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Clinical Trial Results:
Phase II biomarker study evaluating the upfront combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib versus the combination after eight weeks of monotherapy with dabrafenib or trametinib in patients with metastatic and unresectable stage III or IV melanoma harbouring an activating BRAF mutation

Summary
EudraCT number	2012-004577-12
Trial protocol	ES
Global end of trial date	19 Jan 2017

Results information
Results version number	v3(current)
This version publication date	10 Oct 2018
First version publication date	27 Jan 2018
Other versions	v1 , v2
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

116613

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom,

Public contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

23 Mar 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

19 Jan 2017

Was the trial ended prematurely?

Yes

Main objective of the trial

To evaluate biomarkers linked to treatment response, resistance and toxicity including skin toxicity when dabrafenib and trametinib combination is given upfront or as monotherapy before the combination treatment.

Protection of trial subjects

At the time the study was early terminated, subjects who were still receiving clinical benefit and based on the discretion of the Investigator had the option to continue treatment through Sponsor established programs in the local country

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Nov 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 37

Country: Number of subjects enrolled

Spain: 11

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This is an open label, randomized, phase II study to compare the combination of dabrafenib with trametinib versus the combination after eight weeks of monotherapy with dabrafenib or trametinib in metastatic and unresectable stage III or IV melanoma. The study was terminated early due to slow enrollment and limited numbers of viable tissue samples.

Screening details

This study was planned to enroll 54 participants randomized in 1:1:1 ratio into the three treatment arms; dabrafenib followed by combination therapy, trametinib followed by combination therapy and only combination therapy. The study was early terminated with 48 participants enrolled.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Dabrafenib followed by combination therapy

Arm description

Eligible participants received dabrafenib 150 milligrams (mg) twice a day (BID) continuously during 8 weeks of monotherapy treatment followed by the combination of trametinib 2 mg once daily with dabrafenib 150 mg BID until disease progression, death or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

Dabrafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Dabrafenib was given as an oral capsule with a dose of 150 mg twice a day (BID).

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Trametinib was given as an oral film-coated tablet with a dose of 2 milligrams (mg) once daily.

Trametinib followed by combination therapy

Arm description

Eligible participants received trametinib 2 mg per day continuously during 8 weeks of monotherapy treatment followed by the combination of trametinib 2 mg once daily with dabrafenib 150 mg BID until disease progression, death or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Trametinib was given as an oral film-coated tablet with a dose of 2 milligrams (mg) once daily.

Investigational medicinal product name

Dabrafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Dabrafenib was given as an oral capsule with a dose of 150 mg twice a day (BID).

Combination therapy

Arm description

Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Trametinib was given as an oral film-coated tablet with a dose of 2 milligrams (mg) once daily.

Investigational medicinal product name

Dabrafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Dabrafenib was given as an oral capsule with a dose of 150 mg twice a day (BID).

Number of subjects in period 1	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy	Combination therapy
Started	16	16	16
Completed	8	6	7
Not completed	8	10	9
Physician decision	2	1	-
Consent withdrawn by subject	1	-	1
Adverse event, non-fatal	-	6	4
Other (Study Closed/Terminated)	5	3	4

Baseline characteristics

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Reporting group title

Dabrafenib followed by combination therapy

Reporting group description

Reporting group title

Trametinib followed by combination therapy

Reporting group description

Reporting group title

Combination therapy

Reporting group description

Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.

Reporting group values	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy	Combination therapy	Total
Number of subjects	16	16	16
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	56.6 ( 16.43 )	56.5 ( 11.77 )	58.9 ( 13.55 )	-
Gender categorical
Units: Subjects
Female	7	8	6	21
Male	9	8	10	27
Race/Ethnicity, Customized
Units: Subjects
Asian-South East Asian Heritage	0	1	0	1
White - White/Caucasian/European	16	15	16	47

End points

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Reporting group title

Dabrafenib followed by combination therapy

Reporting group description

Reporting group title

Trametinib followed by combination therapy

Reporting group description

Reporting group title

Combination therapy

Reporting group description

Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.

Primary: Number of participants with percentage change from Baseline in extracellular signal-regulated kinase (ERK) phosphorylation (p-ERK) H score from Week 0 to Week 2

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End point title

Number of participants with percentage change from Baseline in extracellular signal-regulated kinase (ERK) phosphorylation (p-ERK) H score from Week 0 to Week 2 ^[1] ^[2]

End point description

Intra-tumoral expression levels of ERK measured using immunohistochemistry methods. The H score value ranged from 0 to a maximum score of 300 (strongest expression) was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0 [no staining], 1+ [weak staining], 2+ [medium staining] and 3+ [strongest staining]). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. The data has been presented for combination therapy calculated from Week 0 to Week 2. The analysis was based on the biomarker Population which included all participants with biopsy performed at screening and at least once during treatment. Only those participants with data available at specific time point were analyzed.

End point type

Primary

End point timeframe

Baseline (Week 0) and up to 2 weeks

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There are no statistical data to report.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.

End point values	Combination therapy
Number of subjects analysed	5 ^[3]
Units: Participants
Any Increase or No Changes	2
Any Decrease up to 80 percent	1
Any Decrease > 80 percent	2

Notes
[3] - Biomarker Population

No statistical analyses for this end point

Primary: Number of participants with percentage change in p-ERK H score from Week 8 to Week 10

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End point title

Number of participants with percentage change in p-ERK H score from Week 8 to Week 10 ^[4] ^[5]

End point description

Intra-tumoral expression levels of ERK were measured using immunohistochemistry methods. The H score value ranged from 0 to a maximum score of 300 (strongest expression) was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0 [no staining], 1+ [weak staining], 2+ [medium staining] and 3+ [strongest staining]). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. The data has been presented for dabrafenib followed by combination therapy and trametinib followed by combination therapy, calculated from Week 8 to Week 10. Only those participants with data available at specific time point were analyzed.

End point type

Primary

End point timeframe

Week 8 and up to 10 weeks

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There are no statistical data to report.
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.

End point values	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy
Number of subjects analysed	1 ^[6]	3 ^[7]
Units: Participants
Any Increase or No Changes	1	1
Any Decrease up to 80 percent	0	1
Any Decrease > 80 percent	0	1

Notes
[6] - Biomarker Population
[7] - Biomarker Population

No statistical analyses for this end point

Secondary: Number of participants with overall response rate (ORR)

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End point title

Number of participants with overall response rate (ORR)

End point description

Clinical response was evaluated by ORR, which was defined as the number of participants with a confirmed or an unconfirmed complete response (CR) or partial response (PR) at any time per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. CR was defined as disappearance of all target lesions. PR was defined as at least a 30 percent decrease in the sum of the diameters of target lesions. Number of participants with ORR (CR+PR) has been presented. The analysis was based on the Intent-to-Treat Population (ITT) which included all the randomized participants whether or not randomized treatment was administered.

