Clinical Trials Register

Summary
EudraCT Number:	2018-001414-15
Sponsor's Protocol Code Number:	REVOLUTION
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:	2022-01-20
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

2018-001414-15

A.3

Full title of the trial

Randomized phasE 2 study of Valproic acid in combination with bevacizumab and Oxaliplatin/fLUoropyrimidine regimens in patients with ras-mutated metastaTIc cOlorectal caNcer

Studio randomizzato di fase 2 sull¿associazione di acido Valproico con FOLFOX/OXXEL e Bevacizumab nel trattamento di pazienti affetti da carcinoma del
colon-retto metastatico con mutazioni di RAS

A.3.1

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

Randomized phasE 2 study of Valproic acid in combination with bevacizumab and Oxaliplatin/fLUoropyrimidine regimens in patients with ras-mutated metastaTIc cOlorectal caNcer

A.3.2

Name or abbreviated title of the trial where available

REVOLUTION

A.4.1

Sponsor's protocol code number

REVOLUTION

A.5.4

Other Identifiers

Name:

REVOLUTION

Number:

REVOLUTION

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 TUMORI - IRCCS FONDAZIONE 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	Ministero della Salute ¿ Ricerca Finalizzata
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 - FONDAZIONE
B.5.2	Functional name of contact point	Unita' Sperimentazioni Cliniche
B.5.3	Address:
B.5.3.1	Street Address	Via M. Semmola - Napoli - 80131
B.5.3.2	Town/ city	Napoli
B.5.3.3	Post code	80131
B.5.3.4	Country	Italy
B.5.4	Telephone number	0815903571
B.5.5	Fax number	0817702938
B.5.6	E-mail	usc-segreteria@istitutotumori.na.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	DEPAKIN - CHRONO 300 MG COMPRESSE A RILASCIO PROLUNGATO BLISTER DA 30 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	SANOFI-AVENTIS FRANCE S.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.3.4	Pharmaceutical form	Prolonged-release 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	ACIDO VALPROICO
D.3.9.2	Current sponsor code	ACIDO VALPROICO
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
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	AVASTIN - 1 FLACONCINO DA 400 MG DI CONCENTRATO PER SOLUZIONE PER INFUSIONE
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION LIMITED
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	Bevacizumab
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.3.9.2	Current sponsor code	bevacizumab
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
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: 3
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	CAPECITABINA ACCORD - 150 MG - COMPRESSA RIVESTITA CON FILM - USO ORALE - BLISTER (ALLU/ALLU) - 30 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	ACCORD HEALTHCARE LIMITED
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	Capecitabina
D.3.2	Product code	Capecitabina
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.3.9.2	Current sponsor code	Capecitabina
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	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
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	OXALIPLATINO ACCORD - 5 MG/ML CONCENTRATO PER SOLUZIONE PER INFUSIONE 1 FLACONCINO IN VETRO DA 20 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	ACCORD HEALTHCARE ITALIA S.R.L.
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	OXALIPLATINO
D.3.2	Product code	OXALIPLATINO
D.3.4	Pharmaceutical form	Powder for suspension 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	OXALIPLATINO
D.3.9.1	CAS number	6312-100-6
D.3.9.2	Current sponsor code	OXALIPLATINO
D.3.9.3	Other descriptive name	OXALIPLATINO
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 5
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	FLUOROURACILE BAXTER - 500 MG/10 ML SOLUZIONE INIETTABILE PER USO EV 5 FLACONI
D.2.1.1.2	Name of the Marketing Authorisation holder	BAXTER 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	fluorouracile
D.3.2	Product code	fluorouracile
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.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	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 with ras-mutated metastaTIc colorectal cancer

pazienti affetti da carcinoma del
colon-retto metastatico con mutazioni di RAS

E.1.1.1

Medical condition in easily understood language

patients with ras-mutated metastaTIc cOlorectal caNcer

pazienti affetti da carcinoma del
colon-retto metastatico con mutazioni di RAS

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10007446
E.1.2	Term	Carcinoma of rectum
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

Primary aim
To test whether the combination of valproic acid with bevacizumab and oxaliplatin/fluoropyrimidine regimens (mFOLFOX6/mOXXEL) can prolong progression free survival (PFS) as compared with bevacizumab and oxaliplatin/fluoropyrimidine regimens alone as first-line treatment in patients with metastatic colorectal cancer with mutation of RAS

¿ Obiettivo primario:
Verificare se l¿associazione di acido valproico alla chemioterapia di prima linea con FOLFOX/OXXEL + Bevacizumab prolunga la sopravvivenza libera da progressione (PFS), valutata dai ricercatori (investigator-assessed, IA), di pazienti affetti da carcinoma del colon-retto con mutazioni RAS.

Nota: Gli esami TC (o altri esami rilevanti) effettuati alla visita basale e nel corso dello studio saranno raccolte per una revisione centralizzata effettuata da un gruppo di radiologi indipendente.

