Clinical Trials Register

Summary
EudraCT Number:	2014-001956-52
Sponsor's Protocol Code Number:	001
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-06-13
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

2014-001956-52

A.3

Full title of the trial

Activity and safety of third line tyrosin kinase inhibitor (TKI) after 2 tyrosin kinase inhibitors(TKIs) in patients with metastatic renal cell carcinoma (mRCC) (Tokio Study)

Attività e sicurezza della terza linea con inibitore delle tirosin chinasi dopo 2 precedenti inibitori delle tirosin chinasi nei pazienti con carcinoma renale metastatico.(Trial Tokio)

A.3.1

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

Clinical trial to evaluate activity and safety of third line of treatment after two previous therapies in patients with renal cell carcinoma

studio per valutare l’attività e la sicurezza della somministrazione della terza linea di trattamento dopo due precedenti terapie in pazienti affetti da carcinoma del rene metastatico

A.3.2

Name or abbreviated title of the trial where available

Tokio

A.4.1

Sponsor's protocol code number

001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Fondazione IRCCS Istituto Nazionale dei Tumori
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	none
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	Trial center
B.5.2	Functional name of contact point	Trial center
B.5.3	Address:
B.5.3.1	Street Address	Via Venezian 1
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.6	E-mail	trialcenter@istitutotumori.mi.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	Nexavar
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Spa
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Sorafenib
D.3.2	Product code	L01XE05
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.3.8	INN - Proposed INN	SORAFENIB
D.3.9.1	CAS number	284461-73-0
D.3.9.4	EV Substance Code	SUB23139
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	200
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)	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.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	Sutent
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer
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	sunitinib
D.3.2	Product code	Sutent
D.3.4	Pharmaceutical form	Capsule
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	SUNITINIB
D.3.9.1	CAS number	557795-19-4
D.3.9.4	EV Substance Code	SUB22321
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	50
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)	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

Metastatic renal cells carcinoma

Carcinoma renale metastatico

E.1.1.1

Medical condition in easily understood language

Metastatic renal cells carcinoma

Tumore del rene metastatico

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	11.0
E.1.2	Level	HLT
E.1.2	Classification code	10038408
E.1.2	Term	Renal cell carcinomas
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

To evaluate the efficacy of a third TKI after two previous lines of therapy with TKIs, in terms of mPFS

Valutare l’attivita’ in termini di sopravvivenza libera da progressione di un inibitore delle tirosin chinasi utilizzato come terza linea in pazienti precedentemente trattati con 2 inibitori delle tirosin chinasi per il carcinoma renale metastatico

E.2.2

Secondary objectives of the trial

• To evaluate the safety of a third line with TKI
• To evaluate the Overall Survival
• To evaluate the Quality of Life through specific questionnaires (FKSI-19; EORTC QLQ-C30).

• Valutare la sicurezza di un inibitore delle tirosin chinasi
• La sopravvivenza complessiva;
• La valutazione della qualità di vita attraverso specifici questionari (FKSI-19; EORTC QLQ-C30).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age ≥ 18 years
• Patients with hystological diagnosis of Renal Cell Carcinoma (RCC)
• Measurable disease
• Previous treatment with two sequences of TKIs including sunitinib followed by axitinib and pazopanib followed by sorafenib.
• ECOG Performance Status of 0 or 1
• All prognostic group according to Heng criteria
• Life expectancy of at least 12 weeks.
• Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening:
- Hemoglobin  10.0 g/dl
- Absolute neutrophil count (ANC) >1,500/mm3
- Platelet count  100,000/ml
- Total bilirubin ≤ 1.5 times the upper limit of normal
- ALT and AST ≤ 2.5 x upper limit of normal
- Alkaline phosphatase ≤ 4 x ULN
- PT-INR/PTT ≤ 1.5 x upper limit of normal [Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists.] For patients on warfarin, close monitoring of at least weekly evaluations will be performed, until INR is stable based on a measurement at pre-dose, as defined by the local standard of care.
• Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and two weeks after the completion of trial.
• Signed informed consent must be obtained prior to any study specific procedures

