Clinical Trials Register

Summary
EudraCT Number:	2009-012293-12
Sponsor's Protocol Code Number:	NO25026
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-10-29
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

Netherlands - Competent Authority

A.2

EudraCT number

2009-012293-12

A.3

Full title of the trial

BRIM 3: A Randomized, Open-label, Controlled, Multicenter, Phase III Study in Previously untreated Patients with Unresectable Stage IIIC or Stage IV Melanoma with V600E BRAF mutation Receiving Vemurafenib (RO5185426) or Dacarbazine.

A.3.2

Name or abbreviated title of the trial where available

BRIM 3

A.4.1

Sponsor's protocol code number

NO25026

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	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, Switzerland
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	0041616881111
B.5.5	Fax number	0041616919319
B.5.6	E-mail	global.rochegenetechtrials@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
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.3.10	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	Comparator
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	Dacarbazine Pliva
D.2.1.1.2	Name of the Marketing Authorisation holder	Pliva Lachema a.s.
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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	Dacarbazine
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Dacarbazine
D.3.9.1	CAS number	4342-03-4
D.3.9.3	Other descriptive name	DTIC
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	100
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Dacarbazine
D.3.9.1	CAS number	4342-03-4
D.3.9.3	Other descriptive name	DTIC
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)	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

First-line therapy for adult patients with histologically confirmed metastatic melanoma (unresectable Stage IIIC or Stage IV) harbouring the V600E positive mutation

E.1.1.1

Medical condition in easily understood language

Malignant melanoma

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10027481
E.1.2	Term	Metastatic melanoma
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 RO5185426 as a monotherapy compared to dacarbazine in terms of progression free survival (PFS) and overall survival (OS) in previously untreated patients with advanced melanoma harbouring the BRAF V600E mutation.

E.2.2

Secondary objectives of the trial

• To further assess efficacy of RO5185426 compared to dacarbazine based on best overall response rate (BORR), time to response, duration of response, and time to treatment failure
• To evaluate the tolerability and safety profile of RO5185426 using the NCI CTCAE (version 4.0)
•To further characterize the pharmacokinetic (PK) profile of RO5185426
•To contribute to the validation of the Roche Companion Diagnostic (CoDx) cobas® 4800 BRAF V600E test for the detection of BRAF mutations in DNA extracted from formalin-fixed paraffin-embedded tumour (FFPET) samples

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients ≥ 18 years of age
2. Patients with histologically confirmed metastatic melanoma (surgically incurable and unresectable stage IIIC or stage IV, AJCC). Unresectable stage IIIC disease must have confirmation from a surgical oncologist
3. Treatment naïve patients (i.e., NO prior systemic anticancer therapy for advanced disease; Stage IIIC and IV). Only prior adjuvant immunotherapy is allowed
4. Patients must have a positive BRAF V600E mutation result determined by a designated laboratory using a Roche CoDx BRAF mutation test prior to administration study treatment
5. ECOG performance status of 0 or 1
6. Life expectancy > 3 months
7. Measurable disease (by RECIST criteria version 1.1) prior to the administration of study treatment
8. Patients must have recovered from effects of any major surgery or significant traumatic injury at least 14 days before the first dose of study treatment
9. Cutaneous SCC lesions identified at baseline, must be excised. Adequate wound healing is required prior to study entry. Baseline skin exam is required for all patients
10. Adequate hematologic, renal, and liver function as defined by laboratory values performed within 28 days prior to initiation of dosing
– Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
– Platelet count ≥ 100 x 109/L
– Hemoglobin ≥ 9 g/dL
– Serum creatinine ≤ 1.5 X ULN
– AST and ALT ≤ 2.5 X ULN
– Bilirubin ≤ 1.5 X ULN (for patients with Gilbert’s Syndrome, bilirubin ≤ 3 X ULN)
– Alkaline phosphatase ≤ 2.5 X ULN (< 5 times ULN for patients with concurrent liver
metastases)
11. Negative serum pregnancy test within 10 days prior to commencement of dosing in pre-menopausal women. Women of non-childbearing potential may be included if
they are either surgically sterile or have been postmenopausal for ≥ 1 year
12. Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician (in accordance with local requirements)
13. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before trial entry
14. Before study entry, written informed consent must be obtained from patient prior to performing any study-related procedures