End point type

Secondary

End point timeframe

Up to 3.2 years

End point values	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy	Combination therapy
Number of subjects analysed	16 ^[8]	16 ^[9]	16 ^[10]
Units: Participants
Participants	11	13	11

Notes
[8] - Intent-to-Treat Population (ITT)
[9] - Intent-to-Treat Population (ITT)
[10] - Intent-to-Treat Population (ITT)

Statistical analysis 1

Statistical analysis description

The odds ratio for dabrafenib followed by combination therapy versus combination therapy has been presented.

Comparison groups

Combination therapy v Dabrafenib followed by combination therapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 1

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.224

upper limit

4.459

Statistical analysis 2

Statistical analysis description

The odds ratio for trametinib followed by combination therapy versus combination therapy has been presented.

Comparison groups

Combination therapy v Trametinib followed by combination therapy

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.4216

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.382

upper limit

10.166

Secondary: Number of participants with change in vital signs from Baseline

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End point title

Number of participants with change in vital signs from Baseline

End point description

Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and heat rate (HR) were measured. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus the Baseline value. The number of participants with heart rate “decrease to < 60” and “increase to >100” have been presented. For SBP and DBP, "any grade increase" have been presented. Any grade increase in SBP, including grade 0 (<120), grade 1 (120-139), grade 2 (140-159), grade 3 (>=160) and DBP including grade 0 (<80), grade 1 (80-89), grade 2 (90-99), grade 3 (>=100) have been presented. The analysis was based on the Safety Population which included all participants who received at least one dose of randomized treatment and was based on the actual treatment received. Only those participants available at specified time point were analyzed (represented by n=x in category titles).

