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Phase II Biomarker Study Comparing the Combination of BRAF Inhibitor Dabrafenib With MEK Inhibitor Trametinib Versus the Combination After Monotherapy With Dabrafenib or Trametinib

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ClinicalTrials.gov Identifier: NCT02314143
Recruitment Status : Terminated (The study was terminated early due to slow enrollment and limited numbers of viable tissue samples.)
First Posted : December 11, 2014
Results First Posted : February 18, 2019
Last Update Posted : February 18, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Diagnostic
Condition Melanoma
Interventions Drug: Dabrafenib
Drug: Trametinib
Enrollment 48
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.
Pre-assignment 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.
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Hide Arm/Group 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. 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. Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
Period Title: Overall Study
Started 16 16 16
Completed 8 6 7
Not Completed 8 10 9
Reason Not Completed
Adverse Event             0             6             4
Other (Study Closed/Terminated)             5             3             4
Physician Decision             2             1             0
Withdrawal by Subject             1             0             1
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy Total
Hide Arm/Group 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. 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. Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity. Total of all reporting groups
Overall Number of Baseline Participants 16 16 16 48
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 16 participants 16 participants 16 participants 48 participants
56.6  (16.43) 56.5  (11.77) 58.9  (13.55) 57.4  (13.79)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 16 participants 16 participants 48 participants
Female
7
  43.8%
8
  50.0%
6
  37.5%
21
  43.8%
Male
9
  56.3%
8
  50.0%
10
  62.5%
27
  56.3%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 16 participants 16 participants 48 participants
Asian-South East Asian Heritage
0
   0.0%
1
   6.3%
0
   0.0%
1
   2.1%
White - White/Caucasian/European
16
 100.0%
15
  93.8%
16
 100.0%
47
  97.9%
1.Primary Outcome
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
Hide 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.
Time Frame Baseline (Week 0) and up to 2 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Biomarker Population. Only those participants with data available at specific time point were analyzed.
Arm/Group Title Combination Therapy
Hide Arm/Group Description:
Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
Overall Number of Participants Analyzed 5
Measure Type: Count of Participants
Unit of Measure: Participants
Any Increase or No Changes
2
  40.0%
Any Decrease up to 80 percent
1
  20.0%
Any Decrease > 80 percent
2
  40.0%
2.Primary Outcome
Title Number of Participants With Percentage Change in p-ERK H Score From Week 8 to Week 10
Hide 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.
Time Frame Week 8 and up to 10 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Biomarker Population. Only those participants with data available at specific time point were analyzed.
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy
Hide Arm/Group 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.
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.
Overall Number of Participants Analyzed 1 3
Measure Type: Count of Participants
Unit of Measure: Participants
Any Increase or No Changes
1
 100.0%
1
  33.3%
Any Decrease up to 80 percent
0
   0.0%
1
  33.3%
Any Decrease > 80 percent
0
   0.0%
1
  33.3%
3.Secondary Outcome
Title Number of Participants With Overall Response Rate (ORR)
Hide 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.
Time Frame Up to 3.2 years
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat Population (ITT)
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Hide Arm/Group 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.
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.
Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
Overall Number of Participants Analyzed 16 16 16
Measure Type: Count of Participants
Unit of Measure: Participants
11
  68.8%
13
  81.3%
11
  68.8%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dabrafenib Followed by Combination Therapy, Combination Therapy
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.000
Confidence Interval (2-Sided) 95%
0.224 to 4.459
Estimation Comments The odds ratio for dabrafenib followed by combination therapy versus combination therapy has been presented.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Trametinib Followed by Combination Therapy, Combination Therapy
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4216
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.970
Confidence Interval (2-Sided) 95%
0.382 to 10.166
Estimation Comments The odds ratio for trametinib followed by combination therapy versus combination therapy has been presented.
4.Secondary Outcome
Title Number of Participants With Change in Vital Signs From Baseline
Hide 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).
Time Frame Baseline and up to 3.2 years
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Hide Arm/Group 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.
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.
Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
Overall Number of Participants Analyzed 16 16 16
Measure Type: Count of Participants
Unit of Measure: Participants
HR; Week 4; Decrease to <60; n=15,16,16 Number Analyzed 15 participants 16 participants 16 participants
1
   6.7%
3
  18.8%
3
  18.8%
HR; Week 4; Increase to >100; n=15,16,16 Number Analyzed 15 participants 16 participants 16 participants
1
   6.7%
0
   0.0%
0
   0.0%
HR; Week 8; Decrease to <60; n=16,16,14 Number Analyzed 16 participants 16 participants 14 participants
1
   6.3%
2
  12.5%
2
  14.3%
HR; Week 8; Increase to >100; n=16,16,14 Number Analyzed 16 participants 16 participants 14 participants
2
  12.5%
0
   0.0%
0
   0.0%
HR; Week 12; Decrease to <60; n=16,16,13 Number Analyzed 16 participants 16 participants 13 participants
2
  12.5%
1
   6.3%
2
  15.4%
HR; Week 12; Increase to >100; n=16,16,13 Number Analyzed 16 participants 16 participants 13 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 16; Decrease to <60; n=14,16,13 Number Analyzed 14 participants 16 participants 13 participants
0
   0.0%
0
   0.0%
2
  15.4%
HR; Week 16; Increase to >100; n=14,16,13 Number Analyzed 14 participants 16 participants 13 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 20; Decrease to <60; n=11,15,13 Number Analyzed 11 participants 15 participants 13 participants
0
   0.0%
1
   6.7%
1
   7.7%
HR; Week 20; Increase to >100; n=11,15,13 Number Analyzed 11 participants 15 participants 13 participants
1
   9.1%
1
   6.7%
0
   0.0%
HR; Week 24; Decrease to <60; n=12,14,13 Number Analyzed 12 participants 14 participants 13 participants
