Clinical Trials Register

Summary
EudraCT Number:	2012-000109-66
Sponsor's Protocol Code Number:	TPU-TAS-102-301
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:	2012-08-02
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

2012-000109-66

A.3

Full title of the trial

RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF TAS-102 PLUS BEST SUPPORTIVE CARE (BSC) VERSUS PLACEBO PLUS BSC IN PATIENTS WITH METASTATIC COLORECTAL CANCER REFRACTORY TO STANDARD CHEMOTHERAPIES

STUDIO RANDOMIZZATO IN DOPPIO CIECO DI FASE 3, PER VALUTARE IL TAS-102 CON AGGIUNTA LA MIGLIORE TERAPIA DI SUPPORTO (BSC), VERSUS PLACEBO CON AGGIUNTA BSC, IN PAZIENTI AFFETTI DA CANCRO DEL COLON-RETTO, METASTATICO E REFRATTARIO A CHEMIOTERAPICI STANDARD

A.3.1

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

This is a clinical research trial to compare the effects, good and/or bad of TAS-102 and best supportive care with placebo (an inactive drug) and best supportive care on you and your refractory colorectal cancer to find out the effects on how long you may live, how much time may pass without disease progression and the safety of TAS-102.

Questa sperimentazione clinica vuole valutare gli effetti positivi e/o negativi del TAS-102 e la migliore terapia di supporto con placebo (una sostanza non attiva) e la migliore terapia di supporto per Lei e per la cura del Suo tumore del colon- retto per valutare gli effetti sulla sua soppravvivenza, sul tempo che intercorre senza progressione di malattia e per valutare la sicurezza del TAS-102

A.3.2

Name or abbreviated title of the trial where available

TPU-TAS-102-301

A.4.1

Sponsor's protocol code number

TPU-TAS-102-301

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01607957

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	TAIHO PHARMA USA, INC
B.1.3.4	Country	United States
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	Taiho Pharma USA, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	United Biosource Corporation
B.5.2	Functional name of contact point	Giancarlo Corsale
B.5.3	Address:
B.5.3.1	Street Address	Via E.Rodolfi N13
B.5.3.2	Town/ city	Orta S.Giulio (NO)
B.5.3.3	Post code	28016
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 0322 066 012
B.5.5	Fax number	+39 0322 1979 225
B.5.6	E-mail	Giancarlo.Corsale@unitedbiosource.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	No
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	TAS-102
D.3.2	Product code	NA
D.3.4	Pharmaceutical form	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.3.9.1	CAS number	70-00-8
D.3.9.2	Current sponsor code	FTD, F3TdR, F3dThd
D.3.9.3	Other descriptive name	Trifluridine, 5-Trifluorothymidine
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.3.9.1	CAS number	183204-72-0
D.3.9.2	Current sponsor code	TPI, TAS-1-462
D.3.9.3	Other descriptive name	thymidine phosphorylase inhibitor
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	7.065
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
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	TAS-102
D.3.2	Product code	NA
D.3.4	Pharmaceutical form	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.3.9.1	CAS number	70-00-8
D.3.9.2	Current sponsor code	FTD, F3TdR, F3dThd
D.3.9.3	Other descriptive name	Trifluridine, 5-Trifluorothymidine
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.3.9.1	CAS number	183204-72-0
D.3.9.2	Current sponsor code	TPI, TAS-1-462
D.3.9.3	Other descriptive name	thymidine phosphorylase inhibitor
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	9.42
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Refractory metastatic colorectal cancer

tumore del colon-retto metastatico refrattario

E.1.1.1

Medical condition in easily understood language

Colon cancer

tumore del colon

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	14.1
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 compare the following endpoints for the TAS-102 (experimental) arm with the placebo (control) arm in patients with refractory metastatic colorectal cancer: Overall survival (OS) Progression-free survival (PFS) Safety and tolerability

Mettere a confronto i seguenti endpoint per il braccio con TAS-102 (sperimentale) e il braccio con placebo (di controllo) in pazienti affetti da tumore del colon-retto metastatico refrattario: • Sopravvivenza complessiva (overall survival, OS) • Sopravvivenza senza progressione (progression-free survival, PFS) • Sicurezza e tollerabilità

E.2.2

Secondary objectives of the trial

To compare the following endpoints for the TAS-102 (experimental) arm with the placebo (control) arm in patients with refractory metastatic colorectal cancer: Progression-free survival (PFS) Safety and tolerability

Mettere a confronto i seguenti endpoint per il braccio con TAS-102 (sperimentale) e il braccio con placebo (di controllo) in pazienti affetti da tumore del colon-retto metastatico refrattario: • Sopravvivenza senza progressione (progression-free survival, PFS) • Sicurezza e tollerabilità

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

A patient must meet all of the following inclusion criteria to be eligible for enrollment in this study: -Has provided written informed consent -Has histologically or cytologically confirmed adenocarcinoma of the colon or rectum. -Has received at least 2 prior regimens of standard chemotherapies for metastatic colorectal cancer and is refractory to or failing those chemotherapies. -ECOG performance status of 0 or 1 -Is able to take medications orally -Has adequate organ function (bone marrow, kidney and liver) -Women of childbearing potential must have a negative pregnancy test and must agree to adequate birth control if conception is possible. Males must agree to adequate birth control

