Clinical Trials Register

Summary
EudraCT Number:	2012-003008-11
Sponsor's Protocol Code Number:	GO28141
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-10-29
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

Spain - AEMPS

A.2

EudraCT number

2012-003008-11

A.3

Full title of the trial

A PHASE III, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF VEMURAFENIB VERSUS VEMURAFENIB PLUS GDC-0973 IN PREVIOUSLY UNTREATED
BRAFV600-MUTATION POSITIVE PATIENTS WITH UNRESECTABLE LOCALLY ADVANCED OR METASTATIC MELANOMA

ESTUDIO DE FASE III, DOBLE CIEGO, CONTROLADO POR PLACEBO DE VEMURAFENIB FRENTE A VEMURAFENIB MÁS GDC-0973 EN PACIENTES CON MELANOMA METASTÁSICO O LOCALMENTE AVANZADO IRRESECABLE, CON RESULTADO POSITIVO PARA LA MUTACIÓN BRAFV600, NO TRATADOS PREVIAMENTE

A.3.1

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

GDC-0973 plus vemurafenib versus vemurafenib alone in patients with unresectable stage IIIC or metastatic melanoma harboring BRAF V600 mutations.

GDC-0973 más vemurafenib versus vemurafenib solo en pacientes con melanoma metástasico o estadio IIIC irresecable positivo para la mutación BRAFV600

A.4.1

Sponsor's protocol code number

GO28141

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	F. Hoffman-La Roche Ltd.
B.1.3.4	Country	Switzerland
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.5.6	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	Yes
D.2.1.1.1	Trade name	Zelboraf 240 mg comprimidos recubiertos con película
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Products 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.3.2	Product code	RO5185426/F17
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	RO5185426-006
D.3.9.3	Other descriptive name	RG7204, PLX4032, Zelboraf
D.3.9.4	EV Substance Code	SUB32161
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.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	GDC-0973
D.3.2	Product code	RO5514041/F04
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	GDC-0973
D.3.9.1	CAS number	934660-93-2
D.3.9.2	Current sponsor code	RO5514041
D.3.9.3	Other descriptive name	GDC-0973/XL518
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	60
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	Film-coated 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

BRAFV600-mutation positive patients with unresectable locally
advanced or metastatic melanoma

Pacientes con melanoma localmente avanzado irresecable o metastásico portadores de la mutación BRAF V600

E.1.1.1

Medical condition in easily understood language

skin cancer

cáncer de piel

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	10025650
E.1.2	Term	Malignant melanoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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	10027480
E.1.2	Term	Metastatic malignant 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 in combination with GDC-0973, compared with vemurafenib and placebo, in previously untreated BRAFV600 mutation-positive patients with unresectable locally advanced or metastatic melanoma, as measured by prolongation of
progression-free survival (PFS), as assessed by the study site investigator.

Evaluar la eficacia del vemurafenib en combinación con GDC-0973, en comparación con vemurafenib y placebo, en pacientes con melanoma localmente avanzado irresecable o metastásico con la mutación BRAFV600 sin tratamiento previo, determinada mediante la prolongación de la supervivencia sin progresión (SSP), según lo evaluado por el investigador del centro del estudio.

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of vemurafenib in combination with GDC-0973, compared with vemurafenib and placebo, in previously untreated BRAFV600 mutation-positive patients with unresectable locally advanced or metastatic melanoma, as measured by overall survival (OS),
objective response rate (ORR), and duration of response (DOR).

Evaluar la eficacia de vemurafenib en combinación con GDC-0973, en comparación con vemurafenib y placebo, en pacientes con melanoma localmente avanzado irresecable o metastásico con la mutación BRAFV600 sin tratamiento previo, determinada mediante la supervivencia global (SG), la tasa de respuesta objetiva (TRO) y la duración de la respuesta (DR).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

?? 18 years of age
?Stage IIIc or Stage IV melanoma harboring BRAF V600 mutation
?BRAF V600 mutation must be confirmed by cobas 4800 BRAF V600 mutation test
?Measurable disease according to RECIST 1.1
?Women of childbearing potential with negative serum pregnancy test prior to randomization
?Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
?Adequate baseline organ function

Mayores de 18 años.
Melanoma estadio IIIc o estadio IV con mutación BRAF V600
La mutación BRAF V600 dbe ser confirmada por el ensayo de mutación cobas 4800 BRAF V600
Enfermedad medible de acuerdo al RECIST 1.1
Las mujeres en edad fértil con prueba de embarazo en suero negativa previos a la aletorización.
Grado de actividad según ECOG (Eastern Clinical Oncology Group) de 0 o 1
Adecuado nivel basal de las gunciones orgánicas

