Clinical Trials Register

Summary
EudraCT Number:	2015-004544-18
Sponsor's Protocol Code Number:	CL2-95005-002
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-09-07
Trial results	View 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

2015-004544-18

A.3

Full title of the trial

An open-label, randomised, non-comparative phase 2 study evaluating S 95005 (TAS-102) plus bevacizumab and capecitabine plus bevacizumab in patients with previously
untreated metastatic COlorectal cancer who are non-eligible for intensive therapy

Studio di fase 2 in aperto, non comparativo, randomizzato, per la valutazione di S 95005 (TAS-102) più bevacizumab e capecitabina più bevacizumab in pazienti con carcinoma del COlon-retto metastatico non precedentemente trattati che non siano candidabili per una terapia intensiva (studio TASCO1)”

A.3.1

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

Phase 2 study evaluating S 95005 (plus bevacizumab and capecitabine plus bevacizumab in patients with previously
untreated metastatic colorectal cancer who are non-eligible for intensive therapy

Studio di fase 2 i, per la valutazione di S 95005 (più bevacizumab e capecitabina più bevacizumab in pazienti con carcinoma del COlon-retto metastatico non precedentemente trattati che non siano candidabili per una terapia intensiva

A.3.2

Name or abbreviated title of the trial where available

TASCO1 study

Studio TASCO1

A.4.1

Sponsor's protocol code number

CL2-95005-002

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	INSTITUT DE RECHERCHES INTERNATIONALES SERVIER
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	ADIR
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Istituto di Ricerca Servier
B.5.2	Functional name of contact point	Project manager: Alessandra Tamburr
B.5.3	Address:
B.5.3.1	Street Address	Via Luca Passi 85
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00166
B.5.3.4	Country	Italy
B.5.4	Telephone number	003906669081
B.5.5	Fax number	00390666908738
B.5.6	E-mail	infoirs@netgrs.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	Lonsurf
D.2.1.1.2	Name of the Marketing Authorisation holder	Les Laboratoires Servier
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	S95005
D.3.2	Product code	[S95005]
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	TRIFLURIDINA
D.3.9.2	Current sponsor code	na
D.3.9.4	EV Substance Code	SUB11291MIG
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	15
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TIPIRACIL HYDROCHLORIDE
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	TIPIRACIL HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB174132
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	7
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	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	Lonsurf
D.2.1.1.2	Name of the Marketing Authorisation holder	Les Laboratoires SERVIER
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	S95005
D.3.2	Product code	[S95005]
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	TRIFLURIDINE
D.3.9.2	Current sponsor code	na
D.3.9.4	EV Substance Code	SUB11291MIG
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	20
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TIPIRACIL HYDROCHLORIDE
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	TIPIRACIL HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB174132
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	9
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: 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	Avastin
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	Pharmaceutical form	Concentrate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BEVACIZUMAB
D.3.9.1	CAS number	216974-75-3
D.3.9.2	Current sponsor code	na
D.3.9.4	EV Substance Code	SUB16402MIG
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	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: 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	Avastin
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	Pharmaceutical form	Concentrate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BEVACIZUMAB
D.3.9.1	CAS number	216974-75-3
D.3.9.2	Current sponsor code	na
D.3.9.4	EV Substance Code	SUB16402MIG
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	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: 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	Xeloda
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Capecitabine
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.3.9.2	Current sponsor code	na
D.3.9.4	EV Substance Code	SUB12474MIG
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	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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 6
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Xeloda
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Capecitabine
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.3.9.2	Current sponsor code	na
D.3.9.4	EV Substance Code	SUB12474MIG
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.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Metastatic colorectal cancer

Cancro metastatico colorettale

E.1.1.1

Medical condition in easily understood language

Colorectal cancer

Cancro colorettale

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	21.0
E.1.2	Level	PT
E.1.2	Classification code	10052358
E.1.2	Term	Colorectal cancer metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 the progression-free survival (PFS) in patients receiving S 95005 + bevacizumab (experimental arm) or capecitabine + bevacizumab (control arm) as first-line treatment for unresectable metastatic colorectal cancer in patients non-eligible for intensive therapy.

Valutare la sopravivvenza libera da progressione (Progression Free Survival, PFS), in pazienti che ricevono S95005 + bevacizumab (braccio sperimentale) o capecitabina + bevacizumab (braccio di controllo) come prima linea di trattamento per cancro metastatico colorettale non resecabile in pazienti non elegibili per terapia intensiva

E.2.2

Secondary objectives of the trial

To evaluate the overall response rate (ORR), duration of response (DR), disease control rate (DCR), overall survival (OS), safety and tolerability, quality of life (QoL) in patients receiving S 95005 + bevacizumab (experimental arm) or capecitabine + bevacizumab (control arm) as first-line treatment for unresectable metastatic colorectal cancer in patients non-eligible for intensive therapy.
Exploratory: Evaluate the biomarkers potentially predictive of response and resistance to S 95005 given in combination using blood samples and archived tumour biopsy (if available).

