Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01072175
First received: February 12, 2010
Last updated: September 19, 2013
Last verified: September 2013
Results First Received: June 27, 2013  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Endpoint Classification: Pharmacokinetics/Dynamics Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Cancer
Interventions: Drug: GSK2118436
Drug: GSK1120212

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
The study was comprised of Parts A, B, and D, which constitute the Phase I part of the study, and Part C, which constitutes the randomized Phase II part of the study. Participants did not enroll in all parts of the study sequentially. Each part of the study was comprised of a separate population of participants.

Reporting Groups
  Description
Part A: Dabrafenib 75 mg + Trametinib 2 mg Participants received a single dose of dabrafenib 75 mg gelatin capsules with repeat dose trametinib (Day 15).
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.
Part C (Randomized): Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C (Randomized): Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C (Randomized): Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg Participants who received dabrafenib 150 mg capsules BID alone in the Randomized Phase were given the opportunity to receive combination dosing of dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD upon disease progression with approval of the GlaxoSmithKline (GSK) Medical Monitor.
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.

Participant Flow for 5 periods

Period 1:   Part A (Drug-Drug Interaction)
    Part A: Dabrafenib 75 mg + Trametinib 2 mg     Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg     Part C (Randomized): Dabrafenib 150 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 1 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 2 mg     Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg     Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
STARTED     8     0     0     0     0     0     0     0     0     0     0     0     0  
COMPLETED     0     0     0     0     0     0     0     0     0     0     0     0     0  
NOT COMPLETED     8     0     0     0     0     0     0     0     0     0     0     0     0  
Physician Decision                 6                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0  
Withdrawal by Subject                 1                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0  
Death                 1                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0  

Period 2:   Part B (Dose Escalation and Expansion)
    Part A: Dabrafenib 75 mg + Trametinib 2 mg     Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg     Part C (Randomized): Dabrafenib 150 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 1 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 2 mg     Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg     Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
STARTED     0     6     23     27     79     0     0     0     0     0     0     0     0  
Ongoing     0     2     10     9     28     0     0     0     0     0     0     0     0  
COMPLETED     0     0     0     0     0     0     0     0     0     0     0     0     0  
NOT COMPLETED     0     6     23     27     79     0     0     0     0     0     0     0     0  
Physician Decision                 0                 1                 3                 4                 13                 0                 0                 0                 0                 0                 0                 0                 0  
Withdrawal by Subject                 0                 0                 0                 2                 2                 0                 0                 0                 0                 0                 0                 0                 0  
Death                 0                 3                 10                 12                 36                 0                 0                 0                 0                 0                 0                 0                 0  
Ongoing                 0                 2                 10                 9                 28                 0                 0                 0                 0                 0                 0                 0                 0  

Period 3:   Part C (Phase II: Randomized Phase)
    Part A: Dabrafenib 75 mg + Trametinib 2 mg     Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg     Part C (Randomized): Dabrafenib 150 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 1 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 2 mg     Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg     Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
STARTED     0     0     0     0     0     54     54     54     0     0     0     0     0  
Ongoing     0     0     0     0     0     35     32     40     0     0     0     0     0  
COMPLETED     0     0     0     0     0     0     0     0     0     0     0     0     0  
NOT COMPLETED     0     0     0     0     0     54     54     54     0     0     0     0     0  
Withdrawal by Subject                 0                 0                 0                 0                 0                 0                 4                 0                 0                 0                 0                 0                 0  
Death                 0                 0                 0                 0                 0                 19                 18                 14                 0                 0                 0                 0                 0  
Ongoing                 0                 0                 0                 0                 0                 35                 32                 40                 0                 0                 0                 0                 0  

Period 4:   Part C (Phase II: Crossover Phase [CP])
    Part A: Dabrafenib 75 mg + Trametinib 2 mg     Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg     Part C (Randomized): Dabrafenib 150 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 1 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 2 mg     Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg     Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
STARTED     0     0     0     0     0     0     0     0     43     0     0     0     0  
Ongoing     0     0     0     0     0     0     0     0     28     0     0     0     0  
COMPLETED     0     0     0     0     0     0     0     0     0     0     0     0     0  
NOT COMPLETED     0     0     0     0     0     0     0     0     43     0     0     0     0  
Death                 0                 0                 0                 0                 0                 0                 0                 0                 15                 0                 0                 0                 0  
Ongoing                 0                 0                 0                 0                 0                 0                 0                 0                 28                 0                 0                 0                 0  

Period 5:   Part D (HPMC Capsules)
    Part A: Dabrafenib 75 mg + Trametinib 2 mg     Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg     Part C (Randomized): Dabrafenib 150 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 1 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 2 mg     Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg     Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
STARTED     0     0     0     0     0     0     0     0     0     12     16     43     39  
Ongoing     0     0     0     0     0     0     0     0     0     10     12     34     34  
COMPLETED     0     0     0     0     0     0     0     0     0     0     0     0     0  
NOT COMPLETED     0     0     0     0     0     0     0     0     0     12     16     43     39  
Lost to Follow-up                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 2                 0  
Withdrawal by Subject                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 1                 0  
Death                 0                 0                 0                 0                 0                 0                 0                 0                 0                 2                 4                 6                 5  
Ongoing                 0                 0                 0                 0                 0                 0                 0                 0                 0                 10                 12                 34                 34  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Part A: Dabrafenib 75 mg + Trametinib 2 mg Participants received a single dose of dabrafenib 75 mg gelatin capsules with repeat dose trametinib (Day 15).
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Total Total of all reporting groups

Baseline Measures
    Part A: Dabrafenib 75 mg + Trametinib 2 mg     Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg     Part C: Dabrafenib 150 mg     Part C: Dabrafenib 150 mg + Trametinib 1 mg     Part C: Dabrafenib 150 mg + Trametinib 2 mg     Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg     Total  
Number of Participants  
[units: participants]
  8     6     23     27     79     54     54     54     12     16     43     39     415  
Age  
[units: Years]
Mean ± Standard Deviation
  52.8  ± 16.04     48.2  ± 7.28     54.2  ± 13.24     52.2  ± 12.09     51.5  ± 12.82     51.8  ± 15.19     49.9  ± 14.70     55.9  ± 11.85     51.8  ± 12.39     53.1  ± 17.04     52.8  ± 14.57     56.7  ± 14.08     52.8  ± 13.74  
Gender  
[units: Participants]
                         
Female     2     2     10     12     44     25     24     20     6     8     18     14     185  
Male     6     4     13     15     35     29     30     34     6     8     25     25     230  
Race/Ethnicity, Customized  
[units: Participants]
                         
