Clinical Trials Register

Summary
EudraCT Number:	2013-002074-46
Sponsor's Protocol Code Number:	FIONA
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-06-24
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

2013-002074-46

A.3

Full title of the trial

Multicentre, two-stage, phase 2 study of neoadjuvant FOLFIRINOX followed by chemo-IMRT in patients with locally advanced unresectable pancreatic cancer

Studio multicentrico di fase II, di chemioterapia con FOLFOXIRI seguito da chemio-radioterapia con intento neoadiuvante in pazienti affetti da carcinoma del pancreas localmente avanzato non operabile.

A.3.1

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

Multicentre, two-stage, phase 2 study of neoadjuvant FOLFIRINOX followed by chemo-IMRT in patients with locally advanced unresectable pancreatic cancer

A.3.2

Name or abbreviated title of the trial where available

FolfIrinOx in NeoAdiuvant setting

A.4.1

Sponsor's protocol code number

FIONA

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 per lo Studio e la Cura dei Tumori di Napoli – Fondazione “G.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	none
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 per lo Studio e la Cura dei Tumori di Napoli – Fondazione “G.Pascale”
B.5.2	Functional name of contact point	Unità Sperimentazioni Cliniche
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.5.6	E-mail	marilina.piccirillo@usc-intnapoli.net

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	oxaliplatin
D.3.4	Pharmaceutical form	Powder 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.3.10	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	85
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.2.1.2	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.3.4	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
D.3.9.1	CAS number	97682-44-5
D.3.9.4	EV Substance Code	SUB08295MIG
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	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.2.1.2	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	fluorouracil
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 use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	5-fluorouracil
D.3.9.3	Other descriptive name	FLUOROURACIL
D.3.9.4	EV Substance Code	SUB07721MIG
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	1600
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

Locally advanced unresectable pancreatic cancer

Carcinoma del pancreas esocrino localmente avanzato non operabile

E.1.1.1

Medical condition in easily understood language

Locally advanced unresectable pancreatic cancer

Carcinoma del pancreas esocrino localmente avanzato non operabile

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	16.0
E.1.2	Level	LLT
E.1.2	Classification code	10033606
E.1.2	Term	Pancreatic cancer non-resectable
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

To evaluate activity (in terms of objective response rate ) and toxcity, of neoadjuvant FOLFIRINOX followed by chemo-IMRT in patients wit locally advanced unresectable pancreatic cancer

Valutare l’attività (in termini di risposte obiettive) e la tossicità di un trattamento ad intento neoadiuvante con FOLFIRINOX seguito da chemio-IMRT (intensity modulated radiotherapy) in pazienti affetti da carcinoma del pancreas localmente avanzato (stadio III) inoperabile.

E.2.2

Secondary objectives of the trial

1. To evaluate:
the rate of conversion to resectability
R0 resection rate
progression free survival
overall survival
2. To validate di predicitive ability of early metabolic tumor change measured by PET/CT
3. To evaluate the predicitve ability of early functional tumor response measured by abdomen-pelvis MRN with Gd-BT-DO3A
4. To validate the prognostic value of the CXCR4-CXCL12 pathway

• Valutare:
o tasso di conversione alla resecabilità
o tasso di resezioni R0
o sopravvivenza libera da progressione (PFS)
o sopravvivenza globale (OS)
• Validare il ruolo predittivo dei cambiamenti metabolici precoci a carico della neoplasia misurati con esame PET/TC
• Valutare il valore predittivo delle variazioni funzionali precoci a carico della neoplasia misurate con esame RM addome e pelvi con e senza mezzo di contrasto paramagnetico Gd-BT-DO3A
• Validare il ruolo prognostico dell’asse CXCR4-CXCL12

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Histologically or cytologically confirmed locally advanced unresectable pancreatic adenocarcinoma
- Unresectable stage III according to NCCN criteria
- Age ≥ 18 and ≤ 70 years
- At least one lesion measurable according to RECIST
- PS ECOG 0-1
- Adequate bone marrow, liver and renal function
- Patients who underwent endoscopic biliary drainage, with self-expandable metallic stent placement, are allowed, provided they have performed appropriate antibiotic prophylaxis and do not show significant alterations of laboratory tests as previously specified
- Life expectancy of ≥ 3 months
- Signed written informed