E.2.2

Secondary objectives of the trial

Secondary aims
¿ To compare the two arms in terms of:
o centrally reviewed PFS (CR-PFS)
o overall survival (OS)
o quality of life (EORTC QLQ C30 + CR 29)
o objective response rate (RECIST1.1)
o adverse events (CTCAE 4.03 version)
o metastases resection rate (R0/R1/R2)
¿ To evaluate mechanistically ¿based pharmacokinetic/pharmacodynamic biomarkers on blood samples
¿ To explore prognostic factors and predictive biomarkers on blood samples, primary tumors, and on resected metastases

¿ Obiettivi secondari:
¿ Valutare l¿impatto della schedula sperimentale su :
o PFS rivista centralmente (centrally-reviewed, CR- PFS)
o Tasso di risposta obiettiva
o Sopravvivenza globale (OS)
o Tossicit¿ (CTCAE ver. 5.0)
o Qualit¿ di vita (EORTC QLQ C30; CR29)
o Tasso di resezioni metastasi epatiche con valutazione del residuo microscopico
o Tasso di risposta patologica completa delle metastasi resecate

¿ Valutare in maniera esplorativa:
o Biomarcatori di farmacodinamica e farmacocinetica su campioni di sangue
o Ruolo prognostico e predittivo di biomarcatori su campioni di sangue, tumore primitivo e metastasi epatiche resecate

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Main inclusion criteria
• Age = 18
• Histologically confirmed diagnosis of colorectal adenocarcinoma
• Stage IV of disease (according to TNM 8th edition)
• RAS mutations
• Clinical or radiologic evidence of disease (at least one target according to RECIST 1.1)
• ECOG performance status 0 to 1
• Life expectancy > 3 months
• Use of an acceptable mean of contraception for men and women of childbearing potential
• Adequate recovery from previous surgery. At least 28 days should elapse from a surgical procedure or from performing a biopsy for the enrolment into the study
• Written informed consent

Criteri di inclusione
¿ Diagnosi istologica di adenocarcinoma del colon o del retto
¿ Stadio IV di malattia (TNM 8° Edizione)
¿ Mutazioni a carico del gene RAS
¿ Presenza di almeno una lesione target o non target (sec. criteri RECIST1.1) non precedentemente irradiata
¿ Età = 18 e =80
¿ Performance status 0-1 secondo ECOG
¿ Aspettativa di vita >3 mesi
¿ Adeguato recupero da un precedente intervento chirurgico. Devono essere trascorsi almeno 28 giorni da un intervento chirurgico o dall’effettuazione di una biopsia per l’inserimento nello studio
¿ Metodi contraccettivi efficaci adottati sia dagli uomini che dalle donne nei casi in cui esiste la possibilità di un concepimento
¿ Consenso informato scritto

E.4

Principal exclusion criteria

Main exclusion criteria
• Tumors without RAS mutations
• Prior chemotherapy or any other medical treatment for advanced mCRC (previous adjuvant chemotherapy is allowed if ended > 6 months before relapse or > 24 months if the adjuvant treatment included oxaliplatin)
• Radiotherapy to any site for any reason within 28 days prior to randomization (palliative radiotherapy to bone lesions is allowed if = 14 days before randomization)
• Any other invasive malignancies within 5 years (except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer or surgically resected prostate cancer with normal PSA)
• Patient who have had prior treatment with an HDAC inhibitor and patients who have received compounds with HDAC inhibitor-like activity, such as valproic acid
• Known dihydropyrimidine dehydrogenase (DPD) deficiency
• Pregnancy or nursing
• Concomitant pathologies or laboratory alterations or concomitant medications use that prevent or contraindicate the use of study drugs
• Brain metastases