E.4

Principal exclusion criteria

?Any prior use of a BRAF or MEK inhibitor
?Prior systemic anti-cancer treatment in the advanced or metastatic setting; prior systemic treatment in the adjuvant setting is allowed
?History of another malignancy except subjects who have been disease free for 3 years or have completely resected non-melanoma skin cancer.
?Patients with active CNS lesions (including carcinomatous meningitis) are excluded. However, patients are eligible if:
a)all known CNS lesions have been treated with stereotactic therapy or surgery, AND
b)no evidence of clinical and radiographic disease progression in the CNS for ? 3 weeks after radiotherapy or surgery.
Whole brain radiotherapy is not allowed with the exception of patients who have had definitive resection or stereotactic therapy of all radiologically detectable parenchymal brain lesions.

?Evidence of cardiovascular risk (LVEF < LLN; QTc ? 450 msec; blood pressure ?140/90 mmHg which cannot be controlled by anti-hypertensive therapy)
?History, risk factors for or evidence of neurosensory retinal detachment, retinal vein occlusion or neovascular macular degeneration.

Tratamiento previo con inhibidores de la vía de BRAF o MEK.
Tratamiento previo con anticancerosos sistémicos en el establecimiento metastásico o avanzado; tratamiento previo sistémico en el establecimiento de la adyuvancia esta permitido
Pacientes con una neoplasia maligna distinta al melanoma excepto lo que han estado libres de enfermedad en los 3 años precedentes, o han sido completamente resecados de cáncer de piel distinto a melanoma.
Pacientes con lesiones activas del SNC (incluyendo meningitis carcinomatosa) son excluidos. No obstante, podrán participar en caso de que:
a) Todas las lesiones del SNC conocidas hayan sido tratadas con tratamiento estereotáctico o cirugía Y
b) No existan indicios de progresión clínica y radiológica de la enfermedad en el SNC durante ? 3 semanas después de la radioterapia o cirugía.
No se permitirá la radioterapia cerebral total, con la excepción de los pacientes que se hayan sometido a una resección definitiva o tratamiento estereotáctico de todas las lesiones cerebrales parenquimatosas radiológicamente detectables.
Evidencia de riesgo cardiovascular (FEVI < LIN; QTc ? 450 msec; blood pressure ?140/90 mmHg que no pueda ser controlada con anti-hipertensivos)
Antecedentes o constancia de patología retiniana en la exploración oftalmológica que se considere un factor de riesgo de desprendimiento de retina neurosensorial, oclusión de venas retinianas (OVR) o degeneración macular neovascular.

E.5 End points

E.5.1

Primary end point(s)

Supervivencia libre de progresión

E.5.1.1

Timepoint(s) of evaluation of this end point

approx. 16 months

aproximadamente 16 meses

E.5.2

Secondary end point(s)

1. Overall Survival

2. Overall Response Rate

3. Duration of Response

1. Supervivencia global

2. Tasa de respuesta global

3. Duración de respuesta

E.5.2.1

Timepoint(s) of evaluation of this end point

1. approx. 36 months

2. Time Frame: approx. 16 months

3. Duration of Response

1. aproximadamente 36 meses

2. Primer análisis provisional: aproximadamente 16 meses

3. Duración de respuesta

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

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

Yes

E.6.13.1

Other scope of the trial description

tolerability, exploratory exposure-response analysis, health-related quality of life, biomarker profiling

tolerabilidad, análisis respuesta a la exposición exploratoria, marcadores de calidad de vida relacionados con la salud, perfil de biomarcadores

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Vemurafenib

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

102

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

Argentina

Australia

Austria

Belgium

Brazil

Canada

Croatia

Czech Republic

Denmark

Finland

France

Germany

Hungary

Israel

Italy

Netherlands

New Zealand

Norway

Spain

Sweden

Switzerland

Turkey

United Kingdom

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 study will end when all patients enrolled have been followed until death, withdrawal of consent, lost to follow-up, or the Sponsor decides to end the trial, whichever occurs first.

El estudio finalizará cuando todos los pacientes reclutados hayan seguidos hasta muerte, retirada del consentimiento, perdida del seguimiento, o por decisión del Promotro de finalizar el ensayo, lo que ocurra primero.

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:

380

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

120

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

264

F.4.2.2

In the whole clinical trial

500

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 on the vemurafenib and placebo treatment arm will not be eligible to cross over to the vemurafenib and GDC-0973 treatment arm at disease progression and will be followed for survival.

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

2013-01-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-07-21

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