White     7     6     22     26     77     52     54     53     12     16     43     39     407  
Asian & White     1     0     0     0     0     0     0     0     0     0     0     0     1  
African American     0     0     0     1     0     0     0     0     0     0     0     0     1  
Asian     0     0     0     0     2     0     0     1     0     0     0     0     3  
Missing     0     0     1     0     0     2     0     0     0     0     0     0     3  



  Outcome Measures
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1.  Primary:   Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib in Part A   [ Time Frame: Day 15 ]

Measure Type Primary
Measure Title Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib in Part A
Measure Description Blood samples for PK analysis of dabrafenib and its the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at pre-dose and at 1, 2, 3, 4, 6, 8, 10, and 24 hours after dabrafenib administration. From the plasma concentration-time curve, the PK parameter Cmax was determined by standard non-compartmental analysis using WinNonlin. Cmax data are reported as geometric least squares means.
Time Frame Day 15  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Pharmacokinetic (PK) Population: all participants who received at least one dose of either dabrafenib or trametinib and for whom a PK sample was obtained and analyzed

Reporting Groups
  Description
Part A: Dabrafenib 75 mg Participants received a single dose of dabrafenib 75 mg gelatin capsules alone on Day 1.
Part A: Dabrafenib 75 mg + Trametinib 2 mg Participants received a single dose of dabrafenib 75 mg gelatin capsules with repeat dose trametinib (Day 15).

Measured Values
    Part A: Dabrafenib 75 mg     Part A: Dabrafenib 75 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  8     8  
Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib in Part A  
[units: Nanograms per milliliter (ng/mL)]
Geometric Mean ( 95% Confidence Interval )
   
GSK2118436     509  
  ( 379 to 685 )  
  524  
  ( 390 to 705 )  
GSK2285403     259  
  ( 190 to 352 )  
  255  
  ( 196 to 331 )  
GSK2298683     724  
  ( 595 to 879 )  
  747  
  ( 587 to 951 )  
GSK2167542     8.37  
  ( 4.82 to 14.5 )  
  8.16  
  ( 5.68 to 11.7 )  


Statistical Analysis 1 for Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib in Part A
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Geometric Mean Ratio [3] 1.03
90% Confidence Interval ( 0.79 to 1.34 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Cmax of dabrafenib was log e transformed and analyzed by a linear mixed effect model with fixed effect for treatment (dabrafenib alone and combined with trametinib) and participant as a random effect. Geometric mean ratio (Day 15/Day 1) and 90% confidence interval were provided.
[3] Other relevant estimation information:
  Geometric mean ratio (Day 15 Cmax/Day 1 Cmax) and 90% confidence interval for dabrafenib were calculated.

Statistical Analysis 2 for Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib in Part A
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Geometric Mean Ratio [3] .99
90% Confidence Interval ( 0.78 to 1.25 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Cmax of GSK2285403 was log e transformed and analyzed by a linear mixed effect model with fixed effect for treatment (dabrafenib alone and combined with trametinib) and participant as a random effect. Geometric mean ratio (Day 15/Day 1) and 90% confidence interval were provided.
[3] Other relevant estimation information:
  Geometric mean ratio (Day 15 Cmax/Day 1 Cmax) and 90% confidence interval for GSK2285403 were calculated.

Statistical Analysis 3 for Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib in Part A
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Geometric Mean Ratio [3] 1.03
90% Confidence Interval ( 0.84 to 1.27 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Cmax of GSK2298683 was log e transformed and analyzed by a linear mixed effect model with fixed effect for treatment (dabrafenib alone and combined with trametinib) and participant as a random effect. Geometric mean ratio (Day 15/Day 1) and 90% confidence interval were provided.
[3] Other relevant estimation information:
  Geometric mean ratio (Day 15 Cmax/Day 1 Cmax) and 90% confidence interval for GSK2298683 were calculated.

Statistical Analysis 4 for Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib in Part A
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Geometric Mean Ratio [3] .98
90% Confidence Interval ( 0.66 to 1.45 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Cmax of GSK2167542 was log e transformed and analyzed by a linear mixed effect model with fixed effect for treatment (dabrafenib alone and combined with trametinib) and participant as a random effect. Geometric mean ratio (Day 15/Day 1) and 90% confidence interval were provided.
[3] Other relevant estimation information:
  Geometric mean ratio (Day 15 Cmax/Day 1 Cmax) and 90% confidence interval for GSK2167542 were calculated.



2.  Primary:   AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites in Part A   [ Time Frame: Day 15 ]

Measure Type Primary
Measure Title AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites in Part A
Measure Description Blood samples for PK analysis of dabrafenib and its metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at pre-dose and at 1, 2, 3, 4, 6, 8, 10, and 24 hours after dabrafenib administration. AUC is defined as the area under the dabrafenib concentration-time curve as a measure of drug exposure. AUC (0-inf) is defined as the area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time. AUC (0-t) is defined as area under the concentration-time curve from time zero (pre-dose) to the last time of quantifiable concentration. Date are reported as geometric least square means.
Time Frame Day 15  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population

Reporting Groups
  Description
Part A: Dabrafenib 75 mg Participants received a single dose of dabrafenib 75 mg gelatin capsules alone on Day 1.
Part A: Dabrafenib 75 mg + Trametinib 2 mg Participants received a single dose of dabrafenib 75 mg gelatin capsules with repeat dose trametinib (Day 15).

Measured Values
    Part A: Dabrafenib 75 mg     Part A: Dabrafenib 75 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  8     8  
AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites in Part A  
[units: ng*hour/mL (ng*hr/mL)]
Geometric Mean ( 95% Confidence Interval )
   
GSK2118436 AUC (0-t), n=8, 8     2734  
  ( 2205 to 3390 )  
  2751  
  ( 2219 to 3411 )  
GSK2118436 AUC (0-inf), n=7, 8     3128  
  ( 2578 to 3797 )  
  2949  
  ( 2445 to 3556 )  
GSK2285403 AUC (0-t), n=8, 8     2232  
  ( 1684 to 2959 )  
  2287  
  ( 1899 to 2753 )  
GSK2285403 AUC (0-inf), n=6, 8     2819  
  ( 2231 to 3562 )  
  2497  
  ( 2097 to 2974 )  
GSK2298683 AUC (0-t), n=8, 8     12761  
  ( 10347 to 15738 )  
  13053  
  ( 10475 to 16266 )  
GSK2298683 AUC (0-inf), n=0, 0     NA  
  ( NA to NA ) [1]
  NA  
  ( NA to NA ) [1]
GSK2167542 AUC (0-t), n=8, 8     270  
  ( 188 to 390 )  
  276  
  ( 230 to 332 )  
GSK2167542 AUC (0-inf), n=8, 8     NA  
  ( NA to NA ) [1]
  NA  
  ( NA to NA ) [1]
[1] PK parameter AUC(0-inf) could not be calculated in some participants.


