Clinical Trials Register

Summary
EudraCT Number:	2012-003008-11
Sponsor's Protocol Code Number:	GO28141
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:	2012-12-11
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

2012-003008-11

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

STUDIO DI FASE III, IN DOPPIO CIECO, CONTROLLATO CON PLACEBO SU VEMURAFENIB RISPETTO A VEMURAFENIB PIU' GDC-0973 IN PAZIENTI AFFETTI DA MELANOMA LOCALMENTE AVANZATO O METASTATICO, NON RESECABILE, POSITIVI ALLA MUTAZIONE BRAFV600 E PRECEDENTEMENTE NON TRATTATI

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 con vemurafenib rispetto a vemurafenib da solo in pazienti affetti da melanoma non resecabile allo stadio IIIC o melanoma metastatico positivi alla mutazione 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. HOFFMANN - 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	Roche SpA
B.5.2	Functional name of contact point	Country Head Clin Ops Italy
B.5.3	Address:
B.5.3.1	Street Address	Vial G.B. Stucchi 110
B.5.3.2	Town/ city	Monza
B.5.3.3	Post code	20900
B.5.3.4	Country	Italy
B.5.4	Telephone number	039 2475070
B.5.5	Fax number	039 2475085
B.5.6	E-mail	sergio.scaccabarozzi@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 Film-coated Tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Products Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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.3.4	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/F17
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

PAZIENTI AFFETTI DA MELANOMA LOCALMENTE AVANZATO O METASTATICO, NON RESECABILE, POSITIVI ALLA MUTAZIONE BRAFV600

E.1.1.1

Medical condition in easily understood language

skin cancer

tumore della pelle

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.

Valutare l’efficacia di vemurafenib in combinazione con GDC-0973, rispetto a vemurafenib e placebo, in pazienti affetti da melanoma localmente avanzato o metastatico, non resecabile, positivi alla mutazione BRAFV600 e precedentemente non trattati, tramite misurazione del prolungamento della sopravvivenza senza progressione (Progression-Free Survival, PFS), come valutata dallo sperimentatore del centro dello studio.

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).

Valutare l’efficacia di vemurafenib in combinazione con GDC-0973, rispetto a vemurafenib e placebo, in pazienti affetti da melanoma localmente avanzato o metastatico, non resecabile, positivi alla mutazione BRAFV600 e precedentemente non trattati, tramite misurazione della sopravvivenza complessiva (Overall Survival, OS), del tasso di risposta obiettiva (Objective Response Rate, ORR) e della durata della risposta (Duration Of Response, DOR).

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

- età ≥18 anni
- Pazienti con melanoma di stadio IIIc non resecabile o di stadio IV metastatico, con positività alla mutazione BRAFV600
- positività alla mutazione BRAFV600
confermata usando il test cobas 4800
-Malattia misurabile in base ai criteri RECIST v1.1.
-Test di gravidanza sul siero negativo nei 10 giorni che precedono l’inizio della somministrazione nelle donne potenzialmente fertili.
-Stato prestazionale dell’Eastern Cooperative Oncology Group di 0 o 1
-Adeguata funzione ematologica e d’organo terminale

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 antihypertensive
therapy)
•History, risk factors for or evidence of neurosensory retinal detachment, retinal vein occlusion or neovascular macular degeneration.

-Anamnesi di precedente trattamento inibitorio della via metabolica di RAF o MEK.
-precendente trattamento antitumorale sistemico per tumori avanzati o metastatici;le terapie adiuvanti sono consentite;
-Neoplasia attiva diversa dal melanoma. I pazienti con una precedente neoplasia riscontrata negli ultimi 3 anni sono da escludere, tranne quelli con carcinoma cutaneo basocellulare (Basal Cell Carcinoma, BCC) o carcinoma cutaneo squamocellulare (Squamous Cell Carcinoma, SCC) resecati, melanoma in situ, carcinoma in situ della cervice e carcinoma in situ mammario.
-pazienti con lesioni al SNC attive (compresa la meningite carcinomatosa). Tuttavia, i pazienti sono idonei se:
a) Tutte le lesioni al SNC note sono state trattate con terapia stereotassica o intervento chirurgico, E
b) Non vi è stata alcuna evidenza di progressione clinica e radiografica della malattia nel SNC per ≥ 3 settimane dopo la radioterapia o l’intervento chirurgico. La radioterapia encefalica integrale non è consentita, con l’eccezione di pazienti che hanno avuto una resezione definitiva o una terapia stereotassica di tutte le lesioni del parenchima encefalico radiologicamente rilevabili.
-Evidenza di rischio cardiovascolare (LVEF < LLN; QTc ≥ 450 msec; pressione arteriosa ≥140/90 mmHg non controllata con antipertensivi)
-Anamnesi o evidenza di patologia retinica dall’esame oftalmologico, ritenuta essere fattore di rischio per il distacco della retina neurosensoriale, occlusione venosa retinica (Retinal Vein Occlusion, RVO) o degenerazione maculare neurovascolare

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

approx. 16 months

circa 16 mesi

E.5.2

Secondary end point(s)

1. Overall Survival
2. Overall Response Rate
3. Duration of Response

1. sopravvivenza complessiva
2. tasso di risposta obiettiva
3. durata della risposta

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. circa 36 mesi
2.intervallo di tempo approssimativo di 16 mesi
3.durata della risposta

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 QOL,biomarker profiling

tollerabilità, analisi esposizione-risposta, qualità della vita, analisi dei biomarcatori

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

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

Brazil

Canada

Israel

New Zealand

Switzerland

Turkey

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.

Lo studio terminerà quando tutti i pazienti arruolati saranno stati seguiti fino al decesso o al ritiro del consenso o persi al follow-up o finché lo Sponsor non deciderà di chiudere la sperimentazione, a seconda di quale evento 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:

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 will be followed for subsequent therapy and survival once completed study therapy.Dermatology examinations and CT chest evaluations for surveillance of second primary malignancies will be scheduled. Patients, investigators and sponsors will remain blinded.Patients may receive any second line therapy for melanoma.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

I pazienti saranno seguiti per ulteriori terapie e sopravvivenza; verranno programmati controlli dermatologici e TC addominale per controllare l'insorgenza di ulteriori malignità primarie;pazienti, sperimentatore e sponsor rimarrano in cieco;i pazienti potranno ricevere un'altra terapia di seconda linea;I pazienti arruolati nel braccio di trattamento Vemurafenib/placebo non potranno passare al braccio di trattamento vemurafenib/GDC-0973 in caso di progressione della malattia.

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

2012-12-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-11-23

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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