correspond à la dernière visite du dernier patient en cours dans l'étude

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

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:

236

F.1.3

Elderly (>=65 years)

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

276

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)

After progression, patients of the study will be follow up by our investigator accordint to national thesaurus of digestive cancerology (TNCD)

Après progression de leur maladie sous l'un des traitement de l'étude, les patients seront suivis selon les habitudes du centre et selon les recommandations nationales du thésaurus national de cancérologie digestive (TNCD)

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

2014-08-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-11

P. End of Trial
P.	End of Trial Status	Completed

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