1
   8.3%
2
  14.3%
2
  15.4%
HR; Week 24; Increase to >100; n=12,14,13 Number Analyzed 12 participants 14 participants 13 participants
1
   8.3%
2
  14.3%
0
   0.0%
HR; Week 28; Decrease to <60; n=8,12,7 Number Analyzed 8 participants 12 participants 7 participants
2
  25.0%
2
  16.7%
2
  28.6%
HR; Week 28; Increase to >100; n=8,12,7 Number Analyzed 8 participants 12 participants 7 participants
1
  12.5%
0
   0.0%
0
   0.0%
HR; Week 32; Decrease to <60; n=7,11,8 Number Analyzed 7 participants 11 participants 8 participants
1
  14.3%
0
   0.0%
0
   0.0%
HR; Week 32; Increase to >100; n=7,11,8 Number Analyzed 7 participants 11 participants 8 participants
1
  14.3%
0
   0.0%
0
   0.0%
HR; Week 36; Decrease to <60; n=5,11,8 Number Analyzed 5 participants 11 participants 8 participants
2
  40.0%
0
   0.0%
1
  12.5%
HR; Week 36; Increase to >100; n=5,11,8 Number Analyzed 5 participants 11 participants 8 participants
0
   0.0%
0
   0.0%
1
  12.5%
HR; Week 40; Decrease to <60; n=6,11,7 Number Analyzed 6 participants 11 participants 7 participants
1
  16.7%
1
   9.1%
0
   0.0%
HR; Week 40; Increase to >100; n=6,11,7 Number Analyzed 6 participants 11 participants 7 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 44; Decrease to <60; n=5,5,4 Number Analyzed 5 participants 5 participants 4 participants
1
  20.0%
0
   0.0%
0
   0.0%
HR; Week 44; Increase to >100; n=5,5,4 Number Analyzed 5 participants 5 participants 4 participants
1
  20.0%
0
   0.0%
1
  25.0%
HR; Week 48; Decrease to <60; n=5,4,4 Number Analyzed 5 participants 4 participants 4 participants
1
  20.0%
0
   0.0%
1
  25.0%
HR; Week 48; Increase to >100; n=5,4,4 Number Analyzed 5 participants 4 participants 4 participants
0
   0.0%
0
   0.0%
1
  25.0%
HR; Week 52; Decrease to <60; n=4,3,4 Number Analyzed 4 participants 3 participants 4 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 52; Increase to >100; n=4,3,4 Number Analyzed 4 participants 3 participants 4 participants
0
   0.0%
0
   0.0%
1
  25.0%
HR; Week 56; Decrease to <60; n=4,3,4 Number Analyzed 4 participants 3 participants 4 participants
1
  25.0%
0
   0.0%
3
  75.0%
HR; Week 56; Increase to >100; n=4,3,4 Number Analyzed 4 participants 3 participants 4 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 60; Decrease to <60; n=3,3,4 Number Analyzed 3 participants 3 participants 4 participants
1
  33.3%
1
  33.3%
1
  25.0%
HR; Week 60; Increase to >100; n=3,3,4 Number Analyzed 3 participants 3 participants 4 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 64; Decrease to <60; n=3,3,3 Number Analyzed 3 participants 3 participants 3 participants
1
  33.3%
0
   0.0%
0
   0.0%
HR; Week 64; Increase to >100; n=3,3,3 Number Analyzed 3 participants 3 participants 3 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 68; Decrease to <60; n=4,2,2 Number Analyzed 4 participants 2 participants 2 participants
1
  25.0%
0
   0.0%
2
 100.0%
HR; Week 68; Increase to >100; n=4,2,2 Number Analyzed 4 participants 2 participants 2 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 72; Decrease to <60; n=3,2,2 Number Analyzed 3 participants 2 participants 2 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 72; Increase to >100; n=3,2,2 Number Analyzed 3 participants 2 participants 2 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 76; Decrease to <60; n=4,1,2 Number Analyzed 4 participants 1 participants 2 participants
1
  25.0%
0
   0.0%
0
   0.0%
HR; Week 76; Increase to >100; n=4,1,2 Number Analyzed 4 participants 1 participants 2 participants
0
   0.0%
0
   0.0%
1
  50.0%
HR; Week 80; Decrease to <60; n=3,1,2 Number Analyzed 3 participants 1 participants 2 participants
1
  33.3%
0
   0.0%
0
   0.0%
HR; Week 80; Increase to >100; n=3,1,2 Number Analyzed 3 participants 1 participants 2 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 84; Decrease to <60; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 84; Increase to >100; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 88; Decrease to <60; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
1
  33.3%
0
   0.0%
0
   0.0%
HR; Week 88; Increase to >100; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 92; Decrease to <60; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
1
  33.3%
0
   0.0%
0
   0.0%
HR; Week 92; Increase to >100; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 96; Decrease to <60; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
1
  33.3%
0
   0.0%
0
   0.0%
HR; Week 96; Increase to >100; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 100; Decrease to <60; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 100; Increase to >100; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 104; Decrease to <60; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 104; Increase to >100; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
0
   0.0%
0
   0.0%
0
   0.0%
HR; Week 108; Decrease to <60; n=2,0,1 Number Analyzed 2 participants 0 participants 1 participants
1
  50.0%
0
   0.0%
HR; Week 108; Increase to >100; n=2,0,1 Number Analyzed 2 participants 0 participants 1 participants
0
   0.0%
0
   0.0%
HR; Week 112; Decrease to <60; n=2,0,0 Number Analyzed 2 participants 0 participants 0 participants
1
  50.0%
HR; Week 112; Increase to >100; n=2, 0,0 Number Analyzed 2 participants 0 participants 0 participants
0
   0.0%
HR; Week 116; Decrease to <60; n=1, 0,0 Number Analyzed 1 participants 0 participants 0 participants
0
   0.0%
HR; Week 116; Increase to >100; n=1, 0,0 Number Analyzed 1 participants 0 participants 0 participants
0
   0.0%
HR; Week 120; Decrease to <60; n=1, 0,0 Number Analyzed 1 participants 0 participants 0 participants
0
   0.0%
HR; Week 120; Increase to >100; n=1, 0,0 Number Analyzed 1 participants 0 participants 0 participants
0
   0.0%
HR; Week 124; Decrease to <60; n=1, 0,0 Number Analyzed 1 participants 0 participants 0 participants
0
   0.0%
HR; Week 124; Increase to >100; n=1, 0,0 Number Analyzed 1 participants 0 participants 0 participants
0
   0.0%
SBP; Week 4; Any grade increase; n=15,16,16 Number Analyzed 15 participants 16 participants 16 participants
1
   6.7%
8
  50.0%
4
  25.0%
SBP; Week 8; Any grade increase; n=16,16,14 Number Analyzed 16 participants 16 participants 14 participants
3
  18.8%
5
  31.3%
4
  28.6%
SBP; Week 12; Any grade increase; n=16,16,13 Number Analyzed 16 participants 16 participants 13 participants
3
  18.8%
5
  31.3%
2
  15.4%
SBP; Week 16; Any grade increase; n=14,16,13 Number Analyzed 14 participants 16 participants 13 participants
4
  28.6%
3
  18.8%
2
  15.4%
SBP; Week 20; Any grade increase; n=11,15, 13 Number Analyzed 11 participants 15 participants 13 participants
2
  18.2%
3
  20.0%
1
   7.7%
SBP; Week 24; Any grade increase; n=12, 14,13 Number Analyzed 12 participants 14 participants 13 participants
2
  16.7%
3
  21.4%
2
  15.4%
SBP; Week 28; Any grade increase; n=8, 12,7 Number Analyzed 8 participants 12 participants 7 participants
2
  25.0%
0
   0.0%
0
   0.0%
SBP; Week 32; Any grade increase; n=7,11, 8 Number Analyzed 7 participants 11 participants 8 participants
2
  28.6%
3
  27.3%
2
  25.0%
SBP; Week 36; Any grade increase; n=5, 11, 8 Number Analyzed 5 participants 11 participants 8 participants