- Carcinoma del pancreas esocrino localmente avanzato documentato mediante esame istologico e/o citologico
- Stadio III non resecabile secondo gli standard definiti dalle linee guida NCCN (invasione dell’asse celiaco, aorta, vena cava inferiore, infiltrazione di vena porta, vena mesenterica superiore, arteria mesenterica superiore maggiore di 180° o di un segmento vasale > 1,5 cm)
- Età ≥ 18 anni e ≤ 70 anni
- Presenza di lesioni target misurabili secondo i criteri RECIST
- Performance Status secondo ECOG = 0-1
- Adeguata funzionalità midollare, epatica e renale
- Pazienti sottoposti a drenaggio biliare per via endoscopica, con posizionamento di protesi metallica autoespandibile, sono ammessi, purchè abbiano eseguito opportuna profilassi antibiotica e non mostrino rilevanti alterazioni degli esami di laboratorio come precedentemente specificato
- Aspettativa di vita stimata > 3 mesi
- Consenso informato scritto

E.4

Principal exclusion criteria

- Metastatic disease
- Previous chemotherapy or radiotherapy for pancreatic cancer
- Previous or concurrent malignancy
- Active acute or chronic systemic infections
- Clinically relevant coronary artery disease or a history of a myocardial infarction within the last 18 months
- Cerebrovascular disease
- Active venous or arterial thromboembolism
- Severe respiratory disease
- Chronic inflammatory bowel disease
- Known HIV infection
- Acute or Chronic HCV or HBV hepatitis
- Peripheral neuropaty
- Chronic liver or renal failure
- Any systemic disease which in the opinion of the investigator would not permit the patient to undergo study treatment
- Major surgery within 28 days from study start
- Minor surgery (except CVC psitioning) within 14 days before treatment
- Pregnancy or breastfeeding
- Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent

- Metastasi a distanza
- Precedente trattamento medico sistemico o radioterapico per la malattia neoplastica
- Presenza di concomitanti e/o pregresse neoplasie maligne
- Presenza di stati infettivi acuti o cronici richiedenti terapie mediche sistemiche.
- Significative patologie cardiovascolari (infarto del miocardio, angina instabile, scompenso cardiaco congestizio, aritmie) occorse meno di 18 mesi prima dell’eventuale arruolamento
- Patologie cerebro-vascolari
- Tromboembolie venose o arteriose in atto
- Gravi patologie respiratorie
- Malattie infiammatorie croniche intestinali
- Sieropositività conosciuta per HIV
- Epatite acuta o cronica da HBV o HCV
- Neuropatia periferica di qualsiasi eziologia
- Insufficienza epatica o renale
- Qualsiasi altra patologia sistemica clinicamente rilevante che si ritenga possa rendere il paziente inidoneo al trattamento in studio
- Intervento di chirurgia maggiore effettuato meno di 28 giorni oppure procedura chirurgica minore praticata meno di 14 giorni prima dell’inizio del trattamento (escluso il posizionamento di CVC)
- Stato di gravidanza o allattamento
- Demenza o altra significativa condizione di alterazione dello stato mentale che possa inficiare la capacità di comprensione degli scopi dello studio da parte del paziente e la corretta concessione del consenso informato da parte dello stesso

E.5 End points

E.5.1

Primary end point(s)

objective response rate and unacceptable toxicity rate

proporzione di risposte obiettive e di tossicità inaccettabile

E.5.1.1

Timepoint(s) of evaluation of this end point

Objective response raste:after 8 and 18 weeks from study start
Toxicity: every week

dopo 8 e dopo 18 settimane dall’inizio del trattamento per la risposta e settimanale per la tossicità

E.5.2

Secondary end point(s)

rate of conversion to resectability
R0 resection rate
progression free survival
overall survival

tasso di conversione alla resecabilità
tasso di resezioni R0
progression free survival
overall survival

E.5.2.1

Timepoint(s) of evaluation of this end point

rate of conversion to resectability: week 19
R0 resection rate: surgery (week 20)
progression free survival: after 8 and 18 weeks from study start and every 3 months later
overall survival: death

tasso di conversione alla resecabilità: settimana 19
tasso di resezioni R0: chirurgia (settimana 20)
progression free survival: dopo 8 e dopo 18 settimane dall’inizio del trattamento e ogni 3 mesi in seguito
overall survival: decesso

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

E.8.1.1

Randomised

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

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

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

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:

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

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)

Not different from clinical practice

Non diverso dalla 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

2013-08-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-06-26

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

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