Statistical Analysis 1 for AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites in Part A
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Geometric Mean Ratio [3] 1.01
90% Confidence Interval ( 0.85 to 1.19 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  AUC(0-t) of dabrafenib was log e transformed and analyzed by a linear mixed effect model with fixed effect for treatment (dabrafenib alone and combined with trametinib) and participant as a random effect. Geometric mean ratio (Day 15/Day 1) and 90% confidence interval were provided.
[3] Other relevant estimation information:
  Geometric mean ratio (Day 15 AUC(0-inf)/ Day 1 AUC(0-inf)) and 90% confidence interval for dabrafenib were calculated.

Statistical Analysis 2 for AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites in Part A
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Geometric Mean Ratio [3] 0.94
90% Confidence Interval ( 0.82 to 1.08 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  AUC(0-inf) of dabrafenib was log e transformed and analyzed by a linear mixed effect model with fixed effect for treatment (dabrafenib alone and combined with trametinib) and participant as a random effect. Geometric mean ratio (Day 15/Day 1) and 90% confidence interval were provided.
[3] Other relevant estimation information:
  Geometric mean ratio (Day 15 AUC(0-inf)/ Day 1 AUC(0-inf)) and 90% confidence interval for dabrafenib were calculated.

Statistical Analysis 3 for AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites in Part A
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Geometric Mean Ratio [3] 1.02
90% Confidence Interval ( 0.84 to 1.25 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  AUC(0-t) of GSK2285403 was log e transformed and analyzed by a linear mixed effect model with fixed effect for treatment (dabrafenib alone and combined with trametinib) and participant as a random effect. Geometric mean ratio (Day 15/Day 1) and 90% confidence interval were provided.
[3] Other relevant estimation information:
  Geometric mean ratio (Day 15 AUC(0-t)/ Day 1 AUC(0-t)) and 90% confidence interval for GSK2285403 were calculated.

Statistical Analysis 4 for AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites in Part A
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Geometric Mean Ratio [3] 0.92
90% Confidence Interval ( 0.81 to 1.03 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  AUC(0-inf) of GSK2285403 was log e transformed and analyzed by a linear mixed effect model with fixed effect for treatment (dabrafenib alone and combined with trametinib) and participant as a random effect. Geometric mean ratio (Day 15/Day 1) and 90% confidence interval were provided.
[3] Other relevant estimation information:
  Geometric mean ratio (Day 15 AUC(0-inf)/ Day 1 AUC(0-inf)) and 90% confidence interval for GSK2285403 were calculated.

Statistical Analysis 5 for AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites in Part A
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Geometric Mean Ratio [3] 1.02
90% Confidence Interval ( 0.81 to 1.29 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  AUC(0-t) of GSK2298683 was log e transformed and analyzed by a linear mixed effect model with fixed effect for treatment (dabrafenib alone and combined with trametinib) and participant as a random effect. Geometric mean ratio (Day 15/Day 1) and 90% confidence interval were provided.
[3] Other relevant estimation information:
  Geometric mean ratio (Day 15 AUC(0-t)/ Day 1 AUC(0-t)) and 90% confidence interval for GSK2298683 were calculated.

Statistical Analysis 6 for AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites in Part A
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Geometric Mean Ratio [3] 1.02
90% Confidence Interval ( 0.76 to 1.37 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  AUC(0-t) of GSK2167542 was log e transformed and analyzed by a linear mixed effect model with fixed effect for treatment (dabrafenib alone and combined with trametinib) and participant as a random effect. Geometric mean ratio (Day 15/Day 1) and 90% confidence interval were provided.
[3] Other relevant estimation information:
  Geometric mean ratio (Day 15 AUC(0-t)/ Day 1 AUC(0-t)) and 90% confidence interval for GSK2167542 were calculated.



3.  Primary:   Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part B   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks ) ]

Measure Type Primary
Measure Title Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part B
Measure Description An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An 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/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks )  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All Treated Participants (ATP) Population: all participants who received at least one dose of either dabrafenib or trametinib

Reporting Groups
  Description
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Measured Values
    Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  6     23     27     79  
Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part B  
[units: Participants]
       
Any AE     6     23     27     79  
Any SAE     0     12     12     44  

No statistical analysis provided for Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part B



4.  Primary:   Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part B   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks) ]

Measure Type Primary
Measure Title Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part B
Measure Description Clinical chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. For clinical chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Clinical chemistry parameters included: hyponatremia, gamma glutamyltransferase (GGT), phosphorous inorganic, alkaline phosphatase, hyperglycemia, aspartate aminotransferase (AST), hypokalemia, albumin, alanine aminotransferase (ALT), total bilirubin, hyperkalemia, hypoglycemia, creatinine, lactate dehydrogenase, urea/blood urea nitrogen (BUN), bicarbonate, chloride, creatine clearance, total protein, uric acid, and troponin T.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ATP Population. Only those participants who were available at the indicated time points were analyzed.

Reporting Groups
  Description
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Measured Values
    Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  6     23     27     79  
Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part B  
[units: Participants]
       
Hyponatremia, G3, n=6, 23, 27, 78     0     2     5     11  
GGT, G3, n=6, 23, 27, 78     1     0     1     12  
Phosphorus, inorganic, G3, n=6, 23, 27, 78     0     2     6     4  
Alkaline phosphatase, G3, n=6, 23, 27, 78     1     2     0     8  
Hyperglycemia, G3, n=6, 23, 27, 78     0     1     2     4  
AST, G3, n=6, 23, 27, 78     0     0     1     4  
Hypokalemia, G3, n=6, 23, 27, 78     0     0     1     4  
Albumin, G3, n=6, 23, 27, 78     0     0     1     3  
ALT, G3, n=6, 23, 27, 78     0     0     1     1  
Total bilirubin, G3, n=6, 23, 27, 77     0     0     0     2  
Hyperkalemia, G3, n=6, 23, 27, 78     0     0     0     1  
Hypoglycemia, G3, n=6, 23, 27, 78     0     0     0     1  
Creatinine, G4, n=6, 23, 27, 78     0     0     1     0  
Lactate dehydrogenase, High, n=6, 23, 27, 78     4     9     10     26  
Urea/BUN, High, n=6, 23, 27, 78     1     9     15     21  
Bicarbonate, High, n=6, 21, 26, 72     3     6     8     19  
Chloride, High, n=6, 23, 27, 78     2     10     8     13  
Creatine clearance, High, n=5, 22, 24, 70     2     5     4     10  
Total protein, High, n=6, 23, 27, 78     3     1     1     5  
Uric acid, High, n=6, 23, 27, 78     2     2     0     5  
Troponin T, High, n=0, 0, 2, 0     0     0     1     0  
Chloride, Low, n=6, 23, 27, 78     0     4     8     30  
Total protein, Low, n=6, 23, 27, 78     0     9     6     23  
Uric acid, Low, n=6, 23, 27, 78     1     4     9     16  
Creatine clearance, Low, n=5, 22, 24, 70     2     3     9     14  
Urea/BUN, Low, n=6, 23, 27, 78     2     3     3     12  
Bicarbonate, Low, n=6, 21, 26, 72     1     1     5     12  
Lactate dehydrogenase, Low, n=6, 23, 27, 78     1     0     0     1  

