Clinical Trials Register

Summary
EudraCT Number:	2013-002616-28
Sponsor's Protocol Code Number:	N13NDT
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2013-09-24
Trial 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

2013-002616-28

A.3

Full title of the trial

Cytoreductive treatment of dabrafenib combined with trametinib to allow complete surgical resection in patients with BRAF mutated, prior unresectable stage III or IV melanoma

A.3.1

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

A trial with patients who have a tumor that is too big to resect via operation, to treat them with systemic treatment to downsize the tumor, so that after 8 weeks the tumor can be resected and the patient is cured.

A.3.2

Name or abbreviated title of the trial where available

Presurgical MAPK inhibition in stage III-IV melanoma

A.4.1

Sponsor's protocol code number

N13NDT

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	NKI-AVL
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-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	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	NKI-AVL
B.5.2	Functional name of contact point	CRA
B.5.3	Address:
B.5.3.1	Street Address	Plesmanlaan 121
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1066CX
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31205122667
B.5.5	Fax number	+31205122679
B.5.6	E-mail	l.pronk@nki.nl

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	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	dabrafenib
D.3.2	Product code	GSK2118436
D.3.4	Pharmaceutical form	Capsule
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	Dabrafenib
D.3.9.1	CAS number	1195765-45-7
D.3.9.2	Current sponsor code	GSK2118436
D.3.9.3	Other descriptive name	DABRAFENIB
D.3.9.4	EV Substance Code	SUB45696
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	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
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	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.3.9.2	Current sponsor code	GSK1120212
D.3.9.3	Other descriptive name	Trametinib
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
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
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

unresectable stage III/IV melanoma

E.1.1.1

Medical condition in easily understood language

skin cancer that has spread out through the body

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	HLT
E.1.2	Classification code	10027156
E.1.2	Term	Skin melanomas (excl ocular)
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

Primary objectives: To assess the ability of dabrafenib + trametinib treatment to downsize melanoma tumor masses to enable R0-resection.

E.2.2

Secondary objectives of the trial

Secondary objectives: Recurrence free survival; time-to-next treatment, overall survival.

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

Objectives translational research:
To investigate treatment induced changes in exome mutations within the tumor, changes in gene expression profiles and development of gene signatures for response to treatment, target protein inhibition (levels of pMEK, pERK, pAKT) and IHC for lymphocytic infiltrates and expression of PD-L1, Gata-3, IDO etc.)
To perform patient derived xenografting (PDX) in immunodeficient mice to investigate development of resistance.

E.3

Principal inclusion criteria

1. Patients have provided signed informed consent.
2. Patients have unresectabel stage III melanoma (documented and based on MSD) or stage IV melanoma with ≤ 3 resectable metastases/organ site.
3. Patients have pathologically confirmed BRAF mutation-positive (V600E/K) melanoma as determined via in-house testing with a BRAF mutation assay.
4. Patients are treatment naïve for unresectable melanoma.
5. Patients for whom the intended operation is considered to offer a chance of cure or substantial palliation.
6. Patients have evaluable disease by CT/MRI or PET with ≤ 3 metastases/organ sites.
7. Patients are ≥18 years of age.
8. Patients are able to swallow and retain oral medication.
9. Women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study.
10. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to the first dose of study treatment.
11. Patients have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
12. Patients must have adequate organ function as defined in the protocol. Treatment with transfusion, growth factors to meet eligibility criteria will not be allowed.

E.4

Principal exclusion criteria

1. Patients with known ocular or primary mucosal melanoma.
2. Patients who used any investigational anti-cancer or other drug within 28 days or 5 half-lives, whichever is longer, preceding the first dose of dabrafenib + trametinib.
3. Patients who currently use a prohibited medication or are expected to require any of these medications during treatment with dabrafenib and trametinib.
4. Patients who had any major surgery, radiotherapy, or immunotherapy within the last 4 weeks.
5. Patients with active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs.
6. Patients with a history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
7. Patients with a history of other malignancy. Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible
8. Patients with a history of alcohol or drug abuse within 6 months prior to screening.
9. Patients with psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, or unwillingness or inability to follow the procedures required in the protocol.
10. Patients with the cardiac abnormalities as defined in the protocol.
11. Pregnant or lactating female.
12. Patients with CNS metastases.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of this study is the % of patients in whom an R0-resection could be performed. This is measured by the pathologist, who handles the resection material (no positive margins) and negative CT-scans. Patients that develop a CR on systemic treatment will of course be included in the analysis. The aim of the study is to enable R0 resection.

E.5.1.1

Timepoint(s) of evaluation of this end point

8 weeks after start study treatment.

E.5.2

Secondary end point(s)

As the secondary endpoint recurrence-free survival will be assessed every 3 months by physical exam and CT-scan for 2 years, thereafter every 6 months for 2 year, and once in year 5. Thereafter by physical exam only. This will be assessed only in patients that undergo radical surgery. For patients not undergoing surgery, PFS will be assessed.
Time to next treatment is defined as the moment the study treatment starts until start of any following treatment (surgery, RT or systemic treatment) for new lesions. This will be measured in all patients, but patients will be stratified for undergoing surgery or not undergoing surgery. Overall survival will be measured using Kaplan-Meier estimation for the total group of patients as well, again stratified for patients undergoing surgery or no surgery.

E.5.2.1

Timepoint(s) of evaluation of this end point

During follow-up of the patient.

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

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)

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.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

It is a two-stage design. If the response in the first 14 patients is sufficient, than another 11 will be treated. The end of trial could be LVLS of the first stage (14 patients), or LVLS of the second stage (25 patients).

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:

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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.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 patient will be treated with dabrafenib and trametinib until PD.

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

2013-09-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-04

P. End of Trial
P.	End of Trial Status	Ongoing

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