3
  60.0%
3
  27.3%
1
  12.5%
SBP; Week 40; Any grade increase; n=6,11, 7 Number Analyzed 6 participants 11 participants 7 participants
1
  16.7%
4
  36.4%
2
  28.6%
SBP; Week 44; Any grade increase; n=5, 5, 4 Number Analyzed 5 participants 5 participants 4 participants
2
  40.0%
0
   0.0%
0
   0.0%
SBP; Week 48; Any grade increase; n=5,4, 4 Number Analyzed 5 participants 4 participants 4 participants
1
  20.0%
1
  25.0%
0
   0.0%
SBP; Week 52; Any grade increase; n=4,3, 4 Number Analyzed 4 participants 3 participants 4 participants
1
  25.0%
0
   0.0%
0
   0.0%
SBP; Week 56; Any grade increase; n=4, 3, 4 Number Analyzed 4 participants 3 participants 4 participants
0
   0.0%
0
   0.0%
0
   0.0%
SBP; Week 60; Any grade increase; n=3, 2, 4 Number Analyzed 3 participants 2 participants 4 participants
1
  33.3%
1
  50.0%
0
   0.0%
SBP; Week 64; Any grade increase; n=3, 3, 3 Number Analyzed 3 participants 3 participants 3 participants
1
  33.3%
0
   0.0%
0
   0.0%
SBP; Week 68; Any grade increase; n=4,2, 2 Number Analyzed 4 participants 2 participants 2 participants
2
  50.0%
0
   0.0%
0
   0.0%
SBP; Week 72; Any grade increase; n=3,2, 2 Number Analyzed 3 participants 2 participants 2 participants
1
  33.3%
0
   0.0%
0
   0.0%
SBP; Week 76; Any grade increase; n=4, 1, 2 Number Analyzed 4 participants 1 participants 2 participants
2
  50.0%
0
   0.0%
0
   0.0%
SBP; Week 80; Any grade increase; n=3, 1, 2 Number Analyzed 3 participants 1 participants 2 participants
2
  66.7%
0
   0.0%
0
   0.0%
SBP; Week 84; Any grade increase; n=3, 1,1 Number Analyzed 3 participants 1 participants 1 participants
2
  66.7%
0
   0.0%
0
   0.0%
SBP; Week 88; Any grade increase; n=3, 1,1 Number Analyzed 3 participants 1 participants 1 participants
0
   0.0%
0
   0.0%
0
   0.0%
SBP; Week 92; Any grade increase; n=3, 1, 1 Number Analyzed 3 participants 1 participants 1 participants
2
  66.7%
0
   0.0%
0
   0.0%
SBP; Week 96; Any grade increase; n=3,1, 1 Number Analyzed 3 participants 1 participants 1 participants
2
  66.7%
1
 100.0%
0
   0.0%
SBP; Week 100; Any grade increase; n=3, 1, 1 Number Analyzed 3 participants 1 participants 1 participants
0
   0.0%
0
   0.0%
0
   0.0%
SBP; Week 104; Any grade increase; n=3, 1, 1 Number Analyzed 3 participants 1 participants 1 participants
1
  33.3%
0
   0.0%
0
   0.0%
SBP; Week 108; Any grade increase; n=2,0, 1 Number Analyzed 2 participants 0 participants 1 participants
1
  50.0%
0
   0.0%
SBP; Week 112; Any grade increase; n=2, 0, 0 Number Analyzed 2 participants 0 participants 0 participants
0
   0.0%
SBP; Week 116; Any grade increase; n=1, 0, 0 Number Analyzed 1 participants 0 participants 0 participants
0
   0.0%
SBP; Week 120; Any grade increase; n=1, 0, 0 Number Analyzed 1 participants 0 participants 0 participants
0
   0.0%
SBP; Week 124; Any grade increase; n=1, 0, 0 Number Analyzed 1 participants 0 participants 0 participants
0
   0.0%
DBP; Week 4; Any grade increase; n=15, 16, 16 Number Analyzed 15 participants 16 participants 16 participants
2
  13.3%
10
  62.5%
5
  31.3%
DBP; Week 8; Any grade increase; n=16, 16,14 Number Analyzed 16 participants 16 participants 14 participants
4
  25.0%
8
  50.0%
3
  21.4%
DBP; Week 12; Any grade increase; n=16, 16, 13 Number Analyzed 16 participants 16 participants 13 participants
4
  25.0%
4
  25.0%
2
  15.4%
DBP; Week 16; Any grade increase; n=14, 16,13 Number Analyzed 14 participants 16 participants 13 participants
5
  35.7%
5
  31.3%
3
  23.1%
DBP; Week 20; Any grade increase; n=11, 15,13 Number Analyzed 11 participants 15 participants 13 participants
4
  36.4%
5
  33.3%
2
  15.4%
DBP; Week 24; Any grade increase; n=12, 14,13 Number Analyzed 12 participants 14 participants 13 participants
3
  25.0%
3
  21.4%
1
   7.7%
DBP; Week 28; Any grade increase; n=8, 12,7 Number Analyzed 8 participants 12 participants 7 participants
1
  12.5%
2
  16.7%
0
   0.0%
DBP; Week 32; Any grade increase; n=7, 11,8 Number Analyzed 7 participants 11 participants 8 participants
2
  28.6%
3
  27.3%
1
  12.5%
DBP; Week 36; Any grade increase; n=5, 11,8 Number Analyzed 5 participants 11 participants 8 participants
2
  40.0%
1
   9.1%
2
  25.0%
DBP; Week 40; Any grade increase; n=6, 11,7 Number Analyzed 6 participants 11 participants 7 participants
1
  16.7%
1
   9.1%
1
  14.3%
DBP; Week 44; Any grade increase; n=5, 5,4 Number Analyzed 5 participants 5 participants 4 participants
4
  80.0%
1
  20.0%
2
  50.0%
DBP; Week 48; Any grade increase; n=5, 4,4 Number Analyzed 5 participants 4 participants 4 participants
2
  40.0%
1
  25.0%
2
  50.0%
DBP; Week 52; Any grade increase; n=4,3,4 Number Analyzed 4 participants 3 participants 4 participants
2
  50.0%
0
   0.0%
0
   0.0%
DBP; Week 56; Any grade increase; n=4,3,4 Number Analyzed 4 participants 3 participants 4 participants
1
  25.0%
1
  33.3%
0
   0.0%
DBP; Week 60; Any grade increase; n=3,2,4 Number Analyzed 3 participants 2 participants 4 participants
2
  66.7%
0
   0.0%
0
   0.0%
DBP; Week 64; Any grade increase; n=3,3, 3 Number Analyzed 3 participants 3 participants 3 participants
1
  33.3%
0
   0.0%
1
  33.3%
DBP; Week 68; Any grade increase; n=4,2, 2 Number Analyzed 4 participants 2 participants 2 participants
2
  50.0%
0
   0.0%
1
  50.0%
DBP; Week 72; Any grade increase; n=3,2,2 Number Analyzed 3 participants 2 participants 2 participants
1
  33.3%
0
   0.0%
1
  50.0%
DBP; Week 76; Any grade increase; n=4,1,2 Number Analyzed 4 participants 1 participants 2 participants
2
  50.0%
0
   0.0%
1
  50.0%
DBP; Week 80; Any grade increase; n=3,1,2 Number Analyzed 3 participants 1 participants 2 participants
1
  33.3%
0
   0.0%
1
  50.0%
DBP; Week 84; Any grade increase; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
1
  33.3%
0
   0.0%
0
   0.0%
DBP; Week 88; Any grade increase; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
1
  33.3%
0
   0.0%
0
   0.0%
DBP; Week 92; Any grade increase; n=3, 1,1 Number Analyzed 3 participants 1 participants 1 participants
1
  33.3%
0
   0.0%
1
 100.0%
DBP; Week 96; Any grade increase; n=3, 1,1 Number Analyzed 3 participants 1 participants 1 participants
2
  66.7%
0
   0.0%
1
 100.0%
DBP; Week 100; Any grade increase; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
1
  33.3%
0
   0.0%
0
   0.0%
DBP; Week 104; Any grade increase; n=3,1,1 Number Analyzed 3 participants 1 participants 1 participants
1
  33.3%
0
   0.0%
1
 100.0%
DBP; Week 108; Any grade increase; n=2,0,1 Number Analyzed 2 participants 0 participants 1 participants
1
  50.0%
0
   0.0%
DBP; Week 112; Any grade increase; n=2,0,0 Number Analyzed 2 participants 0 participants 0 participants
0
   0.0%
DBP; Week 116; Any grade increase; n=1,0,0 Number Analyzed 1 participants 0 participants 0 participants
0
   0.0%
DBP; Week 120; Any grade increase; n=1,0,0 Number Analyzed 1 participants 0 participants 0 participants
0
   0.0%
DBP; Week 124; Any grade increase; n=1,0,0 Number Analyzed 1 participants 0 participants 0 participants
0
   0.0%
5.Secondary Outcome
Title Number of Participants With Clinically Significant Abnormal Findings Undergoing Physical Examinations
Hide 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.
