Clinical Trials Register

Summary
EudraCT Number:	2013-003244-23
Sponsor's Protocol Code Number:	SICOG13/02
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:	2014-02-04
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

2013-003244-23

A.3

Full title of the trial

B-FOLFIRI followed by B-FOLFOX/B-XELOX or the reverse sequence versus standard B-FOLFIRI for the first-line treatment of metastatic colorectal cancer: a randomized SICOG study. SEveSTA study (Sequential vs Standard) SICOG 13/02

B -FOLFIRI seguito da B-FOLFOX/B-XELOX o sequenza inversa versus standard B- FOLFIRI per la prima linea nel carcinoma del colon-retto metastatico: studio di fase III randomizzato. SEveSTA (Sequenziale vs Standard) SICOG 13/02

A.3.1

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

Study evaluating, as first-line treatment of metastatic colorectal cancer, Bevacizumab +FOLFIRI followed by Bevacizumab + FOLFOX( or XELOX) or the reverse sequence Bevacizumab + FOLFOX (or XELOX) folloewed by Bevacizumab + FOLFIRI versus the standard Bevacizumab+ FOLFIRI

Studio che mette a confronto, come trattamento di prima linea del tumore metastatico del colon-retto, il Bevacizumab + FOLFIRI seguito da Bevacizumab + FOLFOX (o XELOX) oppure la squenza inversa Bevacizumab + FOLFOX ( o XELOX) seguito da Bevacizumab + FOLFIRI contro la terapia standard che prevde Bevacizumab + FOLFIRI.

A.3.2

Name or abbreviated title of the trial where available

SEveSTA

A.4.1

Sponsor's protocol code number

SICOG13/02

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	S.I.C.O.G. ONLUS
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	S.I.C.O.G. ONLUS
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	S.I.C.O.G. ONLUS
B.5.2	Functional name of contact point	Data Management
B.5.3	Address:
B.5.3.1	Street Address	Strada Statale 554 Km 4,500 c/o AOU Cagliari Presidio Policlinico - DH Oncologia Medica Piano 1
B.5.3.2	Town/ city	Monserrato
B.5.3.3	Post code	09042
B.5.3.4	Country	Italy
B.5.4	Telephone number	+3907051096614
B.5.5	Fax number	+3907051096614
B.5.6	E-mail	sicog.segreteriascientifica@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.2.1.1.1	Trade name	Avastin
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche
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.3.4	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	BEVACIZUMAB
D.3.9.1	CAS number	216974-75-3
D.3.9.4	EV Substance Code	SUB16402MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	5.0 to 7.5
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	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	Yes
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	CAMPTO
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.3.4	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.3.9.3	Other descriptive name	IRINOTECAN HYDROCHLORIDE TRIHYDRATE
D.3.9.4	EV Substance Code	SUB45873
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	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.2.1.1.1	Trade name	OXALIPLATINO
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA
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.3.4	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	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	range
D.3.10.3	Concentration number	85 to 130
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	XELODA
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE
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.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CAPECITABINE
D.3.9.3	Other descriptive name	CAPECITABINE
D.3.9.4	EV Substance Code	SUB12474MIG
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	1000
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	FLUOROURACILE TEVA
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA
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.3.4	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	5-FLUOROURACIL
D.3.9.3	Other descriptive name	5-FLOUROURACIL
D.3.9.4	EV Substance Code	SUB27520
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	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	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	LEVOFOLENE
D.2.1.1.2	Name of the Marketing Authorisation holder	BAYER
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.3.4	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	FOLINIC ACID
D.3.9.3	Other descriptive name	FOLINIC ACID
D.3.9.4	EV Substance Code	SUB13910MIG
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	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	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

Unresectable and metastatic colorectal cancer

carcinoma del colon-retto inoperabile e metastatico

E.1.1.1

Medical condition in easily understood language

Advanced tumour of colon/rectum

Tumore avanzato del colon-retto

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	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10052362
E.1.2	Term	Metastatic colorectal 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

Progression free survival

Sopravvivenza libera da progressione

E.2.2

Secondary objectives of the trial

Time to treatment failure, response rate, response duration, safety, toxicity, 2-years and 5-yaers Overall survivall

Tempo al fallimento della strategia terapeutica (TTF), tasso e durata di risposta, safety, tossicità e sopravvivenza globale a 2 e 5anni.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Written informed consent

Patients with histologic or cytologic diagnosis of metastatic colorectal cancer surgery is not likely to
colorectal carcinoma metastatic or locally advanced unresectable