Valutare il tasso di risposta globale (Overall Response Rate, ORR)
-Durata della risposta (Duration of Response, DR)
Tasso di controllo della malattia (Disease Control Rate, DCR)
Sopravivvenza globale (Overall Survival, OS)
Sicurezza e tollerabilità
Qualità della vita (QoL) in pazienti che ricevono S95005+bevacizumab (braccio sperimentale) o capecitabina+bevacizumab (braccio di controllo) come trattamento di prima linea per cancro metastatico colorettale non resecabile in pazienti non elegibili per terapia intensiva.
Esploratori: Valutare i biomarcatori potenzialmente predittivi di risposta e di resistenza a S 95005 somministrato in combinazione attraverso campioni di sangue e tessuto tumorale archiviato (se disponibile).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Written informed consent obtained.
- Male or Female participant aged =18 years old.
- Has ECOG performance status of 0, 1 or 2 at the time of the randomisation.
- Has definitive histologically or cytologically confirmed adenocarcinoma of the colon or rectum.
- RAS status must have been determined (mutant or wild).
- Has at least one measurable metastatic lesion.
- No previous systemic anticancer therapy for unresectable metastatic colorectal cancer.
- Previous adjuvant (or neoadjuvant for patients with rectal cancer) chemotherapy is allowed only if it has been completed more than 6 months before start of study treatment.
- Patient is not a candidate for combination chemotherapy with irinotecan or oxaliplatin, or for curative resection of metastatic lesions.
- Is able to take medication orally (i.e., no feeding tube).
- Has adequate organ function.
- Coagulation parameters in normal limit. (or in therapeutic limit for patients treated with anticoagulant drugs).
- Women of childbearing potential must have been tested negative in a serum pregnancy test.
Female participants of childbearing potential and male participants with partners of childbearing potential must agree to use a highly effective method of birth control. Women and female partners using hormonal contraceptive must also use a barrier method.
- Is willing and able to comply with scheduled visits and study procedures.

- Ottenimento del consenso informato scritto
- Uomini o donne di età = 18 anni
- Eastern Cooperative Oncology Group (ECOG) Performance Status di 0, 1 o 2 al momento della randomizzazione
- Adenocarcinoma del colon o retto confermato istologicamente o citologicamente
- Lo stato di RAS (mutante o wild type) deve essere stato determinato
- Presenza di almeno una lesione misurabile metastatica
- Nessuna precedente terapia antitumorale sistemica per il tumore colorettale metastatico non resecabile
- Chemioterapia adiuvante ( o neoadiuvante per i pazienti con tumore rettale) precedente consentita solo se terminata da oltre sei mesi l’inizio del trattamento sperimentale
-Il paziente non è candidabile per chemioterapia combinata con irinotecan o oxaliplatino, o per resezione curativa delle lesioni metastatiche
- Capacità di assumere farmaci orali (ad esempio non i pazienti intubati)
-Funzionalità adeguate degli organi
-Parametri di coagulazione nella norma (o nei limiti terapeutici per i pazienti trattati con farmaci anticoagulanti)
- Per le donne potenzialmente fertili, un test serico di gravidanza negativo prima dell’inizio dell'assunzione del farmaco in studio. I partecipanti donna con potenziale riproduttivo e i partecipanti uomini con partners con potenziale riproduttivo devono utilizzare un metodo contraccettivo altamente efficace.Donne o partner donne che stanno usando un contraccettivo ormonale, devono usare anche un metodo a barriera
- Partecipante che desideri e sia in grado di aderire alle visite e procedure previste dallo studio.

E.4

Principal exclusion criteria

- Foreseeable poor compliance to the study procedures.
- Is a pregnant or lactating female.
- Is inappropriate for entry into this study in the judgment of the Investigator.
- Has certain serious illness or serious medical condition(s) described in the protocol.
- Has had certain other recent treatment e.g. major surgery, field radiation, received investigational agent, within the specified time frames prior to randomisation.
- Has previously received S 95005 or history of allergic reactions attributed to compounds of similar composition to S 95005 or any of its excipients.
-Has rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
- Has contra-indication to bevacizumab or capecitabine

-Prevedibile scarsa compliance alle procedure dello studio
- Donne in gravidanza o allattamento
- Paziente considerato a giudizio dello sperimentatore non adatto a partecipare allo studio
- Partecipante che presenti una patologia severa o condizioni cliniche severe descritte nel protocollo
-Partecipanti che hanno ricevuto altri recenti trattamenti ad esempio interventi chirurgici maggiori, radioterapia su aree estese, che hanno ricevuto un farmaco sperimentale entro il periodo di tempo specificato prima della randomizzazione
- Paziente a cui sia stato precedentemente somministrato S 95005 o con storia di reazioni allergiche attribuibili a componenti di composizione similare al S95005 o a qualsiasi dei suoi eccipienti.
-Paziente con problemi rari ereditari di intolleranza al galattosio, deficienza al Lapp lactase o malasobimento del glucosio-galattosio.
-Paziente con controindicazioni a bevacizumab o capecitabina.