Time Frame Up to 3.2 years
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Hide Analysis Population Description
Safety Population. This analysis was planned but data was not captured in the database.
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Hide Arm/Group 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.
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.
Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
Overall Number of Participants Analyzed 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
6.Secondary Outcome
Title Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline
Hide 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.
Time Frame Baseline and up to 3.2 years
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Hide Arm/Group 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.
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.
Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
Overall Number of Participants Analyzed 16 16 16
Measure Type: Count of Participants
Unit of Measure: Participants
0 to 0
5
  31.3%
5
  31.3%
6
  37.5%
0 to 1
0
   0.0%
0
   0.0%
1
   6.3%
0 to 2
0
   0.0%
0
   0.0%
0
   0.0%
0 to 3
0
   0.0%
0
   0.0%
0
   0.0%
0 to 4-5
0
   0.0%
0
   0.0%
0
   0.0%
1 to 0
6
  37.5%
10
  62.5%
5
  31.3%
1 to 1
3
  18.8%
1
   6.3%
2
  12.5%
1 to 2
0
   0.0%
0
   0.0%
0
   0.0%
1 to 3
0
   0.0%
0
   0.0%
0
   0.0%
1 to 4-5
0
   0.0%
0
   0.0%
0
   0.0%
2 to 0
0
   0.0%
0
   0.0%
0
   0.0%
2 to 1
2
  12.5%
0
   0.0%
2
  12.5%
2 to 2
0
   0.0%
0
   0.0%
0
   0.0%
2 to 3
0
   0.0%
0
   0.0%
0
   0.0%
2 to 4-5
0
   0.0%
0
   0.0%
0
   0.0%
3 to 0
0
   0.0%
0
   0.0%
0
   0.0%
3 to 1
0
   0.0%
0
   0.0%
0
   0.0%
3 to 2
0
   0.0%
0
   0.0%
0
   0.0%
3 to 3
0
   0.0%
0
   0.0%
0
   0.0%
3 to 4-5
0
   0.0%
0
   0.0%
0
   0.0%
4-5 to 0
0
   0.0%
0
   0.0%
0
   0.0%
4-5 to 1
0
   0.0%
0
   0.0%
0
   0.0%
4-5 to 2
0
   0.0%
0
   0.0%
0
   0.0%
4-5 to 3
0
   0.0%
0
   0.0%
0
   0.0%
4-5 to 4-5
0
   0.0%
0
   0.0%
0
   0.0%
7.Secondary Outcome
Title Number of Participants With Abnormal Electrocardiograms (ECG) Findings
Hide 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.
Time Frame Up to 3.2 years
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Hide Arm/Group 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.
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.
Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
Overall Number of Participants Analyzed 16 16 16
Measure Type: Count of Participants
Unit of Measure: Participants
Abnormal - Not Clinically Significant
9
  56.3%
10
  62.5%
9
  56.3%
Abnormal - Clinically Significant
0
   0.0%
1
   6.3%
0
   0.0%
8.Secondary Outcome
Title Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline
Hide 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.
Time Frame Baseline and up to 3.2 years
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Hide Arm/Group 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.
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.
Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
Overall Number of Participants Analyzed 16 16 16
Measure Type: Count of Participants
Unit of Measure: Participants
No Change Or Any Increase
11
  68.8%
14
  87.5%
11
  68.8%
>0-<10 Decrease
4
  25.0%
2
  12.5%
3
  18.8%
>=10 Decrease And >= Lower limit of Normal (Lln)
1
   6.3%
0
   0.0%
2
  12.5%
9.Secondary Outcome
Title Number of Participants With Change in Clinical Chemistry Parameters From Baseline
Hide 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).
Time Frame Baseline and up to 3.2 years
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Hide Arm/Group 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.
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.
Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
Overall Number of Participants Analyzed 16 16 16
Measure Type: Count of Participants
Unit of Measure: Participants
ALT; n=16,16,16 Number Analyzed 16 participants 16 participants 16 participants
3
  18.8%
13
  81.3%
9
  56.3%
Albumin; n=16,16,16 Number Analyzed 16 participants 16 participants 16 participants
2
  12.5%
5
  31.3%
2
  12.5%
Alkaline phosphatase; n=16,16,16 Number Analyzed 16 participants 16 participants 16 participants
5
  31.3%
10
  62.5%
4
  25.0%
AST; n=16,16,16 Number Analyzed 16 participants 16 participants 16 participants
8
  50.0%
15
  93.8%
12
  75.0%
Bilirubin; n=16,16,16 Number Analyzed 16 participants 16 participants 16 participants
0
   0.0%
2
  12.5%
0
   0.0%
CRP;n=12,12,13 Number Analyzed 12 participants 12 participants 13 participants
0
   0.0%
0
   0.0%
0
   0.0%
Creatinine; n=16,16,16 Number Analyzed 16 participants 16 participants 16 participants
0
   0.0%
0
   0.0%
0
   0.0%
Direct bilirubin; n=4,6,3 Number Analyzed 4 participants 6 participants 3 participants
0
   0.0%
0
   0.0%
0
   0.0%
GCT; n=16,16,16 Number Analyzed 16 participants 16 participants 16 participants
6
  37.5%
12
  75.0%
5
  31.3%
Hypercalcemia; n=16,16,16 Number Analyzed 16 participants 16 participants 16 participants
0
   0.0%
0
   0.0%
0
   0.0%
Hyperkalemia; n=16,16,16 Number Analyzed 16 participants 16 participants 16 participants
1
   6.3%
4
  25.0%
0
   0.0%
Hypernatremia; n=16,16,16 Number Analyzed 16 participants 16 participants 16 participants
3
  18.8%
4
  25.0%
1
   6.3%
Hypocalcemia; n=16,16,16 Number Analyzed 16 participants 16 participants 16 participants
7
  43.8%
7
  43.8%
4
  25.0%
Hypokalemia; n=16,16,16 Number Analyzed 16 participants 16 participants 16 participants
1
   6.3%
4
  25.0%
3
  18.8%
Hyponatremia; n=16,16,16 Number Analyzed 16 participants 16 participants 16 participants
7
  43.8%
7
  43.8%
5
  31.3%
LDH; 16,16,15 Number Analyzed 16 participants 16 participants 15 participants
0
   0.0%
0
   0.0%
0
   0.0%
Phosphate; n=16,16,16 Number Analyzed 16 participants 16 participants 16 participants
10
  62.5%
6
  37.5%
4
  25.0%
Protein; n=16,16,16 Number Analyzed 16 participants 16 participants 16 participants
0
   0.0%
0
   0.0%
0
   0.0%
Urea; n=15,15,16 Number Analyzed 15 participants 15 participants 16 participants
0
   0.0%
0
   0.0%
0
   0.0%
CRTCE; n=5,2,5 Number Analyzed 5 participants 2 participants 5 participants
0
   0.0%
0
   0.0%
0
   0.0%
10.Secondary Outcome
Title Number of Participants With Change in Hematology Parameters From Baseline
Hide 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.