End point type

Secondary

End point timeframe

Baseline and up to 3.2 years

End point values	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy	Combination therapy
Number of subjects analysed	16 ^[11]	16 ^[12]	16 ^[13]
Units: Participants
HR; Week 4; Decrease to <60; n=15,16,16	1	3	3
HR; Week 4; Increase to >100; n=15,16,16	1	0	0
HR; Week 8; Decrease to <60; n=16,16,14	1	2	2
HR; Week 8; Increase to >100; n=16,16,14	2	0	0
HR; Week 12; Decrease to <60; n=16,16,13	2	1	2
HR; Week 12; Increase to >100; n=16,16,13	0	0	0
HR; Week 16; Decrease to <60; n=14,16,13	0	0	2
HR; Week 16; Increase to >100; n=14,16,13	0	0	0
HR; Week 20; Decrease to <60; n=11,15,13	0	1	1
HR; Week 20; Increase to >100; n=11,15,13	1	1	0
HR; Week 24; Decrease to <60; n=12,14,13	1	2	2
HR; Week 24; Increase to >100; n=12,14,13	1	2	0
HR; Week 28; Decrease to <60; n=8,12,7	2	2	2
HR; Week 28; Increase to >100; n=8,12,7	1	0	0
HR; Week 32; Decrease to <60; n=7,11,8	1	0	0
HR; Week 32; Increase to >100; n=7,11,8	1	0	0
HR; Week 36; Decrease to <60; n=5,11,8	2	0	1
HR; Week 36; Increase to >100; n=5,11,8	0	0	1
HR; Week 40; Decrease to <60; n=6,11,7	1	1	0
HR; Week 40; Increase to >100; n=6,11,7	0	0	0
HR; Week 44; Decrease to <60; n=5,5,4	1	0	0
HR; Week 44; Increase to >100; n=5,5,4	1	0	1
HR; Week 48; Decrease to <60; n=5,4,4	1	0	1
HR; Week 48; Increase to >100; n=5,4,4	0	0	1
HR; Week 52; Decrease to <60; n=4,3,4	0	0	0
HR; Week 52; Increase to >100; n=4,3,4	0	0	1
HR; Week 56; Decrease to <60; n=4,3,4	1	0	3
HR; Week 56; Increase to >100; n=4,3,4	0	0	0
HR; Week 60; Decrease to <60; n=3,3,4	1	1	1
HR; Week 60; Increase to >100; n=3,3,4	0	0	0
HR; Week 64; Decrease to <60; n=3,3,3	1	0	0
HR; Week 64; Increase to >100; n=3,3,3	0	0	0
HR; Week 68; Decrease to <60; n=4,2,2	1	0	2
HR; Week 68; Increase to >100; n=4,2,2	0	0	0
HR; Week 72; Decrease to <60; n=3,2,2	0	0	0
HR; Week 72; Increase to >100; n=3,2,2	0	0	0
HR; Week 76; Decrease to <60; n=4,1,2	1	0	0
HR; Week 76; Increase to >100; n=4,1,2	0	0	1
HR; Week 80; Decrease to <60; n=3,1,2	1	0	0
HR; Week 80; Increase to >100; n=3,1,2	0	0	0
HR; Week 84; Decrease to <60; n=3,1,1	0	0	0
HR; Week 84; Increase to >100; n=3,1,1	0	0	0
HR; Week 88; Decrease to <60; n=3,1,1	1	0	0
HR; Week 88; Increase to >100; n=3,1,1	0	0	0
HR; Week 92; Decrease to <60; n=3,1,1	1	0	0
HR; Week 92; Increase to >100; n=3,1,1	0	0	0
HR; Week 96; Decrease to <60; n=3,1,1	1	0	0
HR; Week 96; Increase to >100; n=3,1,1	0	0	0
HR; Week 100; Decrease to <60; n=3,1,1	0	0	0
HR; Week 100; Increase to >100; n=3,1,1	0	0	0
HR; Week 104; Decrease to <60; n=3,1,1	0	0	0
HR; Week 104; Increase to >100; n=3,1,1	0	0	0
HR; Week 108; Decrease to <60; n=2,0,1	1	99999	0
HR; Week 108; Increase to >100; n=2,0,1	0	99999	0
HR; Week 112; Decrease to <60; n=2,0,0	1	99999	99999
HR; Week 112; Increase to >100; n=2, 0,0	0	99999	99999
HR; Week 116; Decrease to <60; n=1, 0,0	0	99999	99999
HR; Week 116; Increase to >100; n=1, 0,0	0	99999	99999
HR; Week 120; Decrease to <60; n=1, 0,0	0	99999	99999
HR; Week 120; Increase to >100; n=1, 0,0	0	99999	99999
HR; Week 124; Decrease to <60; n=1, 0,0	0	99999	99999
HR; Week 124; Increase to >100; n=1, 0,0	0	99999	99999
SBP; Week 4; Any grade increase; n=15,16,16	1	8	4
SBP; Week 8; Any grade increase; n=16,16,14	3	5	4
SBP; Week 12; Any grade increase; n=16,16,13	3	5	2
SBP; Week 16; Any grade increase; n=14,16,13	4	3	2
SBP; Week 20; Any grade increase; n=11,15, 13	2	3	1
SBP; Week 24; Any grade increase; n=12, 14,13	2	3	2
SBP; Week 28; Any grade increase; n=8, 12,7	2	0	0
SBP; Week 32; Any grade increase; n=7,11, 8	2	3	2
SBP; Week 36; Any grade increase; n=5, 11, 8	3	3	1
SBP; Week 40; Any grade increase; n=6,11, 7	1	4	2
SBP; Week 44; Any grade increase; n=5, 5, 4	2	0	0
SBP; Week 48; Any grade increase; n=5,4, 4	1	1	0
SBP; Week 52; Any grade increase; n=4,3, 4	1	0	0
SBP; Week 56; Any grade increase; n=4, 3, 4	0	0	0
SBP; Week 60; Any grade increase; n=3, 2, 4	1	1	0
SBP; Week 64; Any grade increase; n=3, 3, 3	1	0	0
SBP; Week 68; Any grade increase; n=4,2, 2	2	0	0
SBP; Week 72; Any grade increase; n=3,2, 2	1	0	0
SBP; Week 76; Any grade increase; n=4, 1, 2	2	0	0
SBP; Week 80; Any grade increase; n=3, 1, 2	2	0	0
SBP; Week 84; Any grade increase; n=3, 1,1	2	0	0
SBP; Week 88; Any grade increase; n=3, 1,1	0	0	0
SBP; Week 92; Any grade increase; n=3, 1, 1	2	0	0
SBP; Week 96; Any grade increase; n=3,1, 1	2	1	0
SBP; Week 100; Any grade increase; n=3, 1, 1	0	0	0
SBP; Week 104; Any grade increase; n=3, 1, 1	1	0	0
SBP; Week 108; Any grade increase; n=2,0, 1	1	99999	0
SBP; Week 112; Any grade increase; n=2, 0, 0	0	99999	99999
SBP; Week 116; Any grade increase; n=1, 0, 0	0	99999	99999
SBP; Week 120; Any grade increase; n=1, 0, 0	0	99999	99999
SBP; Week 124; Any grade increase; n=1, 0, 0	0	99999	99999
DBP; Week 4; Any grade increase; n=15, 16, 16	2	10	5
DBP; Week 8; Any grade increase; n=16, 16,14	4	8	3
DBP; Week 12; Any grade increase; n=16, 16, 13	4	4	2
DBP; Week 16; Any grade increase; n=14, 16,13	5	5	3
DBP; Week 20; Any grade increase; n=11, 15,13	4	5	2
DBP; Week 24; Any grade increase; n=12, 14,13	3	3	1
DBP; Week 28; Any grade increase; n=8, 12,7	1	2	0
DBP; Week 32; Any grade increase; n=7, 11,8	2	3	1
DBP; Week 36; Any grade increase; n=5, 11,8	2	1	2
DBP; Week 40; Any grade increase; n=6, 11,7	1	1	1
DBP; Week 44; Any grade increase; n=5, 5,4	4	1	2
DBP; Week 48; Any grade increase; n=5, 4,4	2	1	2
DBP; Week 52; Any grade increase; n=4,3,4	2	0	0
DBP; Week 56; Any grade increase; n=4,3,4	1	1	0
DBP; Week 60; Any grade increase; n=3,2,4	2	0	0
DBP; Week 64; Any grade increase; n=3,3, 3	1	0	1
DBP; Week 68; Any grade increase; n=4,2, 2	2	0	1
DBP; Week 72; Any grade increase; n=3,2,2	1	0	1
DBP; Week 76; Any grade increase; n=4,1,2	2	0	1
DBP; Week 80; Any grade increase; n=3,1,2	1	0	1
DBP; Week 84; Any grade increase; n=3,1,1	1	0	0
DBP; Week 88; Any grade increase; n=3,1,1	1	0	0
DBP; Week 92; Any grade increase; n=3, 1,1	1	0	1
DBP; Week 96; Any grade increase; n=3, 1,1	2	0	1
DBP; Week 100; Any grade increase; n=3,1,1	1	0	0
DBP; Week 104; Any grade increase; n=3,1,1	1	0	1
DBP; Week 108; Any grade increase; n=2,0,1	1	99999	0
DBP; Week 112; Any grade increase; n=2,0,0	0	99999	99999
DBP; Week 116; Any grade increase; n=1,0,0	0	99999	99999
DBP; Week 120; Any grade increase; n=1,0,0	0	99999	99999
DBP; Week 124; Any grade increase; n=1,0,0	0	99999	99999

Notes
[11] - Safety Population
[12] - Safety Population
[13] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with clinically significant abnormal findings undergoing physical examinations

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End point title

Number of participants with clinically significant abnormal findings undergoing physical examinations

End point description

Complete physical examination included assessments of eyes, neurological and cardiovascular systems, lungs, abdomen, and any other areas with signs and symptoms of disease, and of the head, neck, ears, nose, mouth, throat, thyroid, lymph nodes, extremities, and a full skin exam to assess cutaneous malignancies and proliferative skin diseases. This analysis was planned but data was not captured in the database. Abnormal changes were captured as adverse events if they were clinically significant.

End point type

Secondary

End point timeframe

Up to 3.2 years

End point values	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy	Combination therapy
Number of subjects analysed	0 ^[14]	0 ^[15]	0 ^[16]
Units: Participants
Participants

Notes
[14] - Safety Population. This analysis was planned but data was not captured in the database.
[15] - Safety Population. This analysis was planned but data was not captured in the database.
[16] - Safety Population. This analysis was planned but data was not captured in the database.

No statistical analyses for this end point

Secondary: Number of participants with change in eastern cooperative oncology group (ECOG) performance status scores from Baseline

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End point title

Number of participants with change in eastern cooperative oncology group (ECOG) performance status scores from Baseline

End point description

The ECOG scale of performance status describes the level of functioning of participants in terms of their ability to care for themselves, daily activity, and physical ability. The ECOG performance was recorded as per ECOG performance status grades ranging from 0 (fully active, able to carry on all pre-disease performance without restriction) to 5 (dead). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The Baseline performance status of participants with respect to worst-case on-therapy performance status has been presented.