No statistical analysis provided for Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part B



5.  Primary:   Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part B   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks) ]

Measure Type Primary
Measure Title Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part B
Measure Description Hematology parameters were summarized according to NCI CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. For hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Hematology parameters included: lymphocytes decreased, total neutrophils, hemoglobin decreased, white blood cell counts, platelet counts, monocytes, mean corpuscular hemoglobin concentration (MCHC), eosinophils, basophils, mean corpuscular hemoglobin, mean corpuscular volume, red blood cell count, hemotocrit, and reticulocytes.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ATP Population. Only those participants who were available at the indicated time points were analyzed.

Reporting Groups
  Description
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Measured Values
    Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  6     23     27     79  
Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part B  
[units: Participants]
       
Lymphocytes decreased, G3, n=6, 23, 27, 79     0     5     3     18  
Total neutrophils, G3, n=6, 23, 27, 79     1     1     2     9  
Hemoglobin decreased, G3, n=6, 23, 27, 79     0     0     1     7  
White blood cell count, G3, n=6, 23, 27, 79     0     2     3     5  
Platelet count, G3, n=6, 23, 27, 79     0     0     1     2  
Lymphocytes decreased, G4, n=6, 23, 27, 79     0     1     2     3  
Platelet count, G4, n=6, 23, 27, 79     0     0     0     1  
Monocytes, High, n=6, 23, 27, 79     1     3     8     22  
MCHC, High, n=6, 23, 27, 79     2     4     5     10  
Eosinophils, High, n=6, 23, 27, 79     0     4     6     8  
Basophils, High, n=6, 23, 27, 79     0     1     4     4  
Mean corpuscle hemoglobin, High, n=6, 23, 27, 78     1     3     6     9  
Mean corpuscle volume, High, n=6, 23, 27, 79     1     3     4     5  
Red blood cell count, High, n=6, 23, 27, 79     0     0     1     2  
Hematocrit, High, n=6, 23, 27, 79     0     0     2     2  
Reticulocytes, High, n=6, 17, 22, 27     2     7     6     6  
Red blood cell count, Low, n=6, 23, 27, 79     1     7     5     19  
Hematocrit, Low, n=6, 23, 27, 79     1     4     6     20  
Monocytes, Low, n=6, 23, 27, 79     2     8     8     19  
MCHC, Low, n=6, 23, 27, 79     0     6     9     16  
Mean corpuscle volume, Low, n=6, 23, 27, 78     1     5     5     13  
Mean corpuscle hemoglobin, Low, n=6, 23, 27, 79     0     6     7     11  
Eosinophils, Low, n=6, 23, 27, 79     1     5     6     19  
Reticulocytes, Low, n=6, 17, 22, 27     2     1     5     3  

No statistical analysis provided for Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part B



6.  Primary:   Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part B   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks) ]

Measure Type Primary
Measure Title Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part B
Measure Description Blood pressure and heart rate were summarized according to NCI CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred. Blood pressure measurement included systolic blood pressure (SBP, millimeters of mercury [mmHg]) and diastolic BP (DBP). Heart rate is the measure of heart beats per minute (bpm). Changes in heart rate, either decrease to <60 bpm, change to normal or no change, or increase to >100 bpm are presented.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ATP Population

Reporting Groups
  Description
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Measured Values
    Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  6     23     27     78  
Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part B  
[units: Participants]
       
Heart rate, Decrease to <60 bpm     1     2     5     15  
Heart rate, Change to normal or no change     3     14     15     37  
Heart rate, Increase to >100 bpm     2     7     8     26  
SBP, Increase to G3 or G4     0     2     3     8  
DBP, Increase to G3 or G4     0     1     3     4  

No statistical analysis provided for Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part B



7.  Primary:   Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator in Part C (Randomized)   [ Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 47 weeks) ]

Measure Type Primary
Measure Title Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator in Part C (Randomized)
Measure Description Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be <10 millimeters [mm] in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by an investigator as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
Time Frame From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 47 weeks)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-Treat (ITT) Population: all randomized participants regardless of whether or not treatment was administered

Reporting Groups
  Description
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part C: Dabrafenib 150 mg     Part C: Dabrafenib 150 mg + Trametinib 1 mg     Part C: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  54     54     54  
Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator in Part C (Randomized)  
[units: Participants]
     
CR     2     3     5  
PR     27     24     36  


Statistical Analysis 1 for Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator in Part C (Randomized)
Groups [1] Part C: Dabrafenib 150 mg vs. Part C: Dabrafenib 150 mg + Trametinib 1 mg
Method [2] unconditional exact method
P Value [3] 0.7730
Difference in response rate Arm2 - Arm1 [4] -4
95% Confidence Interval ( -23.1 to 15.9 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



8.  Primary:   Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR) in Part C (Randomized)   [ Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 36 weeks) ]

Measure Type Primary
Measure Title Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR) in Part C (Randomized)
Measure Description Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by BICR as per RECIST, version 1.1.
Time Frame From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 36 weeks)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population

Reporting Groups
  Description
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part C: Dabrafenib 150 mg     Part C: Dabrafenib 150 mg + Trametinib 1 mg     Part C: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  54     54     54  
Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR) in Part C (Randomized)  
[units: Participants]
     
