Clinical Trials Register

Summary
EudraCT Number:	2014-005149-40
Sponsor's Protocol Code Number:	202105
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-01-22
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

France - ANSM

A.2

EudraCT number

2014-005149-40

A.3

Full title of the trial

An open label non randomized access study of Trametinib for patients with advanced unresectable (stage IIIc) or distant metastatic (stage IV) BRAF V600E/K mutation positive cutaneous melanoma

A.3.1

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

An access study of Trametinib for patients with advanced unresectable (stage IIIc) or distant metastatic (stage IV) BRAF V600E/K mutation positive cutaneous melanoma

A.4.1

Sponsor's protocol code number

202105

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	Laboratoire GlaxoSmithKline
B.1.3.4	Country	France
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	GlaxoSmithKline
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Laboratoire GlaxoSmithKline
B.5.2	Functional name of contact point	DIAM
B.5.3	Address:
B.5.3.1	Street Address	100, route de Versailles
B.5.3.2	Town/ city	Marly-le-Roi Cedex
B.5.3.3	Post code	78163
B.5.3.4	Country	France
B.5.4	Telephone number	+33139178444
B.5.6	E-mail	service.diam@gsk.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	Mekinist 0,5 mg comprimés pelliculés
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Group 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.3.1	Product name	Trametinib
D.3.2	Product code	GSK1120212
D.3.4	Pharmaceutical form	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	TRAMETINIB
D.3.9.1	CAS number	GSK1120212
D.3.9.4	EV Substance Code	SUB119776
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	0.5
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	Yes
D.2.1.1.1	Trade name	Mekinist 2 mg comprimés pelliculés
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Group 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.3.1	Product name	Trametinib
D.3.2	Product code	GSK1120212
D.3.4	Pharmaceutical form	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	TRAMETINIB
D.3.9.1	CAS number	GSK1120212
D.3.9.4	EV Substance Code	SUB119776
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	2.0
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 mutation BRAF V 600

E.1.1.1

Medical condition in easily understood language

Metastatic melanoma, a type of skin cancer

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	17.1
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

The objective of this open label access study is to provide access to trametinib to patients with histologically confirmed cutaneous melanoma with a BRAF V600E/K positive mutation that is either advanced unresectable (stage IIIc) or distant metastatic (stage IV), who require treatment with trametinib, either as monotherapy or in combination with dabrafenib.

E.2.2

Secondary objectives of the trial

To describe the frequency and proportion of adverse events (AEs), serious adverse events (SAEs) related to treatment or leading to treatment discontinuation, and response rates to treatment determined clinically and/or radiologically by the investigator.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. Signed, written informed consent. Age ≥18 years.
2. Has histologically confirmed cutaneous melanoma BRAF V600E/K positive mutation either unresectable (stage IIIc) or distant metastatic (stage IV).
3. Is not eligible for enrolment in any other ongoing relevant hypothesis testing clinical study for metastatic melanoma [...]
4. Has not participated in the following GSK sponsored clinical studies (COMBI-v: MEK116513, COMBI-d: MEK115306, COMBI-AD: BRF115532) for melanoma indication prior to participating in this open label access study.
5. Is able to swallow and retain oral medication.
6. For patients with active brain metastases: the patient does not require or is ineligible for immediate local treatment.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2 and in stable clinical condition. (Refer to Appendix 2 Section 12.2)
NOTE: patient in rapidly deteriorating clinical condition prior to start of therapy should not be considered for this open label access study. ECOG 3 patients may be included provided the patient is clinically stable on the investigator’s judgement.
8. Does not require treatment with another anti-cancer therapy while on this open label access study (except dabrafenib if in combination with trametinib).
9. Does not require treatment with prohibited concomitant medications (see Section 6.7.2).
10. Does not have any medical conditions or physical examination or clinical laboratory findings which, in the opinion of the investigator and/or GSK Medical Monitor, would put the patient at high risk for an adverse outcome.
11. Where applicable, female patients of childbearing potential must agree to use one of the contraceptive methods listed below. These patients must have a negative serum pregnancy test within 7 days prior to the first dose of trametinib, preferably as close to the first dose as possible, agree to use adequate contraception from the time of the pregnancy test, throughout the treatment period and for a total of 4 months following the last dose of treatment. 11. Does not have any medical conditions or physical examination or clinical laboratory findings which, in the opinion of the investigator and/or GSK Medical Monitor, would put the patient at high risk for an adverse outcome.
12. For patients enrolled in France: a patient will be eligible for inclusion in this study only if he is, either affiliated to or beneficiary of a social security category.

