Clinical Trials Register

Summary
EudraCT Number:	2011-000954-46
Sponsor's Protocol Code Number:	MO25743
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:	2012-03-07
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

2011-000954-46

A.3

Full title of the trial

An open-label, single-arm, phase II, multicenter study to evaluate the efficacy of vemurafenib in metastatic melanoma patients with brain metastases

Studio di fase II, in aperto, a braccio singolo, multicentrico, volto a valutare l'efficacia di vemurafenib in pazienti affetti da melanoma metastatico con metastasi cerebrali.

A.3.1

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

This open-label study will assess the efficacy and safety of vemurafenib (RO5185426) in metastatic melanoma patients with untreated or treated brain metastases. Patients will receive vemurafenib (RO5185426) at a dose of 960 mg twice daily orally until disease progression or unacceptable toxicity occurs.

Questo studio in aperto valutera' l'efficacia e la sicurezza di vemurafenib(RO5185426)in pazienti affetti da melanoma metastatico con metastasi cerebrali trattate e non trattate. I pazienti riceveranno vemurafenib(RO5185426)alla dose orale di 960 mg due volte al giorno, fino al verificarsi di progressione di malattia o tossicita' inaccettabile.

A.4.1

Sponsor's protocol code number

MO25743

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	ROCHE
B.1.3.4	Country	Italy
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	F.Hoffmann-La Roche Ltd.
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	F.Hoffmann-La Roche Ltd.
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	CH-4070
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	.
B.5.5	Fax number	.
B.5.6	E-mail	global.rochegenentechtrials@roche.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	vemurafenib
D.3.2	Product code	RO5185426/BS1111010
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	Vemurafenib
D.3.9.1	CAS number	918504-65-1
D.3.9.2	Current sponsor code	RO5185426/BS1111010
D.3.9.3	Other descriptive name	RG7204, PLX4032
D.3.9.4	EV Substance Code	NA
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	240
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Metastatic Melanoma with Brain Metastases

Melanoma metastatico con metastasi cerebrali

E.1.1.1

Medical condition in easily understood language

Metastatic Melanoma with Brain Metastases

Melanoma metastatico con metastasi cerebrali

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	LLT
E.1.2	Classification code	10027481
E.1.2	Term	Metastatic melanoma
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 efficacy of vemurafenib using Best Overall Response Rate (BORR), as assessed by an Independent Review Committee (IRC) using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST, v1.1) in the brain of metastatic melanoma patients with previously untreated brain metastases

Valutare l'efficacia di vemurafenib utilizzando il parametro BORR (Best Overall Response Rate, Miglior tasso di risposta complessiva), valutato da un Comitato Indipendente di revisione dei dati (IRC) utilizzando i criteri RECIST (Response Evaluation Criteria in Solid Tumors, Criteri di valutazione della risposta nelle neoplasie solide), versione 1.1 (RECIST, v 1.1) a livello cerebrale, in pazienti affetti da melanoma metastatico con metastasi cerebrali non pretrattate.

E.2.2

Secondary objectives of the trial

•To evaluate the efficacy of vemurafenib using BORR in the brain of pts with previously treated or untreated brain metastases assessed by an IRC using RECIST v1.1 criteria;•To evaluate the efficacy of vemurafenib using BORR in the brain of pts with previously-treated brain metastases as assessed by an IRC using RECIST v1.1 criteria;•To evaluate the safety and tolerability of vemurafenib in pts with melanoma metastatic to the brain, as assessed by the NCI CTCAE, v4.0;•To evaluate BORR outside of the brain as assessed by an IRC, duration of response(DOR)in and outside of the brain,progression-free survival(PFS),time to development of new brain metastases in responding pts,and overall survival(OS)in pts with melanoma metastatic to the brain;•To evaluate the efficacy of vemurafenib using BORR in brain and outside of the brain.