CR     4     4     7  
PR     21     17     26  


Statistical Analysis 1 for Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR) in Part C (Randomized)
Groups [1] Part C: Dabrafenib 150 mg vs. Part C: Dabrafenib 150 mg + Trametinib 1 mg
Method [2] unconditional exact method
P Value [3] 0.5008
Difference in response rate Arm2- Arm1 [4] -7
95% Confidence Interval ( -26.7 to 12.3 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR) in Part C (Randomized)
Groups [1] Part C: Dabrafenib 150 mg vs. Part C: Dabrafenib 150 mg + Trametinib 2 mg
Method [2] unconditional exact method
P Value [3] 0.1486
Difference in response rate Arm3 - Arm1 [4] 15
95% Confidence Interval ( -5.0 to 33.7 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



9.  Primary:   Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator in Part C (Crossover)   [ Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 15 weeks) ]

Measure Type Primary
Measure Title Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator in Part C (Crossover)
Measure Description Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by an investigator as per RECIST, version 1.1.
Time Frame From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 15 weeks)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Crossover Population: participants who were randomized to and received at least one dose of dabrafenib monotherapy, and who elected to crossover to combination therapy following disease progression while on monotherapy

Reporting Groups
  Description
Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg Participants who received dabrafenib 150 mg capsules BID alone in the Randomized Phase were given the opportunity to receive combination dosing of dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD upon disease progression with approval of the GlaxoSmithKline (GSK) Medical Monitor.

Measured Values
    Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  43  
Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator in Part C (Crossover)  
[units: Participants]
 
CR     0  
PR     4  


Statistical Analysis 1 for Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator in Part C (Crossover)
Groups [1] Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg
Response rate [2] 9
95% Confidence Interval ( 2.6 to 22.1 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant estimation information:
  No text entered.



10.  Primary:   Duration of Response as Assessed by the Investigator and Blinded Independent Central Review (BICR) in Part C (Randomized)   [ Time Frame: First documented evidence of PR or CR until the date of the first documented sign of disease progression or the date of death due to any cause (up to approximately 17 months) ]

Measure Type Primary
Measure Title Duration of Response as Assessed by the Investigator and Blinded Independent Central Review (BICR) in Part C (Randomized)
Measure Description Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.
Time Frame First documented evidence of PR or CR until the date of the first documented sign of disease progression or the date of death due to any cause (up to approximately 17 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population. Only those participants who had a CR or PR were analyzed for duration of response.

Reporting Groups
  Description
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part C: Dabrafenib 150 mg     Part C: Dabrafenib 150 mg + Trametinib 1 mg     Part C: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  29     27     41  
Duration of Response as Assessed by the Investigator and Blinded Independent Central Review (BICR) in Part C (Randomized)  
[units: Months]
Median ( 95% Confidence Interval )
     
Investigator assessed, n=29, 27, 41     5.6  
  ( 4.5 to 7.4 )  
  9.5  
  ( 7.4 to NA ) [1]
  10.5  
  ( 7.4 to 14.9 )  
BICR assessed, n=25, 21, 33     7.6  
  ( 5.5 to NA ) [1]
  11.3  
  ( 6.2 to NA ) [1]
  7.6  
  ( 6.9 to NA ) [1]
[1] At the time of this report, the data was not yet mature; therefore, the upper limit (UL) of the CI could not be estimated.

No statistical analysis provided for Duration of Response as Assessed by the Investigator and Blinded Independent Central Review (BICR) in Part C (Randomized)



11.  Primary:   Progression-free Survival (PFS) as Assessed by the Investigator in Part C (Randomized)   [ Time Frame: From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 17 months) ]

Measure Type Primary
Measure Title Progression-free Survival (PFS) as Assessed by the Investigator in Part C (Randomized)
Measure Description PFS is defined as the interval between the first dose of study medication and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not had a documented date of events, PFS and survival were censored at the date of the last adequate assessment.
Time Frame From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 17 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population

Reporting Groups
  Description
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part C: Dabrafenib 150 mg     Part C: Dabrafenib 150 mg + Trametinib 1 mg     Part C: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  54     54     54  
Progression-free Survival (PFS) as Assessed by the Investigator in Part C (Randomized)  
[units: Months]
Median ( Full Range )
  5.8  
  ( 4.6 to 7.4 )  
  9.2  
  ( 6.4 to 11.0 )  
  9.4  
  ( 8.6 to 16.7 )  


Statistical Analysis 1 for Progression-free Survival (PFS) as Assessed by the Investigator in Part C (Randomized)
Groups [1] Part C: Dabrafenib 150 mg vs. Part C: Dabrafenib 150 mg + Trametinib 1 mg
Method [2] Log Rank
P Value [3] 0.0057
Hazard Ratio (HR) [4] 0.56
95% Confidence Interval ( 0.37 to 0.87 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  HRs were estimated using the Pike estimator.

Statistical Analysis 2 for Progression-free Survival (PFS) as Assessed by the Investigator in Part C (Randomized)
Groups [1] Part C: Dabrafenib 150 mg vs. Part C: Dabrafenib 150 mg + Trametinib 2 mg
Method [2] Log Rank
P Value [3] <0.0001
Hazard Ratio (HR) [4] 0.39
95% Confidence Interval ( 0.25 to 0.62 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  HRs were estimated using the Pike estimator.



12.  Primary:   Progression-free Survival (PFS) as Assessed by the Blinded Independent Central Review (BICR) in Part C (Randomized)   [ Time Frame: From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 17 months) ]

Measure Type Primary
Measure Title Progression-free Survival (PFS) as Assessed by the Blinded Independent Central Review (BICR) in Part C (Randomized)
Measure Description PFS is defined as the interval between the first dose of study medication and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the BICR according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not had a documented date of events, PFS and survival were censored at the date of the last adequate assessment
Time Frame From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 17 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population

Reporting Groups
  Description
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part C: Dabrafenib 150 mg     Part C: Dabrafenib 150 mg + Trametinib 1 mg     Part C: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  54     54     54  
Progression-free Survival (PFS) as Assessed by the Blinded Independent Central Review (BICR) in Part C (Randomized)  
[units: Months]
Median ( 95% Confidence Interval )
  7.3  
  ( 5.5 to 9.4 )  
  8.3  
  ( 5.6 to 11.3 )  
  9.2  
  ( 7.6 to NA ) [1]
[1] At the time of this report, the data was not yet mature; therefore, t he upper limit (UL) of the CI could not be estimated.


Statistical Analysis 1 for Progression-free Survival (PFS) as Assessed by the Blinded Independent Central Review (BICR) in Part C (Randomized)
Groups [1] Part C: Dabrafenib 150 mg vs. Part C: Dabrafenib 150 mg + Trametinib 1 mg
Method [2] Log Rank
P Value [3] 0.1721
Hazard Ratio (HR) [4] 0.73
95% Confidence Interval ( 0.45 to 1.19 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  HRs were estimated using the Pike estimator.