E.4

Principal exclusion criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

1. Patients who have received prior therapy with a MEK or BRAF inhibitor.
NOTE: However patients may be eligible in the following cases:
• Patients whose tumor has not progressed based on radiographic and clinical assessments. Such patients may receive therapy with:
- trametinib in combination with dabrafenib (in case of an adverse event related to a previous BRAF or MEK inhibitor other than trametinib or dabrafenib and without cross-reaction anticipated, or if clinically indicated according to investigator judgement). Prior treatment (except trametinib and dabrafenib) should have been stopped for a period of 5 half lives or 28 days (whichever is shorter) before starting treatment of this study (see Section 6.7 concomitant medications)
- trametinib monotherapy if the patient has benefited from a treatment with a BRAF-inhibitor without progression but cannot receive it anymore due to tolerability reason
• Patients who have met the criteria for disease progression may receive trametinib in combination with dabrafenib if:
1) the disease progression was confirmed after a period of at least 6 months of clinical benefit (Response or Stable Disease) on monotherapy and if the progression was characterized by a limited radiographic progression in the absence of clinical signs and symptoms of progression.
2) no treatment-related grade 4 AEs or any SAEs occurred during the last 4 weeks of treatment.

2. Concurrent treatment with other systemic anti-cancer therapies is not allowed (except dabrafenib in combination with trametinib). Patients who are currently being treated with another systemic anti-cancer therapy (e.g. chemo, immune, biologic, or targeted therapy) must discontinue use prior to initiation of treatment in this open label access study for a period of 5 half lives or 28 days (whichever is shorter).

3. Presence of malignancy other than melanoma within 1 year of enrolment into this program or any malignancy with confirmed activating RAS mutation. Patient with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Note: Prospective RAS testing is not required. However, if the results of previous RAS testing are known, they must be used in assessing eligibility.

4. Has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib or dabrafenib, or excipients or to dimethyl sulfoxide (DMSO).

5. Current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)

6. Current evidence of cardiovascular risk including any of the following:
• Left Ventricular Ejection Fraction (LVEF) < lower limit of normal (LLN)
• A QT interval corrected for heart rate using the Bazett’s formula > or = 480 msec;
• Clinically significant uncontrolled arrhythmias
• Acute coronary syndromes (including myocardial infarction and unstable angina).
• Congestive heart failure ≥ Class II as defined by New York Heart Association (NYHA; Appendix 5 Section 12.5).

E.5 End points

E.5.1

Primary end point(s)

Not applicable

E.5.1.1

Timepoint(s) of evaluation of this end point

Not applicable

E.5.2

Secondary end point(s)

- Adverse events (AEs), the serious adverse events (SAEs) related to treatment
- AE/SAE leading to discontinuation of treatment
- Response to treatment determined clinically and/or radiologically by the investigator.

E.5.2.1

Timepoint(s) of evaluation of this end point

- For AE/SAE: on an on-going basis and every 4 weeks during 6 months and every 8 weeks thereafter.
- Response to treatment: as per clinical practice

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

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

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

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

Yes

E.8.1.7.1

Other trial design description

Access trial to a non marketed drug

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.8.3

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

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 trametinib receives regulatory approval for use in combination with dabrafenib and the drug is commercially available, unless the study is terminated early. Participating subjects may then be transitioned to the marketed product if considered appropriate by the investigator.

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

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:

300

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

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

400

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)

When Trametinib will be commercially available, subjects should be transitioned to the marketed product.
The investigator is responsible for ensuring that consideration has been given to the post-study care of the subject’s medical condition, whether or not GSK is providing specific post-study treatment.

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

2015-01-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-02-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-03-01

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