Time Frame Baseline and up to 3.2 years
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Safety Population
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Hide Arm/Group 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.
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.
Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
Overall Number of Participants Analyzed 16 16 16
Measure Type: Count of Participants
Unit of Measure: Participants
Basophils
0
   0.0%
0
   0.0%
0
   0.0%
Eosinophils
0
   0.0%
0
   0.0%
0
   0.0%
Hemoglobin
4
  25.0%
6
  37.5%
4
  25.0%
Leukocytes
5
  31.3%
9
  56.3%
10
  62.5%
Monocytes
0
   0.0%
0
   0.0%
0
   0.0%
Neutrophils
6
  37.5%
9
  56.3%
9
  56.3%
Platelets
2
  12.5%
5
  31.3%
3
  18.8%
Lymphocytopenia
8
  50.0%
6
  37.5%
6
  37.5%
Lymphocytosis
2
  12.5%
0
   0.0%
0
   0.0%
11.Secondary Outcome
Title Number of Participants With Incidence of Squamous Cell Carcinoma and Keratoacanthoma
Hide 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.
Time Frame Up to 3.2 years
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Safety Population
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Hide Arm/Group 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.
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.
Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
Overall Number of Participants Analyzed 16 16 16
Measure Type: Count of Participants
Unit of Measure: Participants
1
   6.3%
0
   0.0%
0
   0.0%
12.Secondary Outcome
Title Number of Participants With On-treatment Serious Adverse Events (SAEs) and Non-SAEs
Hide 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.
Time Frame Up to 3.2 years
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Safety Population
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Hide Arm/Group 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.
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.
Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
Overall Number of Participants Analyzed 16 16 16
Measure Type: Count of Participants
Unit of Measure: Participants
Any Non-SAE
16
 100.0%
16
 100.0%
15
  93.8%
Any SAE
8
  50.0%
7
  43.8%
4
  25.0%
13.Secondary Outcome
Title Plasma Pharmacokinetic Concentration of Trametinib
Hide Description Blood samples were collected for pharmacokinetic analysis of trametinib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method.
Time Frame 4 to 8 hours post-dose at Weeks 2, 8 and 10
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Biomarker Population. Only those participants with data available at specific time point were analyzed (represented by n=x in category titles).
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Hide Arm/Group 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.
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.
Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
Overall Number of Participants Analyzed 13 14 15
Mean (Standard Deviation)
Unit of Measure: Nanograms per milliliter
WEEK 2 ; 4 to 8 HOURS POST-DOSE; n= 12, 14,13 Number Analyzed 12 participants 14 participants 13 participants
1.4  (4.99) 14.6  (5.15) 16.3  (5.73)
WEEK 8 ; 4 to 8 HOURS POST-DOSE; n=12, 12, 10 Number Analyzed 12 participants 12 participants 10 participants
0.6  (2.06) 12.9  (8.82) 13.8  (6.46)
WEEK 10 ; 4 to 8 HOURS POST-DOSE; n=13, 13, 11 Number Analyzed 13 participants 13 participants 11 participants
10.5  (5.33) 8.8  (7.50) 14.7  (6.66)
14.Secondary Outcome
Title Plasma Pharmacokinetic Concentration of Dabrafenib
Hide Description Blood samples were collected for pharmacokinetic analysis of Dabrafenib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method.
Time Frame 4 to 8 hours post-dose at Weeks 2, 8 and 10
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Hide Analysis Population Description
Biomarker Population. Only those participants with data available at specific time point were analyzed (represented by n=x in category titles).
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Hide Arm/Group 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.
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.
Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
Overall Number of Participants Analyzed 13 14 15
Mean (Standard Deviation)
Unit of Measure: Nanograms per milliliter
WEEK 2 ; 4 to 8 HOURS POST-DOSE; n= 12, 14,13 Number Analyzed 12 participants 14 participants 13 participants
219.7  (545.46) 0.0  (0.00) 438.1  (487.26)
WEEK 8 ; 4 to 8 HOURS POST-DOSE; n=12, 12, 10 Number Analyzed 12 participants 12 participants 10 participants
259.1  (669.60) 0.0  (0.00) 226.5  (236.37)
WEEK 10 ; 4 to 8 HOURS POST-DOSE; n=13, 13, 11 Number Analyzed 13 participants 13 participants 11 participants
92.6  (169.45) 81.8  (168.16) 429.2  (735.69)
Time Frame On-treatment serious adverse events (SAEs) and non-SAEs were collected from the start of the study treatment up to 3.2 years.
Adverse Event Reporting 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.