Statistical Analysis 2 for Progression-free Survival (PFS) as Assessed by the Blinded Independent Central Review (BICR) in Part C (Randomized)
Groups [1] Part C: Dabrafenib 150 mg vs. Part C: Dabrafenib 150 mg + Trametinib 2 mg
Method [2] Log Rank
P Value [3] 0.0121
Hazard Ratio (HR) [4] 0.54
95% Confidence Interval ( 0.32 to 0.91 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  HRs were estimated using the Pike estimator.



13.  Primary:   Progression-free Survival (PFS) as Assessed by the Investigator in Part C (Crossover)   [ Time Frame: From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 9 months) ]

Measure Type Primary
Measure Title Progression-free Survival (PFS) as Assessed by the Investigator in Part C (Crossover)
Measure Description PFS is defined as the interval between the first dose of study medication and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants received anti-cancer therapy prior to the date of documented events, and censored at the last adequate assessment, prior to the initiation of therapy. If the participant did not have a documented date of events, PFS and survival were censored at the date of the last adequate assessment.
Time Frame From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 9 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Crossover Population

Reporting Groups
  Description
Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg Participants who received dabrafenib 150 mg capsules BID alone in the Randomized Phase were given the opportunity to receive combination dosing of dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD upon disease progression with approval of the GlaxoSmithKline (GSK) Medical Monitor.

Measured Values
    Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  43  
Progression-free Survival (PFS) as Assessed by the Investigator in Part C (Crossover)  
[units: Months]
Median ( 95% Confidence Interval )
  3.6  
  ( 1.8 to 3.9 )  

No statistical analysis provided for Progression-free Survival (PFS) as Assessed by the Investigator in Part C (Crossover)



14.  Primary:   Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part C (Randomized)   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximatley 75 weeks) ]

Measure Type Primary
Measure Title Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part C (Randomized)
Measure Description An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximatley 75 weeks)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ATP Population

Reporting Groups
  Description
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part C: Dabrafenib 150 mg     Part C: Dabrafenib 150 mg + Trametinib 1 mg     Part C: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  54     54     54  
Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part C (Randomized)  
[units: Participants]
     
Any AE     53     53     55  
Any SAE     13     20     34  

No statistical analysis provided for Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part C (Randomized)



15.  Primary:   Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part C (Randomized)   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 75 weeks) ]

Measure Type Primary
Measure Title Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part C (Randomized)
Measure Description Clinical chemistry parameters were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to any grade, Grade 3 or Grade 4 occurred. For clinical chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Clinical chemistry parameters included: albumin, alkaline phosphate (ALKP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total Bilirubin, calcium, creatine kinase, creatinine, gamma glutamyltransferase (GGT), glucose, potassium, magnesium, sodium, inorganic phosphorus. Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 75 weeks)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ATP Population. Only those participants who were available at the indicated time points were analyzed.

Reporting Groups
  Description
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part C: Dabrafenib 150 mg     Part C: Dabrafenib 150 mg + Trametinib 1 mg     Part C: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  53     54     55  
Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part C (Randomized)  
[units: Participants]
     
Albumin, any Grade, n=53, 54, 55     12     23     29  
Albumin, G3, n=53, 54, 55     0     1     0  
ALP, any Grade, n=53, 54, 55     14     36     33  
ALKP, G3, n=53, 54, 55     1     3     1  
ALT, any Grade, n=53, 54, 55     6     19     23  
ALT, G3, n=53, 54, 55     0     2     2  
AST, any Grade, n=53, 54, 55     8     29     33  
AST, G3, n=53, 54, 55     0     0     3  
Total Bilirubin, any Grade, n=53, 54, 55     0     4     8  
Total Bilirubin, G3, n=53, 54, 55     0     2     0  
Calcium (hypercalcemia), any Grade, n=53, 54, 55     2     10     8  
Calcium (hypercalcemia), G4, n=53, 54, 55     0     1     0  
Calcium (hypocalcemia), any Grade, n=53, 54, 55     5     11     7  
Creatine Kinase, any Grade, n=0, 0, 1     NA [1]   NA [1]   1  
Creatinine, any Grade, n=53, 54, 55     5     11     13  
Creatinine, G3, n=53, 54, 55     0     1     2  
Creatinine, G4, n=53, 54, 55     0     0     1  
GGT, any Grade, n=53, 54, 55     20     29     31  
Gamma glutamyltransferase, G3, n=53, 54, 55     1     9     6  
Glucose (hyperglycemia), any Grade, n=53, 54, 55     26     36     32  
Glucose (hyperglycemia), G3     1     3     3  
Glucose (hypoglycemia), any Grade, n=53, 54, 55     1     8     1  
Potassium (hyperkalemia), any Grade     8     12     10  
Potassium (hyperkalemia), G3, n=53, 54, 55     2     0     0  
Potassium (hypokalemia), any Grade, n=53, 54, 55     12     8     16  
Potassium (hypokalemia), G3, n=53, 54, 55     3     1     0  
Potassium (hypokalemia), G4, n=53, 54, 55     0     0     1  
Magnesium (hypermagnesemia), any Grade, n=53,53,55     4     7     3  
Magnesium (hypermagnesemia), G3, n=53, 54, 55     0     2     1  
Magnesium (hypomagnesemia), any Grade, n=53,53,55     3     1     10  
Magnesium (hypomagnesemia), G3, n=53, 53, 55     0     0     1  
Sodium (hypernatremia), any Grade, n=53, 54, 55     2     4     6  
Sodium (hyponatremia), any Grade, n=53, 54, 55     19     26     30  
Sodium (hyponatremia), G3, n=53, 54, 55     1     8     6  
Phosphorus, inorganic, any Grade, n=53, 54, 55     21     22     26  
Phosphorus, inorganic, G3, n=53, 54, 55     0     6     3  
[1] Baseline grade and increase in grade of these participants was not available as no participants were analyzed.

No statistical analysis provided for Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part C (Randomized)



16.  Primary:   Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part C (Randomized)   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 75 weeks) ]

Measure Type Primary
Measure Title Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part C (Randomized)
Measure Description Hematology parameters were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to any grade, Grade 3 or Grade 4 occurred. For hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Hematology parameters included: hemoglobin, lymphocytes, Total absolute neutrophil count (ANC), platelet count, white blood cells (WBC) count. Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 75 weeks)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ATP Population. Only those participants who were available at the indicated time points were analyzed.