At least one measurable lesion according to the RECIST (Response Evaluation Criteria in Solid Tumors)

Adjuvant treatment should be completed ≥ 6 months before study entry

Age ≥ 18 years

ECOG performance status 0 or 1

Renal function, hepatic and haematological normal at the time of study entry and initiation of therapy, in accordance with the guidelines

Using contraceptive methods during the study (for those of childbearing age and their partners)

• Consenso informato scritto
• Pazienti con diagnosi citologica o istologica di carcinoma del colon retto metastatico non suscettibile di chirurgia
• Carcinoma del colon retto metastatico o localmente avanzato non operabile
• Almeno una lesione misurabile secondo I criteri RECIST (Response Evaluation Criteria in Solid Tumors)
• Trattamento adiuvante deve essere terminato ≥6 mesi prima dell’ingresso nello studio
• Età ≥ 18 anni
• ECOG performance status 0 o 1
• Funzionalità renale, epatica ed ematologica nella norma al momento dell’ingresso nello studio e inizio della terapia, in accordo con le linee guida
• Utilizzo di metodi di contraccezione durante lo studio (per i soggetti in età fertile e per i loro partner)

E.4

Principal exclusion criteria

Absence of written informed consent.

Prior treatment with bevacizumab

Hypersensitivity to any of the medications , or components of the study

In recent treatment or treatment (up to 4 weeks before the starting of the infusion of study drug ) with other experimental drugs

History of other malignancy (except squamous or basal cell carcinoma of the skin, in situ carcinoma of the cervix or in situ carcinoma of the colon or rectum treated effectively ) unless there has been a complete remission and both outside therapy for malignant disease from at least 5 years .

Brain metastases or spinal cord compression

Previous treatment for metastatic colorectal cancer

Previous treatment with anti- angiogenetic agents as adjuvant or metastatic

Concomitant use of anti-neoplastic agents being tested (up to 4 weeks prior to enrollment)

Medical or psychiatric disorders that could interfere with the informed consent or patient compliance for participation in this study and its procedures for follow-up

Active infections requiring antibiotic therapy on day 1

Severe cardiovascular disease grade II or greater according to the classification New York Heart Association (NYHA )

Evidence of bleeding diathesis or coagulopathy

Peripheral neuropathy of grade > 1 (according to the NCI CTCAE , v3.0 )

Lack of physical integrity of the upper gastrointestinal tract , or history of malabsorption syndrome

Blood pressure > 150/100 mmHg

Major surgical procedures , biopsies open or significant trauma up to 30 days before compared to day 1 of therapy ; need to anticipate a major surgery during the study period

Minor surgical procedures such as fine needle biopsy (FNA) biopsy or up to 7 days before the start of therapy

Proteinuria , serum creatinine > = 1.0 at study entry

History of abdominal fistula , gastrointestinal perforation or intra-abdominal abscess up to 6 months before the start of the study

Serious wounds , ulcers or bone fractures

History of myocardial infarction up to 6 months before the start of therapy Day 1

Unstable angina

Peripheral vascular disease clinically important

History of stroke up to 6 months before the first day of therapy

Women pregnant ( positive pregnancy test ) or lactating

Assenza di consenso informato scritto.

Precedente trattamento con Bevacizumab

Ipersensibilità nei confronti di uno qualsiasi dei farmaci o componenti dello studio

In trattamento o recente trattamento (fino a 4 settimane prime dell’inizio dell’infusione dei farmaci dello studio) con altri farmaci sperimentali

Storia di altra patologia maligna (ad eccezione del carcinoma squamoso o basocellulare della pelle, carcinoma in situ della cervice o carcinoma in situ del colon o retto trattato efficacemente) a meno che non vi sia stata una remissione completa e sia fuori terapia per la patologia maligna da almento 5 anni.

Metastasi cerebrali o compressione midollare

Precedente trattamento per carcinoma del colon retto metastatico

Precedente trattamento con agenti anti angiogenetic, come terapia adiuvante o metastatica

Uso concomitante di agenti anti-neoplastici in fase di sperimentazione (fino a 4 settimane prima dell'arruolamento)

Patologie mediche o psichiatriche che potrebbero interferire con il consenso informato o con la compliance del paziente per la partecipazione a questo studio e le sue procedure di follow-up

Infezioni attive che necessitino di antibiotico terapia nel giorno 1

Malattie cardiovascolari severe di grado II o superiori secondo la classificazione New York Heart Association (NYHA)

Evidenza di diatesi emorragica o coagulopatie

Neuropatia periferica di Grado > 1 (secondo la classificazione NCI CTCAE, v3.0)