•Valutare l'efficacia di vemurafenib con il BORR a livello cerebrale in paz.con metast.cerebrali pretrattate o non pretrattate,secondo la valutazione di IRC sulla base criteri RECIST v 1.1.•Valutare l'efficacia di vemurafenib con il BORR a livello cerebrale di paz.con metast.cerebrali pretrattate,secondo la valutazione di IRC sulla base criteri RECIST v 1.1.•Valutare sicurezza e tollerabilità di vemurafenib in paz.affetti da melanoma con metast.cerebrali,in base ai criteri NCI CTCAE,v 4.0.•Valutare il BORR a livello extracerebrale in base al parere di un IRC,la durata della risposta(DOR)a livello cerebrale ed extracerebr.,la sopravvivenza libera da progressione(PFS),il tempo allo sviluppo di nuove metast.cerebrali in paz. responsivi e la sopravvivenza complessiva(OS)in paz.affetti da melanoma con metast. cerebr.•Valutare l'efficacia vemurafenib con BORR a livello cerebrale ed extracereb

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Adult patients, ≥ 18 years of age •Metastatic melanoma (Stage IV, American Joint Committee on Cancer) with BRAF V600 mutation (cobas 4800 BRAF V600 Mutation Test) •Measurable brain metastases, treated or untreated •Patients may or may not have received prior systemic therapy for metastatic melanoma and either a) have received no prior treatment for brain metastases or b) have received prior treatment for brain metastases and have progressed •Patients may or may not have symptoms related to their brain metastases •Eastern Cooperative Oncology Group (ECOG) performance status 0-1 •Patients must have recovered from all side effects of their most recent systemic or local treatment for metastatic melanoma.

•Pazienti di ambo i sessi di età ≥ 18 anni;•Pazienti affetti da melanoma metastatico istologicamente confermato(stadio IV secondo l'American Joint Committee on Cancer)con mutazione BRAF V600 documentata,(cobas 4800 BRAF V600 Mutation Test);•Metastasi cerebrali misurabili trattate e non trattate;•I pazienti possono aver ricevuto o meno una precedente terapia sistemica per il melanoma metastatico (non è consentito l'uso precedente di inibitori di BRAF o MEK) e a)nessuna precedente terapia SRT, WBRT o chirurgia per metastasi cerebrali oppure b)precedente terapia SRT, WBRT o chirurgia per metastasi cerebrali con successiva progressione.•I pazienti possono presentare o meno sintomi correlati alle metastasi cerebrali.•Performance status ECOG pari a 0 o 1.•I pazienti devono essersi ripresi da tutti gli effetti indesiderati del più recente trattamento sistemico o locale per il melanoma metastatico.

E.4

Principal exclusion criteria

•Increasing corticosteroid dose during the 7 days prior to first dose of study drug •Leptominingeal involvement •Previous malignancy requiring active treatment within the past 2 years, except for treated and controlled basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix •Concurrent administration of any anticancer therapies other than those administered in the study •Treatment with any cytotoxic, investigational drug or targeted therapy ≤ 4 weeks prior to first dose of study drug. Radiation therapy ≤ 2 weeks prior to first dose of study drug •Prior treatment with BRAF or MEK inhibitors •Clinically significant cardiovascular disease or event within the 6 months prior to first dose of study drug •History or presence of clinically significant cardiac dysrhythmia •Corrected QT interval ≥ 450 ms or history of congenital long QT syndrome