End point type

Secondary

End point timeframe

Baseline and up to 3.2 years

End point values	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy	Combination therapy
Number of subjects analysed	16 ^[17]	16 ^[18]	16 ^[19]
Units: Participants
0 to 0	5	5	6
0 to 1	0	0	1
0 to 2	0	0	0
0 to 3	0	0	0
0 to 4-5	0	0	0
1 to 0	6	10	5
1 to 1	3	1	2
1 to 2	0	0	0
1 to 3	0	0	0
1 to 4-5	0	0	0
2 to 0	0	0	0
2 to 1	2	0	2
2 to 2	0	0	0
2 to 3	0	0	0
2 to 4-5	0	0	0
3 to 0	0	0	0
3 to 1	0	0	0
3 to 2	0	0	0
3 to 3	0	0	0
3 to 4-5	0	0	0
4-5 to 0	0	0	0
4-5 to 1	0	0	0
4-5 to 2	0	0	0
4-5 to 3	0	0	0
4-5 to 4-5	0	0	0

Notes
[17] - Safety Population
[18] - Safety Population
[19] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with abnormal electrocardiograms (ECG) findings

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End point title

Number of participants with abnormal electrocardiograms (ECG) findings

End point description

Single measurements of 12-lead ECGs were obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, corrected QT interval (QTc), Bazett’s Corrected QT interval (QTcB), Friderica’s Corrected QT interval (QTcF). Number of participants with abnormal ECG findings (Abnormal - Not Clinically Significant and Abnormal - Clinically Significant ) at any time post-Baseline visit have been presented.

End point type

Secondary

End point timeframe

Up to 3.2 years

End point values	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy	Combination therapy
Number of subjects analysed	16 ^[20]	16 ^[21]	16 ^[22]
Units: Participants
Abnormal - Not Clinically Significant	9	10	9
Abnormal - Clinically Significant	0	1	0

Notes
[20] - Safety Population
[21] - Safety Population
[22] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with absolute change in left ventricular ejection fraction from Baseline

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End point title

Number of participants with absolute change in left ventricular ejection fraction from Baseline

End point description

Echocardiograms (ECHO) was performed to assess cardiac ejection fraction and cardiac valve morphology. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on-therapy value has been presented.

End point type

Secondary

End point timeframe

Baseline and up to 3.2 years

End point values	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy	Combination therapy
Number of subjects analysed	16 ^[23]	16 ^[24]	16 ^[25]
Units: Participants
No Change Or Any Increase	11	14	11
>0-<10 Decrease	4	2	3
>=10 Decrease And >= Lower limit of Normal (Lln)	1	0	2

Notes
[23] - Safety Population
[24] - Safety Population
[25] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with change in clinical chemistry parameters from Baseline

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End point title

Number of participants with change in clinical chemistry parameters from Baseline

End point description

Blood samples were collected for evaluation of clinical chemistry parameters including sodium, potassium, calcium, albumin, total protein, blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GCT), phosphate, C-reactive protein (CRP), hypercalcemia, hyperkalemia, hypernatremia, hypocalcemia, hypokalemia, hyponatremia, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, direct bilirubin and estimated creatinine clearance (CRTCE). Baseline was defined as the most recent non-missing value from a central laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on therapy value for number of participants with any grade increase in clinical chemistry parameters for has been presented. Only those participants available at specified time point were analyzed (represented by n=x in category titles).

End point type

Secondary

End point timeframe

Baseline and up to 3.2 years

End point values	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy	Combination therapy
Number of subjects analysed	16 ^[26]	16 ^[27]	16 ^[28]
Units: Participants
ALT; n=16,16,16	3	13	9
Albumin; n=16,16,16	2	5	2
Alkaline phosphatase; n=16,16,16	5	10	4
AST; n=16,16,16	8	15	12
Bilirubin; n=16,16,16	0	2	0
CRP;n=12,12,13	0	0	0
Creatinine; n=16,16,16	0	0	0
Direct bilirubin; n=4,6,3	0	0	0
GCT; n=16,16,16	6	12	5
Hypercalcemia; n=16,16,16	0	0	0
Hyperkalemia; n=16,16,16	1	4	0
Hypernatremia; n=16,16,16	3	4	1
Hypocalcemia; n=16,16,16	7	7	4
Hypokalemia; n=16,16,16	1	4	3
Hyponatremia; n=16,16,16	7	7	5
LDH; 16,16,15	0	0	0
Phosphate; n=16,16,16	10	6	4
Protein; n=16,16,16	0	0	0
Urea; n=15,15,16	0	0	0
CRTCE; n=5,2,5	0	0	0

Notes
[26] - Safety Population
[27] - Safety Population
[28] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with change in hematology parameters from Baseline

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End point title

Number of participants with change in hematology parameters from Baseline

End point description

Blood samples were collected for evaluation of hematology parameters including hemoglobin, white blood cell (WBC), platelet count, basophils, eosinophils, lymphocytes, monocytes, total neutrophils, lymphocytopenia and lymphocytosis. Baseline was defined as the most recent non-missing value from a central laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on therapy value for number of participants with any grade increase in hematology parameters for has been presented.

End point type

Secondary

End point timeframe

Baseline and up to 3.2 years

End point values	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy	Combination therapy
Number of subjects analysed	16 ^[29]	16 ^[30]	16 ^[31]
Units: Participants
Basophils	0	0	0
Eosinophils	0	0	0
Hemoglobin	4	6	4
Leukocytes	5	9	10
Monocytes	0	0	0
Neutrophils	6	9	9
Platelets	2	5	3
Lymphocytopenia	8	6	6
Lymphocytosis	2	0	0

Notes
[29] - Safety Population
[30] - Safety Population
[31] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with incidence of squamous cell carcinoma and keratoacanthoma

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End point title

Number of participants with incidence of squamous cell carcinoma and keratoacanthoma

End point description

The safety profile of dabrafenib and trametinib in monotherapy as well as in combination therapy was characterized by determining the number of participants with incidence of squamous cell carcinoma and keratoacanthoma.

End point type

Secondary

End point timeframe

Up to 3.2 years

End point values	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy	Combination therapy
Number of subjects analysed	16 ^[32]	16 ^[33]	16 ^[34]
Units: Participants
Participants	1	0	0

Notes
[32] - Safety Population
[33] - Safety Population
[34] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants with on-treatment serious adverse events (SAEs) and non-SAEs

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End point title

Number of participants with on-treatment serious adverse events (SAEs) and non-SAEs

End point description

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function.