E.5 End points

E.5.1

Primary end point(s)

Progression free survival (PFS)

Sopravvivenza libera da progressione

E.5.1.1

Timepoint(s) of evaluation of this end point

Tumour measurements within 28 days prior to Day 1 of Cycle 1 and
every 8 weeks thereafter.

Misurazione tumorale entro i 28 giorni precedenti al giorno 1 del ciclo 1 e nelle 8 settimane successive

E.5.2

Secondary end point(s)

Overall Response Rate (ORR). - Duration of Response (DR) - Disease control rate (DCR) - Overall Survival - Safety and tolerability assessed by: * Incidence of Adverse Events (AE). *Laboratory tests: haematology, blood biochemistry, coagulation, urinalysis. * Physical examination and performance status (ECOG). * Vital signs: blood pressure (BP), heart rate (HR), body temperature, respiration rate, body weight. * 12-leads ECG parameters. - Quality of Life assessed by a quality of life questionnaire. - Exploratory endpoints:Biomarkers using blood samples and archived tumour biopsy (if available).

Tasso di risposta totale (ORR) - durata della risposta (DR) - Tasso di controllo della malattia (DCR) - Sopravvivenza totale - Sicurezza e tollerabilità verificato come: -- incidenza degli eventi avversi (AE) --test di laboratorio: ematologia, biochimica, coagulazione, analisi delle urine - -Esame fisico e performance status (ECOG) -- Segni vitali: pressione sanguigna (BP), frequenza cardiaca (HR), temperatura corporea, frequenza respiratoria, peso corporeo --parametri ECG - Qualità della vita verificata con un questionario della qualità della vita - obiettivi esploratori : biomarker, usando campioni di sangue e biopsie tumorali archiviate (se disponibili)

E.5.2.1

Timepoint(s) of evaluation of this end point

-- ORR, DR, DCR: tumour measurements within 28 days prior to Day 1 of Cycle 1 and every 8 weeks thereafter. -Overall Survival: survival status obtained at scheduled 8-week intervals until patient death or and of the study -Adverse Events: all over the study. - Laboratory tests, physical exam, ECOG, vital signs: within 5 days prior randomisation, at the dose of C1D1, C1D15 (except for coagulation, physical exam, ECOG), Day 1 of subsequent cycles, Day 15 of subsequent cycles (only for vital signs), and haematology in the experimental arm) withdrawal visit. - Quality of life assessments: every 12 weeks. - Biomarkers measurements: blood samples collected at C1D1 and withdrawal visit.

- ORR, DR,DCR: misurazione tumorale entro 28 giorni e prima del giorno 1 del ciclo 1 e successivamente ogni 8 settimane -sopravvivenza totale: stato di sopravvivenza ottenuto negli intervalli programmati di 8 settimane fino alla morte del paziente o alla fine dello studio - Eventi avversi: durante tutto lo studio -Test di laboratorio, esame fisico ECOG, segni vitali: entro i 5 giorni precedenti alla randomizzazione , al pre-dose di C1D1, C1D15 (ad eccezione della coagulazione, esame fisico, ECOG) , giorno 1 del ciclo successivo, giorno 15 dei cicli successivi (solo per i segni vitali e l’ematologia nel razzio sperimentale), ), visita di uscita dallo studio -Verifica della qualità della vita: ogni 12 settimane - Misurazione dei biomarker: campioni di sangue prelevati a C1D1 e alla visita d

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

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Brazil

Russian Federation

Belgium

Denmark

France

Germany

Italy

Netherlands

Poland

Spain

United Kingdom

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

12 months after the follow-up start date of the last patient withdrawn. The end of the trial is not the LVLP as a follow-up period is planned in the trial to collect patients survival data after the patients withdrawal. It has been decided to terminate the trial 12 months after the follow-up start date of the last patient withdrawn as we will collect enough data to assess overall survival.

12 mesi dopo la data di inizio del follow-up dell’ultimo paziente uscito dallo studio. La
fine dello studio non corrisponde alla LVLS poiché il periodo di follow-up è pianificato
nello studio al fine di raccogliere i dati di sopravvivenza dei pazienti dopo l’uscita dei
pazienti dallo studio. E’ stato deciso di terminare lo studio 12 mesi dopo la data di
inizio del follow-up dell’ultimo paziente uscito dallo studio così da raccogliere dati
sufficienti a valutare la sopravvivenza totale.

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)

Yes

F.1.3.1

Number of subjects for this age range:

110

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.4.2

For a multinational trial

F.4.2.1

In the EEA

120

F.4.2.2

In the whole clinical trial

150

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After the discontinuation of the IMP, the participant will access to an appropriate medical care by his doctor, who will provide the best support care.
Specific rules may be followed in some countries according to local regulation.

Dopo l'interruzione dell' IMP, il partecipante avrà accesso ad un appropriato supporto medico dal suo medico, il quale fornirà le migliori cure.
Regole specifiche potranno essere seguite in alcuni paesi in accordo alle leggi locali.

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

2016-03-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-01-28

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

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IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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