•Dosi incrementali di corticosteroidi nei 7 giorni precedenti la prima somministrazione di vemurafenib;•Coinvolgimento leptomeningeo;•Sono da escludere i pazienti che hanno sviluppato nei 2 anni precedenti una neoplasia maligna che abbia richiesto un trattamento attivo, eccetto i pazienti con carcinoma a cellule basali o squamose della cute trattato e controllato o con carcinoma cervicale in situ.•Somministrazione concomitante di qualsiasi terapia antineoplastica (es. chemioterapia, altra terapia mirata, farmaco sperimentale, ecc.) diversa da quella somministrata in questo studio;•Trattamento con qualsiasi farmaco citotossico e/o sperimentale o terapia mirata ≤ 4 settimane prima della prima somministrazione di vemurafenib e terapia radiante ≤ 2 settimane prima della prima somministrazione di vemurafenib;•Precedente terapia con inibitori di BRAF o MEK.•Una qualsiasi delle seguenti circostanze nei 6 mesi precedenti la prima somministrazione di vemurafenib: infarto del miocardio, angina grave/instabile, insufficienza cardiaca congestizia sintomatica, ictus cerebrale o attacco ischemico transitorio, embolia polmonare o ipertensione non adeguatamente controllata dalle terapie farmacologiche in atto;•Anamnesi o presenza di disritmie ventricolari o atriali clinicamente significative di grado ≥ 2;•Intervallo QT corretto (QTc) ≥ 450 ms al basale o anamnesi di sindrome congenita del QT lungo.

E.5 End points

E.5.1

Primary end point(s)

Best Overall Response Rate (BORR) in previously untreated brain metastases (assessed by Independent Review Committee using RECIST).

BORR (Best Overall Response Rate)in metastasi cerebrali non pretrattate (valutate da un Comitato indipendente di Revisione utilizzando i criteri RECIST).

E.5.1.1

Timepoint(s) of evaluation of this end point

June 2012

Giugno 2012

E.5.2

Secondary end point(s)

•BORR in previously treated or untreated brain metastases (assessed by Independent Review Committee); •BORR in previously treated brain metastases (assessed by Independent Review Committee); •BORR outside of the brain (assessed by Independent Review Committee); •BORR in brain metastases and outside of the brain (assessed by Investigator) •Duration Of Response, Progression Free Survival, time to development of new brain metastases, Overall Survival; •Safety (assessed by NCI CTCAE)

•BORR in metastasi cerebrali pretrattate o non pretrattate (valutate da un Comitato indipendente di Revisione); •BORR in metastasi cerebrali pretrattate (valutate da un Comitato indipendente di Revisione); •BORR a livello extracerebrale(valutate da un Comitato indipendente di Revisione); •BORR a livello cerebrale ed extracerebrale (valutate dallo sperimentatore); •Durata della risposta, Sopravvivenza libera da progressione, Tempo allo sviluppo di nuove metastasi cerebrali, Sopravvivenza globale; •Sicurezza(valutata in base ai criteri NCI CTCAE;

E.5.2.1

Timepoint(s) of evaluation of this end point

June 2014

Giugno 2014

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

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

QUALITY OF LIFE AND PHYSICAL SYMPTOMS

Qualità di vita e sintomi fisici

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

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

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

Canada

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

The end of study will occur when all patients have been followed up for survival for a maximum period of 24 months, have died, withdraw consent or are lost to follow up, whichever occurs first

Lo studio terminerà quanto tutti i paz.saranno stati sottoposti al follow-up della sopravvivenza per un periodo massimo di 24 mesi,saranno deceduti,avranno revocato il consenso,o saranno persi al follow-up,a seconda di quale ipote si verifichi 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:

106

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.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

132

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)

Patients who discontinue vemurafenib for any reason (i.e., disease progression, an AE, etc.) other than withdrawal of consent will continue to be followed for survival and new anti cancer therapy every 3 months after last dose until death or for a maximum of 24 months, withdrawal of consent, or lost to follow-up.

I pazienti che interromperanno l'assunzione di vemurafenib per una qualsiasi ragione (progressione della malattia, AE, ecc.) diversa dalla revoca del consenso continueranno a essere seguiti per la rilevazione dei dati sulla sopravvivenza e su eventuali nuove terapie antitumorali ogni 3 mesi dopo l'ultima dose o fino al decesso o per un massimo di 24 mesi, oppure fino alla revoca del consenso o alla perdita al follow-up.

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

2011-06-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-06-22

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-07-21

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