End point type

Secondary

End point timeframe

Up to 3.2 years

End point values	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy	Combination therapy
Number of subjects analysed	16 ^[35]	16 ^[36]	16 ^[37]
Units: Participants
Any Non-SAE	16	16	15
Any SAE	8	7	4

Notes
[35] - Safety Population
[36] - Safety Population
[37] - Safety Population

No statistical analyses for this end point

Secondary: Plasma pharmacokinetic concentration of trametinib and dabrafenib

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End point title

Plasma pharmacokinetic concentration of trametinib and dabrafenib

End point description

Blood samples were collected for pharmacokinetic analysis of trametinib and dabrafenib. Data is not available and so will not be posted until October 2018.

End point type

Secondary

End point timeframe

Pre-dose and 4, 8 hours post-dose at Weeks 2, 8 and 10

End point values	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy	Combination therapy
Number of subjects analysed	0 ^[38]	0 ^[39]	0 ^[40]
Units: Nanograms per milliliter (ng/mL)
arithmetic mean (standard deviation)
Nanograms per milliliter (ng/mL)	( )	( )	( )

Notes
[38] - Biomarker Population.Data is not available and so will not be posted until October 2018.
[39] - Biomarker Population. Data is not available and so will not be posted until October 2018.
[40] - Biomarker Population.Data is not available and so will not be posted until October 2018.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

On-treatment serious adverse events (SAEs) and non-serious adverse events (non-SAEs) were collected from the start of the study treatment up to 3.2 years.

Adverse event reporting additional description

On-treatment SAEs and non-SAEs were collected in Safety Population which included all the participants who received at least one dose of randomized treatment and was based on the actual treatment received.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Dabrafenib followed by combination therapy

Reporting group description

Reporting group title

Trametinib followed by combination therapy

Reporting group description

Reporting group title

Combination therapy

Reporting group description

Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.

