Clinical Trials Register

Summary
EudraCT Number:	2015-001731-20
Sponsor's Protocol Code Number:	ML29741
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-02-09
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2015-001731-20

A.3

Full title of the trial

A SINGLE ARM, OPEN LABEL, PHASE II, MULTICENTER STUDY TO ASSESS THE DETECTION OF THE BRAF V600 MUTATION ON cfDNA FROM PLASMA IN PATIENTS WITH ADVANCED MELANOMA

A.3.1

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

A study to assess the detection of the BRAF V600 mutation on cfDNA from plasma in patients with advanced melanoma

A.4.1

Sponsor's protocol code number

ML29741

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	Genentech Inc. c/o 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	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	Cotellic 20 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
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.3.1	Product name	Cobimetinib
D.3.2	Product code	Ro 551-4041/F04-06
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	Cobimetinib
D.3.9.2	Current sponsor code	RO5514041
D.3.9.3	Other descriptive name	COBIMETINIB
D.3.9.4	EV Substance Code	SUB122319
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	20
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.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	Cobimetinib
D.3.2	Product code	RO5514041/F09
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	Cobimetinib
D.3.9.1	CAS number	934660-93-2
D.3.9.2	Current sponsor code	RO5514041
D.3.9.3	Other descriptive name	Cobimetinib (GDC-0973/RO5514041/XL518)
D.3.9.4	EV Substance Code	SUB122319
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Melanoma

E.1.1.1

Medical condition in easily understood language

Melanoma is a type of cancer that develops from the pigment-containing cells known as melanocytes

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10053571
E.1.2	Term	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 estimate the frequency of the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation in a new mutation analysis triggered by a mutant plasma cell-free DNA (cfDNA) test result, for patients with BRAF wild-type status based on a prior test result on tissue

E.2.2

Secondary objectives of the trial

To investigate the clinical outcome of all patients, as well as broken down for patients for whom treatment is based on the mutation identified by the prior test result on tissue, and patients for whom treatment is based upon the mutation identified on the new tissue analysis, triggered by the mutant plasma cfDNA test result

To investigate the correlation of the initial concentration of the BRAF V600 mutation on cfDNA in plasma with progression-free survival time and duration of response, for all treated patients

To estimate the sensitivity and specificity, and the positive and negative predictive value of the results of plasma testing with respect to the prior test result on tissues

To characterize the toxicity profile in patients receiving vemurafenib plus cobimetinib

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Presence and concentration of the BRAF V600 mutation and the NRAS mutation measured on plasma cfDNA will be recorded during treatment with vemurafenib and cobimetinib.
(Please refer to the protocol)

E.3

Principal inclusion criteria

General inclusion criteria:
- Male or female patient aged >= 18 years
- Eastern Coorperative Oncology Group (ECOG) Performance Status of 0-2
- Adequate hematologic and end organ function (renal and liver)
- Negative serum pregnancy test prior to commencement of dosing in women of childbearing potential
- Absence of any psychological, familial, sociological, or geographical condition that potentially hampers compliance with the study protocol and treatment regimen and follow-up after treatment discontinuation schedule; those conditions should be discussed with the patient before trial entry
- Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use 2 effective forms of contraception during the course of this study and for at least 6 months after completion of study therapy
a. Females of childbearing potential are defined as sexually mature women without prior oophorectomy or hysterectomy who have had menses within the last 12 months.
b. Females are not considered to be of childbearing potential if amenorrheic for > 12 months but < 2 years and follicle-stimulating hormone (FSH) level > 40 IU/L.
c. Effective forms of contraception include surgical sterilization, a reliable barrier, method with spermicide, birth control pills, or contraceptive hormone implants. Please note that potential interactions between vemurafenib and hormonal contraceptives may decrease the effectiveness of hormonal contraceptives.
d. d. Male patients who are surgically sterilized are required to use barrier methods of contraception

Disease-specific Inclusion Criteria:
- Patients with histologically confirmed cutaneous melanoma, either unresectable Stage IIIc or Stage IV metastatic melanoma, as defined by AJCC 7th edition
- Documentation of BRAF V600 mutation-positive status in melanoma tumor tissue using a validated tissue test
- Patients with measurable or non-measurable disease (Response Evaluation Criteria in Solid Tumors version 1.1)

E.4

Principal exclusion criteria

Cancer-Related Exclusion Criteria:
1. History of prior RAF or mitogen-activated protein kinase (MEK) pathway inhibitor treatment
2. Treatment related:
a.Palliative radiotherapy within 14 days prior to the first dose of study treatment
b. Use of prior chemotherapy or immunotherapy (incl. treatment with an anti-PD1, or anti-PDL1 or anti-CTLA-4 monoclonal antibody) within 4 weeks before first study drug administration

Exclusion Criteria Based on Organ Function:
- Ocular: Evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/ central serous chorioretinopathy, retinal vein occlusion, or neovascular macular degeneration
- Patients will be excluded if they have one of the following conditions: a) Uncontrolled glaucoma with intra-ocular pressures >= 21 mmHg b) Uncontrolled hypercholesterolemia >= Grade 2 c) Hypertriglyceridemia >= Grade 2 d) Hyperglycemia >= Grade 2
- Cardiac: History of clinically significant cardiac dysfunction

General exclusion criteria:
- Current severe, uncontrolled systemic disease
- Major surgery or traumatic injury within 14 days prior to first dose of study treatment
- History of malabsorption or other condition that would interfere with absorption of study drugs
- the following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment:
a) St. John’s wort or hyperforin (potent CYP3A4 enzyme inducer)
b) Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor)

E.5 End points

E.5.1

Primary end point(s)

1. BRAF V600 mutation status determined on plasma cfDNA at onset of the study

2. BRAF V600 mutation status determined on tissue

3. Occurrence of the BRAF V600 mutation on the new mutation analysis for patients with a BRAF wild-type based on a prior tissue test result and a mutation determined on plasma cfDNA

E.5.1.1

Timepoint(s) of evaluation of this end point

Pre-screening period (Day -56 to Day -1)

E.5.2

Secondary end point(s)

1. Objective response rate

2. Progression-free survival

3. Duration of response

4. Overall survival

5. Incidence, nature and severity of adverse events, serious adverse events, and adverse events of special interest, graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events v 4.03

6. Changes in vital signs, electrocardiograms and clinical lab results during the course of the study

E.5.2.1

Timepoint(s) of evaluation of this end point

Up to 36 months

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

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.8.2.4

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

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

The study will end when all patients enrolled have been followed for 4 weeks after study treatment discontinuation, death by any cause, withdrawal of consent, or lost to follow-up; 18 months after enrollment of last patient in the pre-screening phase; or the Sponsor decides to end the trial, whichever occurs first.

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

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:

150

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

208

F.4.2.2

In the whole clinical trial

208

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)

The Sponsor will offer post-trial access to the study drug free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product. The Roche Global Policy on Continued Access to Investigational Medicinal Product is available at the following Web site: http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf

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

2016-02-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-03-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-06-27

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