Il paziente per essere eleggibile deve soddisfare i seguenti criteri di inclusione: • Deve aver firmato il consenso informato • Deve essere affetto da adenocarcinoma del colon o del retto confermato istologicamente o citologicamente • Deve aver ricevuto almeno 2 regimi chemioterapici standard precedenti per il tumore del colon-retto metastatico e deve essere refrattario ovvero non rispondente a dette chemioterapie. • ECOG (Eastern Cooperative Group) pari a 0 o 1 • Deve essere in grado di assumere il farmaco per via orale • Deve avere un’ adeguata funzionalità d’ organo (midollo osseo, rene e fegato) • Le donne potenzialmente fertili devono avere un test di gravidanza negativo e devono acconsentire ad utilizzare un adeguato metodo contraccettivo in caso. Gli uomini devono acconsentire ad utilizzare un adeguato metodo contraccettivo

E.4

Principal exclusion criteria

Exclusion Criteria: 1. Certain serious illnesses or medical condition(s) 2. Has had certain other recent treatment e.g. major surgery, anticancer therapy, extended field radiation, received investigational agent, within the specified time frames prior to study drug administration. 3. Has received TAS-102. 4.Has unresolved toxicity to less than or equal to CTCAE Grade 1 attributed to any prior therapies Is a pregnant or lactating female. Other protocol-defined inclusion/exclusion criteria may apply.

• Alcune gravi malattie o condizioni patologiche • Recente trattamento ad esempio interventi chirurgici gravi, terapia antitumorale, radioterapia estesa, farmaci sperimentali entro i tempi specificati prima della sommistrazione del farmaco. • Il paziente ha ricevuto TAS • Il paziente ha una tossicità non risolta meno di 0 o 1 del grado CTCAE attribuita a qualsiasi precendente terapia • Gravidanza o allattamento Vengono applicati ulteriori criteri di inclusione/ esclusione

E.5 End points

E.5.1

Primary end point(s)

Survival is the primary endpoint of this study and is defined as the time (in months) from the date of randomization to the death date. In the absence of death confirmation or for patients alive as of the OS cut-off date, survival time will be censored at the date of last study follow-up, or the cut-off date, whichever is earlier.

L’endpoint primario dello studio è la sopravvivenza ed è definito come il tempo (in mesi) dalla data della randomizzazione a quella del decesso. In assenza di mancaza di conferma del decesso o nel caso di pazienti in vita alla data di cut-off dell’OS, il tempo di sopravvivenza sarà determinato alla data dell’ ultimo follow up nello studio, o la data di cut-off , a secondo cosa avviene prima

E.5.1.1

Timepoint(s) of evaluation of this end point

Every 8 weeks. Survival status should be collected for up to 12 months after the last patient is randomized or until the target number of events (deaths) is met, whichever is later

Ogni 8 settimane. La sopravvivenza deve essere valutata fino a 12 mesi dopo l'ultimo paziente randomizzato o fino al raggiungimento del numero target di eventi (decessi), a secondo cosa avviene prima

E.5.2

Secondary end point(s)

•To compare the Progression-Free-Survival (PFS) for TAS-102 (experimental arm) with placebo (control arm) in patients with refractory metastatic colorectal cancer. •To assess the safety and tolerability for TAS-102 (experimental arm) in patients with refractory metastatic colorectal cancer.

• Mettere a confronto la Sopravvivenza senza progressione (progression-free survival, PFS) del TAS-102 (braccio sperimentale) e il braccio con placebo (braccio di controllo) in pazienti affetti da tumore del colon-retto metastatico refrattario • Valutare la Sicurezza e tollerabilità del TAS-102 (braccio sperimentale) in pazienti affetti da tumore del colon-retto metastatico refrattario

E.5.2.1

Timepoint(s) of evaluation of this end point

Every 8 weeks. Tumor assessments will be performed until the patients develops radiologic progression or until the start of new anticancer treatment, for up to 12 months after the last patient is randomized or until the target number of events (deaths) is met, whichever is later. Safety and tolerability will be assessed until 30 days following last administration of study medication or until initiation of new anticancer treatment.

Ogni 8 settimane. Le valutazioni oncologiche saranno effettuate fino a quando il paziente mostra progressione radiologica o fino all’inizio di una nuova terapia antitumorale, fino a 12 mesi dopo l’ultimo paziente randomizzato o fino al raggiungimento del numero target di eventi (decessi) a seconda di quale si verifichi prima. La Sicurezza e tollerabilità saranno valutati fino a 30 giorni dopo l’ ultima sommistrazione del farmaco sperimentale o fino all’inizio di una nuova terapia antitumorale,

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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

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

Japan

United States

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 first dose of study medication for the last patient randomized or until the target number of events (deaths) is met, whichever is later.

12 mesi dopo la prima dose di farmaco dello studio dell’ultimo paziente randomizzato o fino al raggiungimento del numero target di eventi (decessi), a secondo cosa avviene prima.

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

Number of subjects for this age range:

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:

440

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

360

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.4.2

For a multinational trial

F.4.2.1

In the EEA

420

F.4.2.2

In the whole clinical trial

800

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)

There are no plan to provide medication after the trial has ended. However, if study treatment discontinuation criteria have been met but there is strong evidence of clinical benefit to justify continuation of dosing with study medication on protocol, this decision should be reviewed with the Sponsor's Medical Monito

Non si prevede il rifornimento del farmaco dopo il termine dello studio. Tuttavia, se si verifica un criterio di interruzione ma vi è una forte evidenza di un benefico clinico che giustifichi la continuazione del trattamento con il farmaco in studio, questa decisione potrebbe essere riesaminata con il Medical Monitor dello Sponsor.

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

2012-08-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-07-13

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

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