Serious adverse events	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy	Combination therapy
Total subjects affected by serious adverse events
subjects affected / exposed	8 / 16 (50.00%)	7 / 16 (43.75%)	4 / 16 (25.00%)
number of deaths (all causes)	1	0	2
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma stage 0
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to meninges
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	2 / 16 (12.50%)	3 / 16 (18.75%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	2 / 3	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Metrorrhagia
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumothorax
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary sarcoidosis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Panic attack
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Left ventricular dysfunction
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Haemorrhage intracranial
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Histiocytosis haematophagic
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatocellular injury
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Dabrafenib followed by combination therapy	Trametinib followed by combination therapy	Combination therapy
Total subjects affected by non serious adverse events
subjects affected / exposed	16 / 16 (100.00%)	16 / 16 (100.00%)	15 / 16 (93.75%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin Papilloma
subjects affected / exposed	5 / 16 (31.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	6	0	0
Papilloma
subjects affected / exposed	3 / 16 (18.75%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	3	0	0
Basal Cell Carcinoma
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	0	3
Malignant Melanoma
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Metastases To Meninges
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Tumour Pain
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Haemangioma
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Vascular disorders
Hot Flush
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	2 / 16 (12.50%)
occurrences all number	3	0	2
Hypertension
subjects affected / exposed	1 / 16 (6.25%)	2 / 16 (12.50%)	1 / 16 (6.25%)
occurrences all number	3	3	1
Hypotension
subjects affected / exposed	3 / 16 (18.75%)	1 / 16 (6.25%)	1 / 16 (6.25%)
occurrences all number	3	1	1
Haematoma
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	0	1
Lymphoedema
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Peripheral Venous Disease
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	5 / 16 (31.25%)	13 / 16 (81.25%)	6 / 16 (37.50%)
occurrences all number	12	49	18
Hyperthermia
subjects affected / exposed	4 / 16 (25.00%)	4 / 16 (25.00%)	4 / 16 (25.00%)
occurrences all number	13	15	22
Asthenia
subjects affected / exposed	10 / 16 (62.50%)	10 / 16 (62.50%)	9 / 16 (56.25%)
occurrences all number	14	20	17
Chills
subjects affected / exposed	3 / 16 (18.75%)	10 / 16 (62.50%)	4 / 16 (25.00%)
occurrences all number	4	15	8
Oedema Peripheral
subjects affected / exposed	4 / 16 (25.00%)	6 / 16 (37.50%)	4 / 16 (25.00%)
occurrences all number	7	8	4
Chest Pain
subjects affected / exposed	3 / 16 (18.75%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	6	2	0
Mucosal Inflammation
subjects affected / exposed	1 / 16 (6.25%)	4 / 16 (25.00%)	1 / 16 (6.25%)
occurrences all number	1	4	1
Influenza Like Illness
subjects affected / exposed	3 / 16 (18.75%)	2 / 16 (12.50%)	3 / 16 (18.75%)
occurrences all number	3	2	3
Xerosis
subjects affected / exposed	3 / 16 (18.75%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	3	2	0
Malaise
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	0	2
Chest Discomfort
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Feeling Of Body Temperature Change
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Ill-Defined Disorder
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Discomfort
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Face Oedema
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Inflammation
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Inflammatory Pain
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Mucosal Dryness
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Nodule
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Hernia
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Hypothermia
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Oedema Due To Cardiac Disease
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Immune system disorders
Allergy To Arthropod Sting
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Reproductive system and breast disorders
Amenorrhoea
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	1	1	0
Erectile Dysfunction
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Vulvovaginal Dryness
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Breast Pain
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Vaginal Haemorrhage
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Vulvovaginal Pruritus
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Adenomyosis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	4 / 16 (25.00%)	3 / 16 (18.75%)	2 / 16 (12.50%)
occurrences all number	6	4	2
Epistaxis
subjects affected / exposed	0 / 16 (0.00%)	4 / 16 (25.00%)	2 / 16 (12.50%)
occurrences all number	0	5	4
Dyspnoea
subjects affected / exposed	3 / 16 (18.75%)	3 / 16 (18.75%)	0 / 16 (0.00%)
occurrences all number	3	3	0
Nasal Dryness
subjects affected / exposed	1 / 16 (6.25%)	2 / 16 (12.50%)	1 / 16 (6.25%)
occurrences all number	1	3	1
Rhinitis Allergic
subjects affected / exposed	0 / 16 (0.00%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	0	3	0
Dry Throat
subjects affected / exposed	1 / 16 (6.25%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	1	2	0
Dyspnoea Exertional
subjects affected / exposed	1 / 16 (6.25%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	1	2	0
Oropharyngeal Pain
subjects affected / exposed	1 / 16 (6.25%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	1	2	0
Pneumonitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	2	0
Rhinorrhoea
subjects affected / exposed	0 / 16 (0.00%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	0	2	0
Asthma
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Catarrh
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	1 / 16 (6.25%)
occurrences all number	1	1	1
Lower Respiratory Tract Congestion
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Productive Cough
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Atelectasis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Oropharyngeal Discomfort
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Dysphonia
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Psychiatric disorders
Insomnia
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	2	1	0
Anxiety
subjects affected / exposed	1 / 16 (6.25%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	1	2	0
Irritability
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Mood Altered
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Sleep Disorder
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	1 / 16 (6.25%)
occurrences all number	1	1	1
Stress
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Depression
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Hallucination
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	0 / 16 (0.00%)	5 / 16 (31.25%)	0 / 16 (0.00%)
occurrences all number	0	15	0
Gamma-Glutamyltransferase Increased
subjects affected / exposed	1 / 16 (6.25%)	2 / 16 (12.50%)	1 / 16 (6.25%)
occurrences all number	1	10	1
Aspartate Aminotransferase Increased
subjects affected / exposed	0 / 16 (0.00%)	5 / 16 (31.25%)	0 / 16 (0.00%)
occurrences all number	0	14	0
Blood Creatine Phosphokinase Increased
subjects affected / exposed	5 / 16 (31.25%)	7 / 16 (43.75%)	5 / 16 (31.25%)
occurrences all number	8	9	7
Blood Alkaline Phosphatase Increased
subjects affected / exposed	1 / 16 (6.25%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	1	7	0
Lipase Increased
subjects affected / exposed	1 / 16 (6.25%)	2 / 16 (12.50%)	2 / 16 (12.50%)
occurrences all number	2	4	2
Blood Lactate Dehydrogenase Increased
subjects affected / exposed	1 / 16 (6.25%)	2 / 16 (12.50%)	1 / 16 (6.25%)
occurrences all number	1	3	1
C-Reactive Protein Increased
subjects affected / exposed	1 / 16 (6.25%)	3 / 16 (18.75%)	0 / 16 (0.00%)
occurrences all number	1	3	0
Ejection Fraction Decreased
subjects affected / exposed	0 / 16 (0.00%)	3 / 16 (18.75%)	1 / 16 (6.25%)
occurrences all number	0	3	1
Electrocardiogram Qt Prolonged
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	3	0
Weight Decreased
subjects affected / exposed	2 / 16 (12.50%)	1 / 16 (6.25%)	1 / 16 (6.25%)
occurrences all number	2	2	1
Amylase Increased
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	1 / 16 (6.25%)
occurrences all number	0	2	1
Blood Triglycerides Increased
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	2
Neutrophil Count Decreased
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	1 / 16 (6.25%)
occurrences all number	0	1	2
Intraocular Pressure Increased
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
White Blood Cell Count Increased
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Blood Albumin Decreased
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Platelet Count Decreased
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Weight Increased
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Blood Fibrinogen Increased
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Hepatic Enzyme Increased
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Injury, poisoning and procedural complications
Foot Fracture
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	2	0	0
Arthropod Bite
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Ligament Sprain
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Limb Injury
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Procedural Pain
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Traumatic Haematoma
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Fall
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Cardiac disorders
Bradycardia
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	1	1	0
Palpitations
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	1	1	0
Sinus Bradycardia
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Tachycardia
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	0	1
Extrasystoles
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Tricuspid Valve Incompetence
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Atrial Fibrillation
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Mitral Valve Incompetence
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Nervous system disorders
Headache
subjects affected / exposed	9 / 16 (56.25%)	9 / 16 (56.25%)	6 / 16 (37.50%)
occurrences all number	16	15	9
Tremor
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	3 / 16 (18.75%)
occurrences all number	0	1	7
Paraesthesia
subjects affected / exposed	2 / 16 (12.50%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	5	0	1
Dizziness
subjects affected / exposed	3 / 16 (18.75%)	1 / 16 (6.25%)	2 / 16 (12.50%)
occurrences all number	3	1	2
Hyperaesthesia
subjects affected / exposed	3 / 16 (18.75%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	3	1	0
Burning Sensation
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	2	0	0
Dysaesthesia
subjects affected / exposed	2 / 16 (12.50%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	2	0	2
Cervical Radiculopathy
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Epilepsy
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Neuralgia
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	0	1
Sciatica
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Syncope
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	1 / 16 (6.25%)
occurrences all number	1	1	1
Amnesia
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Aphasia
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Memory Impairment
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Migraine With Aura
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Presyncope
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Stupor
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Demyelinating Polyneuropathy
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Head Discomfort
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Hypoaesthesia
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Muscle Contractions Involuntary
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Peripheral Sensory Neuropathy
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	1 / 16 (6.25%)	3 / 16 (18.75%)	3 / 16 (18.75%)
occurrences all number	1	14	4
Anaemia
subjects affected / exposed	4 / 16 (25.00%)	1 / 16 (6.25%)	2 / 16 (12.50%)
occurrences all number	4	1	3
Eosinophilia
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Leukopenia
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Lymphadenitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	1 / 16 (6.25%)
occurrences all number	0	1	1
Thrombocytopenia
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	1 / 16 (6.25%)
occurrences all number	0	1	1
Histiocytosis Haematophagic
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Eye disorders
Visual Impairment
subjects affected / exposed	2 / 16 (12.50%)	1 / 16 (6.25%)	2 / 16 (12.50%)
occurrences all number	3	2	2
Eye Pain
subjects affected / exposed	0 / 16 (0.00%)	2 / 16 (12.50%)	1 / 16 (6.25%)
occurrences all number	0	3	1
Dry Eye
subjects affected / exposed	1 / 16 (6.25%)	2 / 16 (12.50%)	1 / 16 (6.25%)