Criteri di esclusione
¿ Precedente trattamento chemioterapico per la malattia metastatica (consentito precedente trattamento adiuvante se l’intervallo libero da malattia è > 6 mesi se il trattamento non includeva oxaliplatino e > 24 se invece il paziente ha ricevuto oxaliplatino)
¿ Radioterapia di qualsiasi sito nei 28 giorni precedenti la randomizzazione (la radioterapia ossea con finalità palliativa è permessa fino a 14 gg prima della randomizzazione)
¿ Terapia in corso con warfarin a dose piena
¿ Uso di aspirina >325 mg/die nei 10 giorni precedenti dalla randomizzazione o terapia cronica con anti-infiammatori non steroidei
¿ Precedente trattamento con inibitori dell’ istone de acetilasi (HDAC) o con farmaci con attività analoga a quella degli inibitori di HDCA come ad esempio l’ acido valproico
¿ Deficienza nota dell’ enzima diidropirimidina deidrogenasi (DPD)
¿ APTT > 1.5 LSN o INR >1.5
¿ GOT e/o GPT > 2.5 volte il limite del valore normale e/o bilirubina >1.5 volte il limite del valore normale (oppure GOT e/o GPT > 5 volte il limite del valore normale e/o bilirubina >3 volte il limite del valore normale)
¿ Livelli di creatinina sierica >1.5 LSN o clearance renale <50 ml/min
¿ Dipstick positiva per proteinuria >2+
¿ Neutrofili < 2000/mm3 o piastrine < 100.000/ mm3 o emoglobina <9 g/dl
¿ Gravidanza o allattamento
¿ Ipertensione non controllata
¿ Presenza nei 6 mesi precedenti la randomizzazione di: patologia sistemica grave, angina instabile, cardiopatia congestizia II classe NYHA, vascolopatia periferica clinicamente significativa, fistola addominale, perforazione gastrointestinale, ascesso intra-addominale
¿ Storia di aritmia (battiti ventricolari multifocali prematuri [PVCs], bigeminismo, trigeminismo, tachicardia ventricolare, fibrillazione atriale non controllata) che sia sintomatica o richieda trattamento (CTCAE grado 3) o tachicardia ventricolare sostenuta asintomatica.
¿ Sindrome da QT lungo o intervallo QTc con durata >480 msec o uso di farmaci concomitanti che possono prolungare l’intervallo QTc
¿ Presenza di ferite non rimarginate, ulcere o fratture
¿ Storia precedente di malattia infiammatoria intestinale o malattia in atto
¿ Diatesi emorragica o coagulopatia o emorragia interna severa o acuta nei6 mesi precedenti la randomizzazione
¿ Storia di emorragia cerebrale o ictus cerebrale (ischemico o emorragico) nei 6 mesi precedenti la randomizzazione
¿ Chirurgia maggiore o lesioni da trauma nei 28 giorni precedenti la randomizzazione
¿ Chirurgia minore, ago aspirato o core-biopsy nei 7 giorni precedenti la randomizzazione
¿ Incapacità ad assumere farmaci orali o necessità di alimentazione intravenosa o alimentazione parenterale totale
¿ Confusione o disorientamento o storia di patologia psichiatrica maggiore che possa compromettere la comprensione del consenso informato o la capacità di aderire alle procedure dello studio
¿ Diagnosi di altra neoplasia nei 5 anni precedenti la randomizzazione, ad eccezione dei tumori della pelle, tranne il melanoma, o del carcinoma in situ della cervice o del carcinoma della prostata resecato con normali valori di PSA
¿ Metastasi cerebrali note o sospette (da verificare esclusivamente in presenza di almeno un sintomo clinico)
¿ Pazienti HIV positivi
¿ Qualunque altra patologia concomitante o alterazione degli esami di laboratorio o farmaco concomitante che potrebbe controindicare l’uso dei farmaci in studio

E.5 End points

E.5.1

Primary end point(s)

PFS progression free survival

PFS sopravvivenza libera da progressione

E.5.1.1

Timepoint(s) of evaluation of this end point

12 th and 24 th weeks, every 3 months thereafter until disease progression

12a e 24a settimana dopo l’inizio del trattamento e successivamente ogni 3 mesi fino progressione di malattia

E.5.2

Secondary end point(s)

PFS centrally reviewed (CR- PFS); Objective Response Rate; Overall survival (OS); Toxicity (CTCAE ver. 5.0); Quality of life (EORTC QLQ C30; CR29); liver metastases resection rate (R0/R1/R2) and metastases patologic complete response rate

PFS rivista centralmente (CR- PFS); Tasso di risposta obiettiva; Sopravvivenza globale (OS); Tossicit¿ (CTCAE ver. 5.0) ; Qualit¿ di vita (EORTC QLQ C30; CR29); Tasso di resezioni metastasi epatiche con valutazione del residuo microscopico e Tasso di risposta patologica completa delle metastasi resecate

E.5.2.1

Timepoint(s) of evaluation of this end point

12 th and 24 th weeks, every 3 months thereafter until disease progression; 12 th and 24 th weeks, every 3 months thereafter until disease progression; death; at the end of each cycle (at day 1 of any cycle before receving treatment) ; 12 th and 24 th weeks, every 3 months thereafter until disease progression; alla chirurgia (questo endpoint viene valutato solo in caso di intervento chirurgico di resezione delle metastasi)

12a e 24a settimana dopo l¿inizio del trattamento e successivamente ogni 3 mesi fino progressione di malattia ; 12a e 24a settimana dopo l¿inizio del trattamento e successivamente ogni 3 mesi fino progressione di malattia ; morte; alla fine di ogni ciclo (al giorno 1 di ogni ciclo prima della somministrazione del trattamento); 12a e 24a settimana dopo l¿inizio del trattamento e successivamente ogni 3 mesi fino progressione di malattia ; at surgery (this endpoint is evaluated if the surgery is performed)

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

Yes

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

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

chemioterapia standard in associazione a bevacizumab

standard chemotherapy plus bevacizumab

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.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

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:

150

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

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

200

F.4.2

For a multinational trial

F.4.2.1

In the EEA

200

F.4.2.2

In the whole clinical trial

200

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)

n.a.

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

2018-07-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-23

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

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