Clinical Trials Register

Summary
EudraCT Number:	2012-005048-46
Sponsor's Protocol Code Number:	2012-005048-46
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:	2013-05-06
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

2012-005048-46

A.3

Full title of the trial

First-line FOLFIRI and bevacizumab in patients with advanced colorectal cancer prospectively stratified according to serum LDH

FOLFIRI e bevacizumab nel trattamento di prima linea in pazienti con carcinoma colo-rettale avanzato stratificati in base ai livelli sierici di LDH

A.3.1

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

patients with colorectal carcinoma compared to patients with normal LDH serum levels

pazienti con carcinoma del colon retto, stratificati prospetticamente in base ai livelli sierici di LDH

A.3.2

Name or abbreviated title of the trial where available

CENTRAL (ColorEctalavastiNTRiALdh)

A.4.1

Sponsor's protocol code number

2012-005048-46

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	Fondazione GISCAD
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	Roche SpA
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	Fondazione GISCAD
B.5.2	Functional name of contact point	Data Center
B.5.3	Address:
B.5.3.1	Street Address	Via Vittorio Alfieri, 45
B.5.3.2	Town/ city	Parabiago (MI)
B.5.3.3	Post code	20015
B.5.3.4	Country	Italy
B.5.4	Telephone number	390331480052
B.5.5	Fax number	390331553720
B.5.6	E-mail	centrotrialgiscad@yahoo.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	avastin
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche SpA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	bevacizumab
D.3.2	Product code	Ro4876646
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.3.11 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	Yes
D.3.11.13.1	Other medicinal product type	monoclonal antibody
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	Campto
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Italia Srl
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	irinotecan
D.3.2	Product code	cas 100286-90-6
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.3.11 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	Fluorouracil
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Pharma Italia
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	5FU
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.3.11 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	Calcio Folinato
D.2.1.1.2	Name of the Marketing Authorisation holder	Wyeth Lederle S.p.A
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	lederfolin
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.3.11 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

patients treated with first-line chemotherapy and bevacizumab will be prospectively stratified according to LDH serum levels

pazienti trattati con bevacizumab e chemioterapia in prima linea saranno stratificati prospetticamente in base ai livelli sierici di LDH

E.1.1.1

Medical condition in easily understood language

advanced metastatic colorectal carcinoma

carcinoma colo-rettale avanzato e metastatico

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Response rate (to ascertain whether bevacizumab in combination with chemotherapy could determine an improved response rate in patients with high LDH serum levels compared to patients with normal LDH serum levels

Risposta Obiettiva (Confronto del tasso di risposte obiettive in pazienti con livelli sierici elevati di LDH rispetto a pazienti con livelli sierici normali di LDH)

E.2.2

Secondary objectives of the trial

-comparison between response rate according to the RECIST criteria and the criteria defined by Chun (Jama 2009)
-evaluation of serum IL-8, bFGF, HGF, PlGF, SDF-1, MCP-3 as a marker of early progression
-Progression free survival (to ascertain whether bevacizumab in combination with chemotherapy could determine an improved progression survival in patients with high serum LDH levels compared to patients with normal LDH serum levels

-Confronto tra tasso di risposte obiettive secondo i criteri RECIST e tasso di risposte secondo i criteri definiti da Chun (JAMA 2009)
-Valutazione di IL-8 (Interleukin-8), bFGF (basic Fibroblast Growth Factor), HGF (Hepatocyte Growth Factor), PlGF (Placental Growth Factor), SDF-1 (Stromal Derived Factor 1a/CXCL12), MCP-3 (monocyte chemotactic protein) come marcatori precoci di progressione
-Sopravvivenza libera da progressione (PFS) calcolata come l’intervallo di tempo tra l’inizio del trattamento e la progressione clinica, il decesso o l’ultima visita di follow up in caso di non progressione