• Età ≥ 18 anni
• Pazienti con diagnosi istologica di carcinoma renale (RCC) Malattia metastatica misurabile
• ECOG Performance Status di 0 o 1
• Aspettativa di vita di almeno 12 settimane.
• Adeguata funzionalità midollare epatica e renale come dimostrato dai parametri ematici eseguiti alla visita di screening e che devono essere:
- Emoglobina  10.0 g/dl
- Conta dei neutrofili (ANC) >1,500/mm3
- Conta Piastrinica  100,000/ml
- Bilirubina totale ≤ 1.5 x il limite superiore di normalità
- ALT e AST ≤ 2.5 x il limite superiore di normalità
- Fosfatasi alcalina ≤ 4 x il limite superiore di normalità
- PT-INR/PTT ≤ 1.5 x il limite superiore di normalità [pazienti in corso di terapia eparinica o con coumadin possono partecipare allo studio se questi parametri non erano alterati prima dell’inizio della terapia anticoagulante]. Per i pazienti in trattamento con warfarin un monitoraggio settimane dell’INR è raccomandato fino a stabilizzazione dei valori.
• Categoria prognostica secondo Motzer/Heng: buona, intermedia o cattiva
• Precedente trattamento con sunitinib seguito da axitinib o pazopanib seguito da sorafenib
• Le donne in età fertile devono avere un test di gravidanza negativo nei 7 giorni precedenti l’inizio della terapia. Sia uomini che donne in età fertile arruolati nel seguente studio devono adottare adeguati sistemi di protezione durante il corso del trattamento e per le due settimane successive all’interruzione.
• Il consenso informato scritto deve essere ottenuto prima di ogni procedura relativa allo studio.

E.4

Principal exclusion criteria

• Previous treatment for metastatic RCC other than pazopanib followed by sorafenib or sunitinib followed by axitinib
• History of cardiac disease: congestive heart failure >NYHA class 2; active CAD (MI more than 6 mo prior to study entry is allowed); cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled hypertension (>= 160 mmHg systolic and/or 90 mmHg diastolic).
• History of HIV infection
• Active clinically serious infections (> grade 2 NCI-CTC version 3.0)
• Patients with seizure disorder requiring medication (such as steroids or anti-epileptics)
• History of organ allograft
• Patients with evidence or history of bleeding diasthesis
• Patients undergoing renal dialisis
• History of other disease, metabolic dysfunction, physical examination findings or clinical laboratory findings giving reasonable suspicion of a disease condition that contraindicates use of an investigational drug or patient at high risk from treatment complications
• Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively treated > 2 years prior to study entry.

• Precedenti trattamenti diversi da pazopanib seguito da sorafenib o sunitinib seguito da axitinib .
• Storia di patologie cardiache: insufficienza cardiaca congestizia classe NYHA > 2; Coronaropatia in fase attiva (IMA nei sei mesi precedente la terapia); aritmia richiedente specifica terapia (beta beta bloccanti o digossina sono permessi) o ipertensione incontrollata (sistolica ≥ 160 mmHg e/o diastolica ≥ 90 mmHg).
• Infezione da HIV
• Infezioni in fase attiva (> grado 2 NCI-CTC versione 3.0)
• Paziente con storia di crisi epilettiche che richiedono terapie specifiche (come steroidi e/o antiepilettici)
• Storia di trapianto d’organo
• Pazienti con evidenza di emorragie o diastasi
• Pazienti in corso di dialisi
• Storia di malattie come disfunzioni metaboliche, anomalie all’esame fisico o laboratoristiche che possano far sospettare per la presenza di condizioni di malattia sottostante che possano controindicare l’uso del farmaco oggetto di studio o che possano mettere il paziente a rischio di tossicità.
• Precedente o concomitante diagnosi di cancro distinto per il sito primario o per la forma istologica con l’eccezione del carcinoma cervicale in situ, il carcinoma basocellulare della cute, il tumore superficiale della vescica [Ta, Tis & T1] o ogni tumore trattato in maniera curativa in un periodo di tempo superiore a 3 anni precedenti lo studio.

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

every 8 weeks (+/- 7 days) for the first six months and then every 12 weeks (+/- 7 days) until PD.

ogni 8 settimane per i primi sei mesi e poi ogni 12 settimane fino a progressione

E.5.2

Secondary end point(s)

• To evaluate the safety of a third line with TKI
• To evaluate the Overall Survival
• To evaluate the Quality of Life through specific questionnaires (FKSI-19; EORTC QLQ-C30).

Sicurezza della terza linea con TKI
Sopravvivenza globale
Qualità della vita tramite questionari

E.5.2.1

Timepoint(s) of evaluation of this end point

safety and QoL: every month
OS: until death of patient

Sicurezza e qdv: ogni mese
Sopravvivenza: fino a decesso

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

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

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:

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.4.2.2

In the whole clinical trial

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)

treatment will be done according to clinical practice

trattamenti successivi secondo pratica clinica

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

2014-08-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-22

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2017-11-08

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