Reporting Groups
  Description
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part C: Dabrafenib 150 mg     Part C: Dabrafenib 150 mg + Trametinib 1 mg     Part C: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  53     54     55  
Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part C (Randomized)  
[units: Participants]
     
Hemoglobin (Increased), any Grade     1     1     1  
Hemoglobin (Anemia), any Grade     15     25     30  
Hemoglobin (Anemia), G3     0     4     2  
Lymphocytes (Increased), any Grade     0     4     1  
Lymphocytes (Decreased), any Grade     21     32     30  
Lymphocytes (Decreased), G3     3     9     9  
Lymphocytes (Decreased), G4     0     1     3  
Total ANC, any Grade     5     20     30  
Total ANC, G3     1     1     4  
Total ANC, G4     0     0     3  
Platelet count, any Grade     4     17     17  
Platelet count, G3     0     0     1  
Platelet count, G4     0     0     1  
WBC count, any Grade     11     25     34  
WBC count, G3     0     2     3  

No statistical analysis provided for Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part C (Randomized)



17.  Primary:   Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part C (Randomized)   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximlately 75 weeks) ]

Measure Type Primary
Measure Title Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part C (Randomized)
Measure Description Blood pressure were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred.lood pressure measurement included systolic blood pressure (BP, milimeter of mercury [mmHg]) and diastolic BP (DBP). Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value. Heart Rate is the measure of heart beats per minute (bpm). Changes in heart rate, either decrease to <60 bpm, change to normal or no change, or increase to >100 bpm are presented.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximlately 75 weeks)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ATP Population

Reporting Groups
  Description
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part C: Dabrafenib 150 mg     Part C: Dabrafenib 150 mg + Trametinib 1 mg     Part C: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  53     54     55  
Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part C (Randomized)  
[units: Participants]
     
Systolic BP (mmHg) , G3 or G4     5     4     12  
Diastolic BP (mmHg), G3 or G4     4     4     4  
Heart rate, Decrease to <60 bpm     9     8     11  
Heart rate, Change to normal or no change     34     30     28  
Heart rate, Increase to >100 bpm     10     16     18  

No statistical analysis provided for Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part C (Randomized)



18.  Primary:   Maximum Plasma Concentration (Cmax) of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)   [ Time Frame: Day 1 and Day 21 ]

Measure Type Primary
Measure Title Maximum Plasma Concentration (Cmax) of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)
Measure Description The PK parameter Cmax was assessed. Blood samples for PK analysis of dabrafenib were obtained at pre-dose Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours (24 hour on Day 1 only) post-dose administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin. Cmax data are reported as geometric least squares means.
Time Frame Day 1 and Day 21  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population: all participants who received at least one dose of either dabrafenib or trametinib and for whom a PK sample was obtained and analyzed

Reporting Groups
  Description
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  15     14     15     15  
Maximum Plasma Concentration (Cmax) of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)  
[units: ng/mL]
Geometric Mean ( 95% Confidence Interval )
       
Day 1, n=15, 14, 15, 15     1117  
  ( 914 to 1365 )  
  1669  
  ( 1059 to 2631 )  
  1227  
  ( 924 to 1764 )  
  2289  
  ( 1622 to 3231 )  
Day 21, n=14, 11, 14, 12     1050  
  ( 811 to 1358 )  
  1746  
  ( 1344 to 2269 )  
  1217  
  ( 895 to 1654 )  
  2052  
  ( 1472 to 2860 )  


Statistical Analysis 1 for Maximum Plasma Concentration (Cmax) of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)
Groups [1] Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg vs. Part D: Dabrafenib 150 mg + Trametinib 2 mg
Non-Inferiority/Equivalence Test [2] Yes
Geometric Mean Ratio [3] 1.51
90% Confidence Interval ( 1.10 to 2.08 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Following loge tranformation, Cmax of dabrafenib after repeat doses from the pooled data in Part B and D were analyzed by a linear model with the following fixed effects as categorical variables: Capsule type (Gelatin or HPMC), BRAF dose (75 or 150 mg BID), Capsule type by BRAF dose interaction, Day (Day 15 or 21), MEK dose (0, 1, 1.5 or 2 mg QD). Geometric mean ratio (HPMC/Gelatin) and the corresponding 90% CI were provided for BRAF dose level 150 mg BID.
[3] Other relevant estimation information:
  Geometric mean ratio (HPMC/Gelatin) and the corresponding 90% CI were provided for BRAF dose level 150 mg BID.



19.  Primary:   The Tmax of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)   [ Time Frame: Day 1 and Day 21 ]

Measure Type Primary
Measure Title The Tmax of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)
Measure Description tmax is defined as the time of occurenceof Cmax. Blood samples for PK analysis of dabrafenib were obtained at Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours (24 hour on Day 1 only) post-dose administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin.
Time Frame Day 1 and Day 21  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population. Only participants available at the indicated timepoints were analyzed.

Reporting Groups
  Description
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  15     14     15     15  
The Tmax of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)  
[units: Hours]
Median ( Full Range )
       
Day 1, n=15, 14, 15, 15     2.00  
  ( 1.00 to 3.00 )  
  2.00  
  ( 1.00 to 6.00 )  
  2.00  
  ( 1.00 to 3.00 )  
  1.50  
  ( 1.00 to 10.00 )  
Day 21, n=14, 11, 14, 12     1.50  
  ( 1.00 to 2.00 )  
  1.55  
  ( 0.98 to 3.00 )  
  1.75  
  ( 1.00 to 3.00 )  
  1.50  
  ( 1.00 to 3.00 )  

No statistical analysis provided for The Tmax of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)



20.  Primary:   AUC (0-tau) and AUC (0-inf) of Single and Repeat Doses of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)   [ Time Frame: Day 1 and Day 21 ]

Measure Type Primary
Measure Title AUC (0-tau) and AUC (0-inf) of Single and Repeat Doses of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)
Measure Description The PK parameters were determined for area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration AUC (0-tau) and from time zero (pre-dose) extrapolated to infinite time AUC (0-inf). Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours (24 hour only on Day 1) post-dose administration.
Time Frame Day 1 and Day 21  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population. Only participants available at the indicated timepoints were analyzed.