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Written informed consent
• No prior treatment for advanced disease (adjuvant therapy allowed)
• age < 75 years < 18 years
• Histologically/cytologically confirmed advanced, colorectal cancer
• At least one lesion measurable with CT or MRI scan
• Performance Status (ECOG) 0-1 at study entry)
• Life expectancy of at least 6 months
• Neutrophils count =/> 1.5 x 109/L, platelets count =/> 100 x 109/L, HGB =/> 10 g/dL
• total bilirubin < 1.5 x UNL • SGOT and SGPT =/< 2.5 x UNL (=/< 5 x UNL in patients with liver metastases)
• Creatinine < 1.5 x UNL

• Consenso informato scritto
• Nessun precedente trattamento per la malattia avanzata (terapia adiuvante consentita)
• Età < 75 anni
• Diagnosi confermata istologicamente/citologicamente di carcinoma del colon-retto metastatico
• Almeno una lesione misurabile alla TC o RM secondo i criteri RECIST
• Performance Status (ECOG) 0-1
• Aspettativa di vita di almeno 6 mesi
• Neutrofili =/> 1.5 x 109/L, Piastrine =/> 100 x 109/L, Emoglobina =/> 10 g/dL
• Bilirubina totale < 1.5 x UNL
• SGOT e SGPT =/< 2.5 x UNL (=/< 5 x UNL in pazienti con metastasi epatiche)
• Creatinina < 1.5 x UNL

E.4

Principal exclusion criteria

. CNS metastases
• Severe cardiovascular disease
• Uncontrolled infections
• Radiotherapy within 4 weeks of study entry
• Any experimental drug administered within 4 weeks of study entry
• Known hypersensitivity to study drug
• Known drugs or alcohol abuse
• Pregnant or lactating women (serum Betahcg test)
• Other tumours, except in situ melanoma or cervix cancer if radically removed
• Incapability to sign informed consent

. Metastasi al SNC (SIstema Nervoso Centrale)
• Malattie cardiovascolari severe
• Infezioni non controllate
• Radioterapia nelle 4 settimane precedenti l’ingresso nello studio
• Qualsiasi farmaco sperimentale nelle 4 settimane precedenti l’ingresso nello studio
• Nota ipersensibilità ad un farmaco oggetto dello studio
• Noto abuso di alcol o droghe
• Gravidanza o allattamento
• Altre neoplasie maligne, eccetto melanoma in situ o carcinoma della cervice uterina
• Incapacità di fornire consenso informato

E.5 End points

E.5.1

Primary end point(s)

Response Rate

Risposta Obiettiva

E.5.1.1

Timepoint(s) of evaluation of this end point

Response rate will be evaluated every 12 weeks

la risposta obiettiva sarà valutata ogni 12 settimane

E.5.2

Secondary end point(s)

comparison between response rate according to the RECIST criteria and the criteria defined by Chun (Jama 2009)

Confronto tra tasso di risposte obiettive secondo i criteri RECIST e tasso di risposte secondo i criteri definiti da Chun (JAMA 2009)

E.5.2.1

Timepoint(s) of evaluation of this end point

according to the RECIST criteria and those defined by Chun (JAMA 2009)

secondo I criteri RECIST e secondo I criteri morfologici di Chun (JAMA 2009)

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

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

Yes

E.6.13.1

Other scope of the trial description

it will be to prospectively ascertain whether bevacizumab in combination with chemotherapy has an improved clinical activity in patients with high LDH serum levels compared to patients with normal LDH serum levels

accertare se il bevacizumab in combinazione con la chemioterapia abbia una migliore attività clinica in pazienti con elevati livelli sierici di LDH rispetto ai pazienti con livelli di LDH normali.

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

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:

F.1.3

Elderly (>=65 years)

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.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)

Examination of end treatment and before follow-up
Clinical examination every 12 weeks
Laboratory examinations
Instrumental evaluation for disease with TC or MR
II line therapy if indicated
Follow-up according to II line therapy

visita di fine trattamento ed inizio follow-up
Valutazione clinica ogni 12 settimane
esami di laboratorio (emocromo, funzionalità epatica e renale, CEA) ogni 8 settimane
Valutazione strumentale di malattia ogni 12 settimane con TC spirale o RM dinamica
Trattamento di II linea se indicato
Follow-up secondo il regime di II linea impiegato

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

2013-06-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-01-17

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

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