occurrences all number	1	2	1
Iridocyclitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	2	0
Vision Blurred
subjects affected / exposed	0 / 16 (0.00%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	0	2	0
Eyelid Ptosis
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Keratitis
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Ocular Hyperaemia
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Visual Acuity Reduced
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	1 / 16 (6.25%)
occurrences all number	1	1	1
Eyelid Oedema
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Uveitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Chalazion
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Chorioretinopathy
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Conjunctival Hyperaemia
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Diplopia
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Vitreous Detachment
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	6 / 16 (37.50%)	7 / 16 (43.75%)	5 / 16 (31.25%)
occurrences all number	9	19	7
Nausea
subjects affected / exposed	8 / 16 (50.00%)	4 / 16 (25.00%)	5 / 16 (31.25%)
occurrences all number	12	11	5
Vomiting
subjects affected / exposed	4 / 16 (25.00%)	4 / 16 (25.00%)	3 / 16 (18.75%)
occurrences all number	6	9	3
Constipation
subjects affected / exposed	2 / 16 (12.50%)	5 / 16 (31.25%)	2 / 16 (12.50%)
occurrences all number	6	6	3
Abdominal Pain
subjects affected / exposed	2 / 16 (12.50%)	2 / 16 (12.50%)	1 / 16 (6.25%)
occurrences all number	4	6	1
Abdominal Pain Upper
subjects affected / exposed	4 / 16 (25.00%)	4 / 16 (25.00%)	0 / 16 (0.00%)
occurrences all number	4	5	0
Abdominal Distension
subjects affected / exposed	2 / 16 (12.50%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	4	0	1
Dry Mouth
subjects affected / exposed	2 / 16 (12.50%)	4 / 16 (25.00%)	3 / 16 (18.75%)
occurrences all number	3	4	3
Gastrooesophageal Reflux Disease
subjects affected / exposed	1 / 16 (6.25%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	1	3	0
Dysphagia
subjects affected / exposed	0 / 16 (0.00%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	0	2	0
Odynophagia
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	0	2
Aerophagia
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Aphthous Ulcer
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	1	1	0
Ascites
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Colitis
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Dyspepsia
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Gastrointestinal Disorder
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Gastrointestinal Haemorrhage
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Gingival Pain
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Mouth Ulceration
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Painful Defaecation
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Rectal Haemorrhage
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	1	0	1
Tooth Demineralisation
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Tooth Discolouration
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Toothache
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Anal Fissure
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Food Poisoning
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Salivary Hypersecretion
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Haematochezia
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Tongue Discolouration
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Cheilitis
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Gingival Bleeding
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Hepatobiliary disorders
Hepatocellular Injury
subjects affected / exposed	1 / 16 (6.25%)	3 / 16 (18.75%)	2 / 16 (12.50%)
occurrences all number	1	3	2
Cholestasis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	1 / 16 (6.25%)
occurrences all number	0	1	1
Hepatitis
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	4 / 16 (25.00%)	8 / 16 (50.00%)	3 / 16 (18.75%)
occurrences all number	5	15	3
Palmar-Plantar Erythrodysaesthesia Syndrome
subjects affected / exposed	6 / 16 (37.50%)	2 / 16 (12.50%)	1 / 16 (6.25%)
occurrences all number	9	3	1
Palmoplantar Keratoderma
subjects affected / exposed	7 / 16 (43.75%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	7	0	0
Alopecia
subjects affected / exposed	4 / 16 (25.00%)	6 / 16 (37.50%)	1 / 16 (6.25%)
occurrences all number	6	7	1
Dermatitis Acneiform
subjects affected / exposed	0 / 16 (0.00%)	4 / 16 (25.00%)	1 / 16 (6.25%)
occurrences all number	0	7	1
Night Sweats
subjects affected / exposed	0 / 16 (0.00%)	3 / 16 (18.75%)	0 / 16 (0.00%)
occurrences all number	0	5	0
Skin Lesion
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	0	5
Erythema Nodosum
subjects affected / exposed	3 / 16 (18.75%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	4	2	0
Hyperkeratosis
subjects affected / exposed	3 / 16 (18.75%)	1 / 16 (6.25%)	2 / 16 (12.50%)
occurrences all number	4	1	2
Keratosis Pilaris
subjects affected / exposed	4 / 16 (25.00%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	4	0	0
Dry Skin
subjects affected / exposed	3 / 16 (18.75%)	4 / 16 (25.00%)	3 / 16 (18.75%)
occurrences all number	3	4	3
Pruritus
subjects affected / exposed	2 / 16 (12.50%)	3 / 16 (18.75%)	2 / 16 (12.50%)
occurrences all number	2	4	3
Pigmentation Disorder
subjects affected / exposed	3 / 16 (18.75%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	3	0	0
Panniculitis
subjects affected / exposed	0 / 16 (0.00%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	0	3	0
Erythema
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	2 / 16 (12.50%)
occurrences all number	0	1	3
Onychoclasis
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	2	0	0
Eczema
subjects affected / exposed	0 / 16 (0.00%)	2 / 16 (12.50%)	1 / 16 (6.25%)
occurrences all number	0	2	1
Rash Macular
subjects affected / exposed	0 / 16 (0.00%)	2 / 16 (12.50%)	1 / 16 (6.25%)
occurrences all number	0	2	1
Skin Fissures
subjects affected / exposed	0 / 16 (0.00%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	0	2	0
Urticaria
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	1 / 16 (6.25%)
occurrences all number	1	1	2
Hyperhidrosis
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	1	1	0
Intertrigo
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Nail Dystrophy
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Nail Pigmentation
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Hypertrichosis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Nail Discolouration
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Nail Disorder
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Prurigo
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Rash Maculo-Papular
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Seborrhoeic Dermatitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Neutrophilic Panniculitis
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Renal and urinary disorders
Dysuria
subjects affected / exposed	1 / 16 (6.25%)	2 / 16 (12.50%)	1 / 16 (6.25%)
occurrences all number	1	2	1
Haematuria
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	2	0
Pollakiuria
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Renal Failure
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Renal Tubular Acidosis
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Urinary Retention
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Endocrine disorders
Adrenal Insufficiency
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Hyperthyroidism
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	7 / 16 (43.75%)	4 / 16 (25.00%)	2 / 16 (12.50%)
occurrences all number	9	5	2
Muscle Spasms
subjects affected / exposed	5 / 16 (31.25%)	6 / 16 (37.50%)	2 / 16 (12.50%)
occurrences all number	7	9	2
Arthralgia
subjects affected / exposed	5 / 16 (31.25%)	3 / 16 (18.75%)	3 / 16 (18.75%)
occurrences all number	7	8	3
Myalgia
subjects affected / exposed	4 / 16 (25.00%)	5 / 16 (31.25%)	4 / 16 (25.00%)
occurrences all number	5	8	7
Pain In Extremity
subjects affected / exposed	3 / 16 (18.75%)	5 / 16 (31.25%)	3 / 16 (18.75%)
occurrences all number	7	7	5
Neck Pain
subjects affected / exposed	1 / 16 (6.25%)	2 / 16 (12.50%)	2 / 16 (12.50%)
occurrences all number	1	6	3
Musculoskeletal Stiffness
subjects affected / exposed	3 / 16 (18.75%)	3 / 16 (18.75%)	2 / 16 (12.50%)
occurrences all number	3	5	2
Groin Pain
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	2	0	0
Musculoskeletal Pain
subjects affected / exposed	2 / 16 (12.50%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	2	0	1
Flank Pain
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	2
Limb Discomfort
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	1	1	0
Muscle Contracture
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Muscular Weakness
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	1 / 16 (6.25%)
occurrences all number	1	1	1
Musculoskeletal Chest Pain
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Osteoarthritis
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Spinal Pain
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Tendonitis
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Joint Stiffness
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Myopathy
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Infections and infestations
Folliculitis
subjects affected / exposed	1 / 16 (6.25%)	7 / 16 (43.75%)	2 / 16 (12.50%)
occurrences all number	1	8	2
Nasopharyngitis
subjects affected / exposed	1 / 16 (6.25%)	5 / 16 (31.25%)	3 / 16 (18.75%)
occurrences all number	1	5	3
Urinary Tract Infection
subjects affected / exposed	1 / 16 (6.25%)	4 / 16 (25.00%)	3 / 16 (18.75%)
occurrences all number	1	4	4
Bronchitis
subjects affected / exposed	2 / 16 (12.50%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	3	0	1
Gastroenteritis
subjects affected / exposed	2 / 16 (12.50%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	2	0	1
Influenza
subjects affected / exposed	2 / 16 (12.50%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	2	0	0
Cellulitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	2	0
Cystitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	2	0
Conjunctivitis
subjects affected / exposed	0 / 16 (0.00%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	0	2	0
Pharyngitis
subjects affected / exposed	0 / 16 (0.00%)	2 / 16 (12.50%)	1 / 16 (6.25%)
occurrences all number	0	2	1
Rash Pustular
subjects affected / exposed	1 / 16 (6.25%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	1	2	0
Fungal Skin Infection
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	0	2
Paronychia
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	2
Rhinitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	2 / 16 (12.50%)
occurrences all number	0	1	2
Erysipelas
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Molluscum Contagiosum
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Respiratory Syncytial Virus Infection
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Streptococcal Sepsis
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Tonsillitis
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Tracheitis
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Vulvovaginal Candidiasis
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	1	0	0
Vulvovaginal Mycotic Infection
subjects affected / exposed	1 / 16 (6.25%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	1	1	0
Fungal Oesophagitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Lung Infection
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Moraxella Infection
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Sinusitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Escherichia Urinary Tract Infection
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Viral Rhinitis
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Febrile Infection
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Viral Upper Respiratory Tract Infection
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	1 / 16 (6.25%)	4 / 16 (25.00%)	2 / 16 (12.50%)
occurrences all number	1	7	3
Hypocalcaemia
subjects affected / exposed	3 / 16 (18.75%)	3 / 16 (18.75%)	1 / 16 (6.25%)
occurrences all number	4	3	1
Hyperkalaemia
subjects affected / exposed	0 / 16 (0.00%)	2 / 16 (12.50%)	0 / 16 (0.00%)
occurrences all number	0	3	0
Increased Appetite
subjects affected / exposed	1 / 16 (6.25%)	0 / 16 (0.00%)	0 / 16 (0.00%)
occurrences all number	2	0	0
Hyponatraemia
subjects affected / exposed	0 / 16 (0.00%)	2 / 16 (12.50%)	1 / 16 (6.25%)
occurrences all number	0	2	1
Diabetes Mellitus
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Hypercholesterolaemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Hyperglycaemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Hypernatraemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Hypoalbuminaemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Hypoglycaemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Hypokalaemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	1 / 16 (6.25%)
occurrences all number	0	1	1
Hypomagnesaemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Iron Deficiency
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Vitamin D Deficiency
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Weight Fluctuation
subjects affected / exposed	0 / 16 (0.00%)	1 / 16 (6.25%)	0 / 16 (0.00%)
occurrences all number	0	1	0
Hypercalcaemia
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1
Hypophosphataemia
subjects affected / exposed	0 / 16 (0.00%)	0 / 16 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	0	1