 
Arm/Group Title Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Hide Arm/Group 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. 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. Eligible participants received trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
All-Cause Mortality
Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/16 (6.25%)      0/16 (0.00%)      2/16 (12.50%)    
Show Serious Adverse Events Hide Serious Adverse Events
Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   8/16 (50.00%)      7/16 (43.75%)      4/16 (25.00%)    
Blood and lymphatic system disorders       
Histiocytosis haematophagic  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Neutropenia  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Cardiac disorders       
Left ventricular dysfunction  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Endocrine disorders       
Adrenal insufficiency  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Gastrointestinal disorders       
Vomiting  1  0/16 (0.00%)  0 1/16 (6.25%)  3 0/16 (0.00%)  0
Abdominal pain  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Diarrhoea  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Subileus  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
General disorders       
Pyrexia  1  2/16 (12.50%)  3 3/16 (18.75%)  4 0/16 (0.00%)  0
Hepatobiliary disorders       
Hepatocellular injury  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Infections and infestations       
Cellulitis  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Urinary tract infection  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Back pain  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Adenocarcinoma gastric  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Basal cell carcinoma  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Lung adenocarcinoma stage 0  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Metastases to meninges  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Squamous cell carcinoma  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Nervous system disorders       
Haemorrhage intracranial  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Peripheral sensory neuropathy  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Spinal cord compression  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Psychiatric disorders       
Panic attack  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Reproductive system and breast disorders       
Metrorrhagia  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Pneumothorax  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Pulmonary sarcoidosis  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Vascular disorders       
Hypotension  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Peripheral ischaemia  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
1
Term from vocabulary, MedDRA19.0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Dabrafenib Followed by Combination Therapy Trametinib Followed by Combination Therapy Combination Therapy
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   16/16 (100.00%)      16/16 (100.00%)      15/16 (93.75%)    
Blood and lymphatic system disorders       
Neutropenia  1  1/16 (6.25%)  1 3/16 (18.75%)  14 3/16 (18.75%)  4
Anaemia  1  4/16 (25.00%)  4 1/16 (6.25%)  1 2/16 (12.50%)  3
Eosinophilia  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Leukopenia  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Lymphadenitis  1  0/16 (0.00%)  0 1/16 (6.25%)  1 1/16 (6.25%)  1
Thrombocytopenia  1  0/16 (0.00%)  0 1/16 (6.25%)  1 1/16 (6.25%)  1
Histiocytosis Haematophagic  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Cardiac disorders       
Bradycardia  1  1/16 (6.25%)  1 1/16 (6.25%)  1 0/16 (0.00%)  0
Palpitations  1  1/16 (6.25%)  1 1/16 (6.25%)  1 0/16 (0.00%)  0
Sinus Bradycardia  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Tachycardia  1  1/16 (6.25%)  1 0/16 (0.00%)  0 1/16 (6.25%)  1
Extrasystoles  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Tricuspid Valve Incompetence  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Atrial Fibrillation  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Mitral Valve Incompetence  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Ear and labyrinth disorders       
Vertigo  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Endocrine disorders       
Adrenal Insufficiency  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Hyperthyroidism  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Eye disorders       
Visual Impairment  1  2/16 (12.50%)  3 1/16 (6.25%)  2 2/16 (12.50%)  2
Eye Pain  1  0/16 (0.00%)  0 2/16 (12.50%)  3 1/16 (6.25%)  1
Dry Eye  1  1/16 (6.25%)  1 2/16 (12.50%)  2 1/16 (6.25%)  1
Iridocyclitis  1  0/16 (0.00%)  0 1/16 (6.25%)  2 0/16 (0.00%)  0
Vision Blurred  1  0/16 (0.00%)  0 2/16 (12.50%)  2 0/16 (0.00%)  0
Eyelid Ptosis  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Keratitis  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Ocular Hyperaemia  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Visual Acuity Reduced  1  1/16 (6.25%)  1 1/16 (6.25%)  1 1/16 (6.25%)  1
Eyelid Oedema  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Uveitis  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Chalazion  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Chorioretinopathy  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Conjunctival Hyperaemia  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Diplopia  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Vitreous Detachment  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Gastrointestinal disorders       
Diarrhoea  1  6/16 (37.50%)  9 7/16 (43.75%)  19 5/16 (31.25%)  7
Nausea  1  8/16 (50.00%)  12 4/16 (25.00%)  11 5/16 (31.25%)  5
Vomiting  1  4/16 (25.00%)  6 4/16 (25.00%)  9 3/16 (18.75%)  3
Constipation  1  2/16 (12.50%)  6 5/16 (31.25%)  6 2/16 (12.50%)  3
Abdominal Pain  1  2/16 (12.50%)  4 2/16 (12.50%)  6 1/16 (6.25%)  1
Abdominal Pain Upper  1  4/16 (25.00%)  4 4/16 (25.00%)  5 0/16 (0.00%)  0
Abdominal Distension  1  2/16 (12.50%)  4 0/16 (0.00%)  0 1/16 (6.25%)  1
Dry Mouth  1  2/16 (12.50%)  3 4/16 (25.00%)  4 3/16 (18.75%)  3
Gastrooesophageal Reflux Disease  1  1/16 (6.25%)  1 2/16 (12.50%)  3 0/16 (0.00%)  0
Dysphagia  1  0/16 (0.00%)  0 2/16 (12.50%)  2 0/16 (0.00%)  0
Odynophagia  1  1/16 (6.25%)  1 0/16 (0.00%)  0 1/16 (6.25%)  2
Aerophagia  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Aphthous Ulcer  1  1/16 (6.25%)  1 1/16 (6.25%)  1 0/16 (0.00%)  0
Ascites  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Colitis  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Dyspepsia  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Gastrointestinal Disorder  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Gastrointestinal Haemorrhage  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Gingival Pain  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Mouth Ulceration  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Painful Defaecation  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Rectal Haemorrhage  1  1/16 (6.25%)  1 0/16 (0.00%)  0 1/16 (6.25%)  1
Tooth Demineralisation  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Tooth Discolouration  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Toothache  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Anal Fissure  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Food Poisoning  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Haematochezia  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Salivary Hypersecretion  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Tongue Discolouration  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Cheilitis  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Gingival Bleeding  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