Mancanza di integrità fisica del tratto gastrointestinale superiore o storia di sindrome malassorbimento

Pressione sanguigna > 150/100 mmHg

Procedure chirurgiche maggiori, biopsie a cielo aperto o traumi significativi fino a 30 giorni prima rispetto a giorno 1 di terapia; necessità di anticipare un intervento di chirurgia maggiore durante il periodo di studio

Procedure di chirurgia minore come agobiopsia con ago sottile (FNA) o biopsie fino a 7 giorni prima dell’inizio della terapia

Proteinuria; valori di creatinina >= 1.0 all’ingresso nello studio

Storia di fistola addominale, perforazione gastrointestinale o ascesso intraddominale fino a 6 mesi prima dell’inizio della studio

Ferite serie, ulcere o fratture ossee

Storia di infarto del miocardio fino a 6 mesi prima dell’inizio della terapia Day 1

Angina instabile

Patologie vascolari periferiche clinicamente importanti

Storia di stroke fino a 6 mesi prima del giorno 1 di terapia

Donne gravide (test di gravidanza positivo) o in allattamento

E.5 End points

E.5.1

Primary end point(s)

Progression free survival

Sopravvivenza libera da progressione

E.5.1.1

Timepoint(s) of evaluation of this end point

PFS will be assessed according to RECIST criteria every 6 cycles (3 months)

La Sopravvivenza libera da malattia sarà valutata secondo i criteri RECIST ogni 6 cicli ( 3 mesi)

E.5.2

Secondary end point(s)

Assuming that the average Time to Treatment Failure TTF is 6 months in regimens containing B-FOLFIRI, we determined that in the experimental arm we want to get a time to failure of the therapeutic strategy of 9 months

Response rate: 45-50% in regimens containing FOLFIRI-B-, with the experimental arm we want to get a 15% increase

Compliance and duration of treatment: historical average of 50% of patients performing 11-12 cycles in regimens containing B-FOLFIRI, we want to get in the ex perimental arm at least 75% of patients performing all 12 cycles expectedof induction treatment ;

Safety: With the experimental arm we want to reduce by 50% the overall AEs of grade 3/4

Premettendo che il TTF ( tempo al fallimento del trattamento) è mediamente 6 mesi nei regimi contenenti B-FOLFIRI, abbiamo stabilito che nel braccio definito sperimentale vogliamo ottenere una tempo al fallimento della strategia terapeutica di 9 mesi

Tasso di risposta: 45-50%; nei regimi contenenti B-FOLFIRI ; con il braccio definito sperimentale vogliamo ottenere un aumento del 15 %

Compliance e durata del trattamento: storico mediamente il 50% dei pazienti eseguono 11-12 cicli nei regimi contenenti B-FOLFIRI ; con il braccio definito sperimentale vogliamo ottenere che almeno il 75% dei pazienti esegua tutti i 12 cicli di trattamento di induzione previsti;

Safety: con il braccio definito sperimentale vogliamo ridurre del 50% gli AEs globali di grado 3/4

E.5.2.1

Timepoint(s) of evaluation of this end point

TTF: continuous during the study

Response rate and duration:every 3 months

Safety and toxicity: evaluation every 2-3 weeks

Overall survival: continuous during the study

TTF: continuo valutazione durante lo studio

Tasso di risposta e durata: ogni 3 mesi

Sicurezza e tossicità: la valutazione avverràogni 2-3 settimane

La sopravvivenza globale: continua valutazione durante lo studio

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

Yes

E.6.13.1

Other scope of the trial description

TRANLATIONAL RESEARCH:
In this trial will be performed the mutational analysis, by nucleotide sequencing on paraffin-embedded tumor tissues, of exon 15 of BRAF (which includes all the mutations at codon V600), exons 2 and 3 of the KRAS (entire coding region, which includes the codons 12, 13, 61 and all the other less frequent) and exons 2 and 3 NRAS (entire coding region)

STUDIO TRASLAZIONALE

Lo studio prevede l’ analisi mutazionale mediante sequenziamento nucleotidico, su tessuti tumorali inclusi in paraffina, dell’esone 15 di BRAF (che include tutte le mutazioni al codone V600), degli esoni 2 e 3 di KRAS (intera regione codificante, che include i codoni 12, 13, 61 e tutti gli altri meno frequenti) e degli esoni 2 e 3 di NRAS (intera regione codificante)

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

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

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

Ultima visita dell'ultimo paziente

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:

400

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

400

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

400

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)

None

Nessuno

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

2014-03-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-03-19

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

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