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Were there any global substantial amendments to the protocol? Yes

28 Oct 2013

Amendment 1 - Updated figure 1 Trial design to better reflect the design of the study. - Replaced “treatment vials” with “treatment bottles” as the study drugs are tablets. - Change of brain magnetic resonance imaging (MRI) from 4 weeks to 5 weeks before Day 1. - Amendment and further clarification around the biopsies taken for this study as requested by The National Agency for the Safety of Medicines and Health Products (ANSM). This includes: a) That the biopsies were only to be done on cutaneous and subcutaneous lesions only if they are easily accessible; b) confirmation that no deep lesion biopsies were be performed; c) clarification of who is qualified to perform the biopsies. - Clarification regarding the confirmation of response. - Clarification to the pharmacokinetic blood sampling. - New France specific Appendix. - Added to reflect the monitoring required for Cutaneous Squamous Cell Carcinoma (CuSCC), new primary melanoma and non- cutaneous secondary/recurrent malignancy as requested by ANSM. These amendments were not considered to have affected the interpretation of study results as they were minor and occurred prior to study unblinding.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of participants with percentage change from Baseline in extracellular signal-regulated kinase (ERK) phosphorylation (p-ERK) H score from Week 0 to Week 2

Primary: Number of participants with percentage change from Baseline in extracellular signal-regulated kinase (ERK) phosphorylation (p-ERK) H score from Week 0 to Week 2

Primary: Number of participants with percentage change in p-ERK H score from Week 8 to Week 10

Primary: Number of participants with percentage change in p-ERK H score from Week 8 to Week 10

Secondary: Number of participants with overall response rate (ORR)

Secondary: Number of participants with overall response rate (ORR)

Secondary: Number of participants with change in vital signs from Baseline

Secondary: Number of participants with change in vital signs from Baseline

Secondary: Number of participants with clinically significant abnormal findings undergoing physical examinations

Secondary: Number of participants with clinically significant abnormal findings undergoing physical examinations

Secondary: Number of participants with change in eastern cooperative oncology group (ECOG) performance status scores from Baseline

Secondary: Number of participants with change in eastern cooperative oncology group (ECOG) performance status scores from Baseline

Secondary: Number of participants with abnormal electrocardiograms (ECG) findings

Secondary: Number of participants with abnormal electrocardiograms (ECG) findings

Secondary: Number of participants with absolute change in left ventricular ejection fraction from Baseline

Secondary: Number of participants with absolute change in left ventricular ejection fraction from Baseline

Secondary: Number of participants with change in clinical chemistry parameters from Baseline

Secondary: Number of participants with change in clinical chemistry parameters from Baseline

Secondary: Number of participants with change in hematology parameters from Baseline

Secondary: Number of participants with change in hematology parameters from Baseline

Secondary: Number of participants with incidence of squamous cell carcinoma and keratoacanthoma

Secondary: Number of participants with incidence of squamous cell carcinoma and keratoacanthoma

Secondary: Number of participants with on-treatment serious adverse events (SAEs) and non-SAEs

Secondary: Number of participants with on-treatment serious adverse events (SAEs) and non-SAEs

Secondary: Plasma pharmacokinetic concentration of trametinib and dabrafenib

Secondary: Plasma pharmacokinetic concentration of trametinib and dabrafenib

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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