General disorders       
Pyrexia  1  5/16 (31.25%)  12 13/16 (81.25%)  49 6/16 (37.50%)  18
Hyperthermia  1  4/16 (25.00%)  13 4/16 (25.00%)  15 4/16 (25.00%)  22
Asthenia  1  10/16 (62.50%)  14 10/16 (62.50%)  20 9/16 (56.25%)  17
Chills  1  3/16 (18.75%)  4 10/16 (62.50%)  15 4/16 (25.00%)  8
Oedema Peripheral  1  4/16 (25.00%)  7 6/16 (37.50%)  8 4/16 (25.00%)  4
Chest Pain  1  3/16 (18.75%)  6 1/16 (6.25%)  2 0/16 (0.00%)  0
Mucosal Inflammation  1  1/16 (6.25%)  1 4/16 (25.00%)  4 1/16 (6.25%)  1
Influenza Like Illness  1  3/16 (18.75%)  3 2/16 (12.50%)  2 3/16 (18.75%)  3
Xerosis  1  3/16 (18.75%)  3 2/16 (12.50%)  2 0/16 (0.00%)  0
Malaise  1  0/16 (0.00%)  0 0/16 (0.00%)  0 2/16 (12.50%)  2
Chest Discomfort  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Feeling Of Body Temperature Change  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Ill-Defined Disorder  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Discomfort  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Face Oedema  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Inflammation  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Inflammatory Pain  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Mucosal Dryness  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Nodule  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Hernia  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Hypothermia  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Oedema Due To Cardiac Disease  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Hepatobiliary disorders       
Hepatocellular Injury  1  1/16 (6.25%)  1 3/16 (18.75%)  3 2/16 (12.50%)  2
Cholestasis  1  0/16 (0.00%)  0 1/16 (6.25%)  1 1/16 (6.25%)  1
Hepatitis  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Immune system disorders       
Allergy To Arthropod Sting  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Infections and infestations       
Folliculitis  1  1/16 (6.25%)  1 7/16 (43.75%)  8 2/16 (12.50%)  2
Nasopharyngitis  1  1/16 (6.25%)  1 5/16 (31.25%)  5 3/16 (18.75%)  3
Urinary Tract Infection  1  1/16 (6.25%)  1 4/16 (25.00%)  4 3/16 (18.75%)  4
Bronchitis  1  2/16 (12.50%)  3 0/16 (0.00%)  0 1/16 (6.25%)  1
Gastroenteritis  1  2/16 (12.50%)  2 0/16 (0.00%)  0 1/16 (6.25%)  1
Influenza  1  2/16 (12.50%)  2 0/16 (0.00%)  0 0/16 (0.00%)  0
Cellulitis  1  0/16 (0.00%)  0 1/16 (6.25%)  2 0/16 (0.00%)  0
Conjunctivitis  1  0/16 (0.00%)  0 2/16 (12.50%)  2 0/16 (0.00%)  0
Cystitis  1  0/16 (0.00%)  0 1/16 (6.25%)  2 0/16 (0.00%)  0
Pharyngitis  1  0/16 (0.00%)  0 2/16 (12.50%)  2 1/16 (6.25%)  1
Rash Pustular  1  1/16 (6.25%)  1 2/16 (12.50%)  2 0/16 (0.00%)  0
Fungal Skin Infection  1  0/16 (0.00%)  0 0/16 (0.00%)  0 2/16 (12.50%)  2
Paronychia  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  2
Rhinitis  1  0/16 (0.00%)  0 1/16 (6.25%)  1 2/16 (12.50%)  2
Erysipelas  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Molluscum Contagiosum  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Respiratory Syncytial Virus Infection  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Streptococcal Sepsis  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Tonsillitis  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Tracheitis  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Vulvovaginal Candidiasis  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Vulvovaginal Mycotic Infection  1  1/16 (6.25%)  1 1/16 (6.25%)  1 0/16 (0.00%)  0
Fungal Oesophagitis  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Lung Infection  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Moraxella Infection  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Sinusitis  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Escherichia Urinary Tract Infection  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Febrile Infection  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Viral Rhinitis  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Viral Upper Respiratory Tract Infection  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Injury, poisoning and procedural complications       
Foot Fracture  1  1/16 (6.25%)  2 0/16 (0.00%)  0 0/16 (0.00%)  0
Arthropod Bite  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Ligament Sprain  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Limb Injury  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Procedural Pain  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Traumatic Haematoma  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Fall  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Investigations       
Alanine Aminotransferase Increased  1  0/16 (0.00%)  0 5/16 (31.25%)  15 0/16 (0.00%)  0
Aspartate Aminotransferase Increased  1  0/16 (0.00%)  0 5/16 (31.25%)  14 0/16 (0.00%)  0
Gamma-Glutamyltransferase Increased  1  1/16 (6.25%)  1 2/16 (12.50%)  10 1/16 (6.25%)  1
Blood Creatine Phosphokinase Increased  1  5/16 (31.25%)  8 7/16 (43.75%)  9 5/16 (31.25%)  7
Blood Alkaline Phosphatase Increased  1  1/16 (6.25%)  1 2/16 (12.50%)  7 0/16 (0.00%)  0
Lipase Increased  1  1/16 (6.25%)  2 2/16 (12.50%)  4 2/16 (12.50%)  2
Blood Lactate Dehydrogenase Increased  1  1/16 (6.25%)  1 2/16 (12.50%)  3 1/16 (6.25%)  1
C-Reactive Protein Increased  1  1/16 (6.25%)  1 3/16 (18.75%)  3 0/16 (0.00%)  0
Ejection Fraction Decreased  1  0/16 (0.00%)  0 3/16 (18.75%)  3 1/16 (6.25%)  1
Electrocardiogram Qt Prolonged  1  0/16 (0.00%)  0 1/16 (6.25%)  3 0/16 (0.00%)  0
Weight Decreased  1  2/16 (12.50%)  2 1/16 (6.25%)  2 1/16 (6.25%)  1
Amylase Increased  1  0/16 (0.00%)  0 1/16 (6.25%)  2 1/16 (6.25%)  1
Blood Triglycerides Increased  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  2
Neutrophil Count Decreased  1  0/16 (0.00%)  0 1/16 (6.25%)  1 1/16 (6.25%)  2
Intraocular Pressure Increased  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
White Blood Cell Count Increased  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Blood Albumin Decreased  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Platelet Count Decreased  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Weight Increased  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Blood Fibrinogen Increased  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Hepatic Enzyme Increased  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Metabolism and nutrition disorders       
Decreased Appetite  1  1/16 (6.25%)  1 4/16 (25.00%)  7 2/16 (12.50%)  3
Hypocalcaemia  1  3/16 (18.75%)  4 3/16 (18.75%)  3 1/16 (6.25%)  1
Hyperkalaemia  1  0/16 (0.00%)  0 2/16 (12.50%)  3 0/16 (0.00%)  0
Increased Appetite  1  1/16 (6.25%)  2 0/16 (0.00%)  0 0/16 (0.00%)  0
Hyponatraemia  1  0/16 (0.00%)  0 2/16 (12.50%)  2 1/16 (6.25%)  1
Diabetes Mellitus  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Hypercholesterolaemia  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Hyperglycaemia  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Hypernatraemia  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Hypoalbuminaemia  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Hypoglycaemia  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Hypokalaemia  1  0/16 (0.00%)  0 1/16 (6.25%)  1 1/16 (6.25%)  1
Hypomagnesaemia  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Iron Deficiency  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Vitamin D Deficiency  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Weight Fluctuation  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Hypercalcaemia  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Hypophosphataemia  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Musculoskeletal and connective tissue disorders       