E.4

Principal exclusion criteria

1. Patients with active CNS lesions are excluded (i.e., those with radiographically unstable, symptomatic lesions). However, patients treated with stereotactic therapy or surgery are eligible if patient remains without evidence of disease progression in brain ≥ 3 months. They must also be off corticosteroid therapy for ≥ 3 weeks. Whole brain radiotherapy is not allowed with the exception of patients who have had definitive resection or stereotactic therapy of all radiologically detectable parenchymal lesions
2. History of carcinomatous meningitis
3. Regional limb infusion or perfusion therapy
4. Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study
5. Pregnant or lactating women
6. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant small bowel resection that would preclude adequate RO5185426 absorption. Patients must be able to swallow pills
7. Mean QTc interval ≥ 450 msec at screening
8. NCI CTCAE Version 4.0 grade 3 hemorrhage within 4 weeks of starting the study treatment
9. Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, serious cardiac arrhythmia requiring medication, uncontrolled hypertension, cerebrovascular accident or transient ischemic attack, or symptomatic pulmonary embolism
10. Known clinically significant active infection
11. History of allogenic bone marrow transplantation or organ transplantation
12. Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, which in the judgment of the investigator would make the patient inappropriate for entry into this study
13. Patients with a previous malignancy within the past 5 years are excluded except for patients with basal or squamous cell carcinoma (SCC) of the skin, melanoma in-situ, and carcinoma in-situ of the cervix. Isolated elevation in PSA in the absence of radiographic evidence of metastatic prostate cancer is allowed
14. Patients who have been previously treated with a BRAF inhibitor
15. Known HIV positivity or AIDS-related illness, or active HBV, and active HCV
16. Patients who have been previously randomized to this trial at another participating site

E.5 End points

E.5.1

Primary end point(s)

The co-primary efficacy endpoints are progression-free survival and overall survival. PFS, according to the RECIST 1.1 criteria, is defined as the interval (days) between randomization and the date of progression (based on the actual tumour assessment date), or death for any cause, whichever comes first. The death of a patient without a reported progression will be considered as an event on the date of death. Patients who have neither
progressed nor died will be censored on the date of last evaluable tumour assessment (TA). Patients who had no post-baseline assessments and did not have an event will be censored at the time of randomization (i.e., Day 1).
OS is defined as the interval (days) between randomization and death for any cause. For a patient alive at the time of analysis data cutoff, OS time will be censored at the last date the patient was known to be alive.

E.5.1.1

Timepoint(s) of evaluation of this end point

Overall survival: event-driven, assessed approximately 2 years after first patient is randomized
Progression-free survival (PFS): tumour assessments after 6 and 12 weeks, and every 9 weeks thereafter

E.5.2

Secondary end point(s)

- Best overall response rate (BORR), time to response, duration of Response, time to treatment failure
- Safety and tolerability: AEs, laboratory parameters
- To further characterize the pharmacokinetics of RO5185426 (arm A only) by measuring maximum plasma concentration (Cmax), and area under the plasma concentration-time curve (AUC)

E.5.2.1

Timepoint(s) of evaluation of this end point

- best overall response rate (BORR), time to response, duration of assessments after 6 and 12 weeks, and every 9 weeks thereafter]
- Safety and tolerability: AEs, laboratory parameters [Time
Frame:throughout study, laboratory assessments every 3 weeks]
- To further characterize the pharmacokinetics of RO5185426 (arm A only) by measuring maximum plasma concentration (Cmax), and area under the plasma concentration-time curve (AUC) [Time Frame: multiple sampling on day 1, cycles 1,2,3 and every 2 cycles thereafter]

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

Yes

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

Tumour assessments, performance status, quality of life, physical Symptoms improvement, Biomarkers

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

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

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

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

Canada

France

Germany

Israel

Italy

Netherlands

New Zealand

Sweden

Switzerland

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, or lost to follow up.

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:

520

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

160

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2009-10-29.

Yes

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

283

F.4.2.2

In the whole clinical trial

680

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)

Please refer to the Protocol Section 3.3.

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

2009-11-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-01-25

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

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