Back Pain  1  7/16 (43.75%)  9 4/16 (25.00%)  5 2/16 (12.50%)  2
Muscle Spasms  1  5/16 (31.25%)  7 6/16 (37.50%)  9 2/16 (12.50%)  2
Arthralgia  1  5/16 (31.25%)  7 3/16 (18.75%)  8 3/16 (18.75%)  3
Myalgia  1  4/16 (25.00%)  5 5/16 (31.25%)  8 4/16 (25.00%)  7
Pain In Extremity  1  3/16 (18.75%)  7 5/16 (31.25%)  7 3/16 (18.75%)  5
Neck Pain  1  1/16 (6.25%)  1 2/16 (12.50%)  6 2/16 (12.50%)  3
Musculoskeletal Stiffness  1  3/16 (18.75%)  3 3/16 (18.75%)  5 2/16 (12.50%)  2
Groin Pain  1  1/16 (6.25%)  2 0/16 (0.00%)  0 0/16 (0.00%)  0
Musculoskeletal Pain  1  2/16 (12.50%)  2 0/16 (0.00%)  0 1/16 (6.25%)  1
Flank Pain  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  2
Limb Discomfort  1  1/16 (6.25%)  1 1/16 (6.25%)  1 0/16 (0.00%)  0
Muscle Contracture  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Muscular Weakness  1  1/16 (6.25%)  1 1/16 (6.25%)  1 1/16 (6.25%)  1
Musculoskeletal Chest Pain  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Osteoarthritis  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Spinal Pain  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Tendonitis  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Joint Stiffness  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Myopathy  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Skin Papilloma  1  5/16 (31.25%)  6 0/16 (0.00%)  0 0/16 (0.00%)  0
Papilloma  1  3/16 (18.75%)  3 0/16 (0.00%)  0 0/16 (0.00%)  0
Basal Cell Carcinoma  1  0/16 (0.00%)  0 0/16 (0.00%)  0 2/16 (12.50%)  3
Malignant Melanoma  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Metastases To Meninges  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Tumour Pain  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Haemangioma  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Nervous system disorders       
Headache  1  9/16 (56.25%)  16 9/16 (56.25%)  15 6/16 (37.50%)  9
Tremor  1  0/16 (0.00%)  0 1/16 (6.25%)  1 3/16 (18.75%)  7
Paraesthesia  1  2/16 (12.50%)  5 0/16 (0.00%)  0 1/16 (6.25%)  1
Dizziness  1  3/16 (18.75%)  3 1/16 (6.25%)  1 2/16 (12.50%)  2
Hyperaesthesia  1  3/16 (18.75%)  3 1/16 (6.25%)  1 0/16 (0.00%)  0
Burning Sensation  1  1/16 (6.25%)  2 0/16 (0.00%)  0 0/16 (0.00%)  0
Dysaesthesia  1  2/16 (12.50%)  2 0/16 (0.00%)  0 1/16 (6.25%)  2
Cervical Radiculopathy  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Epilepsy  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Neuralgia  1  1/16 (6.25%)  1 0/16 (0.00%)  0 1/16 (6.25%)  1
Sciatica  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Syncope  1  1/16 (6.25%)  1 1/16 (6.25%)  1 1/16 (6.25%)  1
Amnesia  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Aphasia  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Memory Impairment  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Migraine With Aura  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Presyncope  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Stupor  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Demyelinating Polyneuropathy  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Head Discomfort  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Hypoaesthesia  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Muscle Contractions Involuntary  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Peripheral Sensory Neuropathy  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Psychiatric disorders       
Insomnia  1  1/16 (6.25%)  2 1/16 (6.25%)  1 0/16 (0.00%)  0
Anxiety  1  1/16 (6.25%)  1 2/16 (12.50%)  2 0/16 (0.00%)  0
Irritability  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Mood Altered  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Sleep Disorder  1  1/16 (6.25%)  1 1/16 (6.25%)  1 1/16 (6.25%)  1
Stress  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Depression  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Hallucination  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Renal and urinary disorders       
Dysuria  1  1/16 (6.25%)  1 2/16 (12.50%)  2 1/16 (6.25%)  1
Haematuria  1  0/16 (0.00%)  0 1/16 (6.25%)  2 0/16 (0.00%)  0
Pollakiuria  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Renal Failure  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Renal Tubular Acidosis  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Urinary Retention  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Reproductive system and breast disorders       
Amenorrhoea  1  1/16 (6.25%)  1 1/16 (6.25%)  1 0/16 (0.00%)  0
Erectile Dysfunction  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Vulvovaginal Dryness  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Breast Pain  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Vaginal Haemorrhage  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Vulvovaginal Pruritus  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Adenomyosis  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Cough  1  4/16 (25.00%)  6 3/16 (18.75%)  4 2/16 (12.50%)  2
Epistaxis  1  0/16 (0.00%)  0 4/16 (25.00%)  5 2/16 (12.50%)  4
Dyspnoea  1  3/16 (18.75%)  3 3/16 (18.75%)  3 0/16 (0.00%)  0
Nasal Dryness  1  1/16 (6.25%)  1 2/16 (12.50%)  3 1/16 (6.25%)  1
Rhinitis Allergic  1  0/16 (0.00%)  0 2/16 (12.50%)  3 0/16 (0.00%)  0
Dry Throat  1  1/16 (6.25%)  1 2/16 (12.50%)  2 0/16 (0.00%)  0
Dyspnoea Exertional  1  1/16 (6.25%)  1 2/16 (12.50%)  2 0/16 (0.00%)  0
Oropharyngeal Pain  1  1/16 (6.25%)  1 2/16 (12.50%)  2 0/16 (0.00%)  0
Pneumonitis  1  0/16 (0.00%)  0 1/16 (6.25%)  2 0/16 (0.00%)  0
Rhinorrhoea  1  0/16 (0.00%)  0 2/16 (12.50%)  2 0/16 (0.00%)  0
Asthma  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Catarrh  1  1/16 (6.25%)  1 1/16 (6.25%)  1 1/16 (6.25%)  1
Lower Respiratory Tract Congestion  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Productive Cough  1  1/16 (6.25%)  1 0/16 (0.00%)  0 0/16 (0.00%)  0
Atelectasis  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Oropharyngeal Discomfort  1  0/16 (0.00%)  0 1/16 (6.25%)  1 0/16 (0.00%)  0
Dysphonia  1  0/16 (0.00%)  0 0/16 (0.00%)  0 1/16 (6.25%)  1
Skin and subcutaneous tissue disorders       
Rash  1  4/16 (25.00%)  5 8/16 (50.00%)  15 3/16 (18.75%)  3
Palmar-Plantar Erythrodysaesthesia Syndrome  1  6/16 (37.50%)  9 2/16 (12.50%)  3 1/16 (6.25%)  1
Palmoplantar Keratoderma  1  7/16 (43.75%)  7 0/16 (0.00%)  0 0/16 (0.00%)  0
Alopecia  1  4/16 (25.00%)  6 6/16 (37.50%)  7 1/16 (6.25%)  1
Dermatitis Acneiform  1  0/16 (0.00%)  0 4/16 (25.00%)  7 1/16 (6.25%)  1
Night Sweats  1  0/16 (0.00%)  0 3/16 (18.75%)  5 0/16 (0.00%)  0
Skin Lesion  1  0/16 (0.00%)  0 0/16 (0.00%)  0 2/16 (12.50%)  5
Erythema Nodosum  1  3/16 (18.75%)  4 1/16 (6.25%)  2 0/16 (0.00%)  0
Hyperkeratosis  1  3/16 (18.75%)  4 1/16 (6.25%)  1 2/16 (12.50%)  2
Keratosis Pilaris  1  4/16 (25.00%)  4 0/16 (0.00%)  0 0/16 (0.00%)  0
Dry Skin  1  3/16 (18.75%)  3 4/16 (25.00%)  4 3/16 (18.75%)  3
Pruritus  1  2/16 (12.50%)  2 3/16 (18.75%)  4 2/16 (12.50%)  3
Pigmentation Disorder  1  3/16 (18.75%)  3 0/16 (0.00%)  0 0/16 (0.00%)  0
Panniculitis  1  0/16 (0.00%)  0 2/16 (12.50%)  3 0/16 (0.00%)  0
Erythema  1  0/16 (0.00%)  0 1/16 (6.25%)  1 2/16 (12.50%)  3
Onychoclasis  1  1/16 (6.25%)  2 0/16 (0.00%)  0 0/16 (0.00%)  0
Eczema  1  0/16 (0.00%)  0 2/16 (12.50%)  2 1/16 (6.25%)  1
Rash Macular  1  0/16 (0.00%)  0 2/16 (12.50%)  2 1/16 (6.25%)  1
Skin Fissures  1  0/16 (0.00%)  0 2/16 (12.50%)  2 0/16 (0.00%)  0
Urticaria  1  1/16 (6.25%)  1 1/16 (6.25%)  1 1/16 (6.25%)  2
Hyperhidrosis  1  1/16 (6.25%)  1