Reporting Groups
  Description
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  15     14     15     15  
AUC (0-tau) and AUC (0-inf) of Single and Repeat Doses of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)  
[units: ng*hr/mL]
Geometric Mean ( 95% Confidence Interval )
       
AUC (0-tau), Day 1, n=15, 13, 15, 15     3593  
  ( 3008 to 4293 )  
  6507  
  ( 4288 to 9872 )  
  4618  
  ( 3525 to 6051 )  
  7331  
  ( 5355 to 10037 )  
AUC (0-tau), Day 21, n=14, 11, 14, 12     3020  
  ( 2390 to 3816 )  
  4663  
  ( 3511 to 6194 )  
  3434  
  ( 2679 to 4403 )  
  5886  
  ( 4608 to 7517 )  
AUC (0-inf), Day 1, n=14, 13, 13, 14     3982  
  ( 3325 to 4770 )  
  7291  
  ( 4830 to 11005 )  
  5321  
  ( 4192 to 6755 )  
  8152  
  ( 5860 to 11341 )  
AUC (0-inf), Day 21, n=14, 11, 14, 12     NA  
  ( NA to NA ) [1]
  NA  
  ( NA to NA ) [1]
  NA  
  ( NA to NA ) [1]
  NA  
  ( NA to NA ) [1]
[1] AUC(0-inf) is not applicable to Day 21.


Statistical Analysis 1 for AUC (0-tau) and AUC (0-inf) of Single and Repeat Doses of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)
Groups [1] Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg vs. Part D: Dabrafenib 150 mg + Trametinib 2 mg
Non-Inferiority/Equivalence Test [2] Yes
Geometric Mean Ratio [3] 1.23
90% Confidence Interval ( 0.89 to 1.69 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Following loge transformation, AUC(0-tau) of dabrafenib was analyzed by a linear mixed effect model with dosing chort and day as fixed effects and subject as random effect. Based on the model, geometric mean ratio (Day 21 Dabrafenib 150 mg BID+Trametinib 2 mg QD/Day 21 Dabrafenib 150 mg BID alone) and the corresponding 90% confidence interval were provided.
[3] Other relevant estimation information:
  Geometric mean ratio (Day 21 Dabrafenib 150 mg BID+Trametinib 2 mg QD/Day 21 Dabrafenib 150 mg BID alone) and the corresponding 90% confidence interval were provided.

Statistical Analysis 2 for AUC (0-tau) and AUC (0-inf) of Single and Repeat Doses of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)
Groups [1] Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg vs. Part D: Dabrafenib 150 mg + Trametinib 2 mg
Non-Inferiority/Equivalence Test [2] Yes
Geometric Mean Ratio [3] 1.10
90% Confidence Interval ( 0.84 to 1.44 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  Following loge tranformation, AUC(0-tau) of dabrafenib after repeat doses from the pooled data in Part B and D were analyzed by a linear model with the following fixed effects as categorical variables: Capsule type (Gelatin or HPMC), BRAF dose (75 or 150 mg BID), Capsule type by BRAF dose interaction, Day (Day 15 or 21), MEK dose (0, 1, 1.5, 2 or 2 mg QD). Geometric mean ratio (HPMC/Gelatin) and the corresponding 90% CI were then provided for BRAF dose level 150 mg BID.
[3] Other relevant estimation information:
  Geometric mean ratio (HPMC/Gelatin) and the corresponding 90% CI were provided for BRAF dose level 150 mg BID.



21.  Primary:   Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part D   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks) ]

Measure Type Primary
Measure Title Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part D
Measure Description An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event for possible drug-induced liver injury. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ATP Population

Reporting Groups
  Description
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  15     15     41     39  
Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part D  
[units: Participants]
       
Any AE     15     15     41     38  
Any SAE     7     12     22     25  

No statistical analysis provided for Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part D



22.  Primary:   Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part D   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks) ]

Measure Type Primary
Measure Title Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part D
Measure Description Clinical chemistry parameters were summarized according to NCI CTCAE grade, version 4.0. G1, Mild; G2, Moderate; G3, Severe; G4, Life-threatening or disabling; G5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred. Changes above (High) and below (Low) the normal range were evaluated for parameters not graded. Included:hyponatremia,gamma glutamyltransferase (GGT),aspartate aminotransferase (AST),hyperglycemia,alkaline phosphatase,hypokalemia,alanine aminotransferase (ALT),phosphorus inorganic,creatine kinase,total bilirubin,albumin,hyperkalemia, hypomagnesemia,lipase,hypokalemia,hyponatremia,urea/blood urea nitogen (BUN),bicarbonate,creatine clearance,chloride,C-reactive protein,total protein,uric acid,troponin I,direct bilirubin,creatine kinase MB mass, chloride,total protein,bicarbonate,uric acid,creatine clearance,lactate dehydrogenase. Worst case change from BL was calculated as the post-BL value minus the BL value.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ATP Population. Only those participants available at indicated timepoints were analyzed.

Reporting Groups
  Description
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  15     15     41     39  
Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part D  
[units: Participants]
       
Hyponatremia, G3, n=15, 15, 40, 39     1     4     4     3  
Gamma glutamyltransferase, G3, n=15, 15, 40, 39     2     2     3     3  
AST, G3, n= 15, 15, 40, 39     2     0     3     1  
Hyperglycemia, G3, n=15, 15, 40, 39     1     2     2     1  
Alkaline phosphatase, G3, n=15, 15, 40, 39     1     1     0     2  
Hypokalemia, G3, n=15, 15, 40, 39     0     1     1     2  
ALT, G3, n=15, 15, 40, 39     2     0     1     0  
Phosphorus, inorganic, G3, n=15, 15, 40, 39     0     0     1     2  
Creatine kinase, G3, n=2, 1, 4, 1     0     1     1     0  
Total bilirubin, G3, n=15, 15, 40, 39     1     0     0     1  
Albumin, G3, n=15, 15, 40, 39     0     1     0     0  
Hyperkalemia, G3, n=15, 15, 40, 39     0     0     1     0  
Hypomagnesemia, G3, n=15, 15, 40, 39     0     0     1     0  
Lipase, G4, n=15, 15, 40, 39     0     2     0     1  
Gamma glutamyltransferase, G4, n=15, 15, 40, 39     1     1     0     0  
Hypokalemia, G4, n=15, 15, 40, 39     0     0     1     0  
Hyponatremia, G4, n=15, 15, 40, 39     0     0     0     1  
Lactate dehydrogenase, High, n=15, 15, 40, 39     7     6     17     20  
Urea/BUN, High, n=15, 15, 40, 39     3     4     8     10  
Bicarbonate, High, n=15, 15, 40, 39     4     3     9     8  
Creatine clearance, High, n=2, 1, 11 ,6     2     1     11     6  
Chloride, High,n=15, 15, 40, 39     2     2     5     6  
C-reactive protein, High, n=2, 3, 2 7     2     3     2     7  
Total protein, High, n=15, 15, 40, 39     1     0     4     4  
Uric acid, High, n=15, 15, 40, 39     2     0     1     1  
Troponin I, High, n=15, 15, 40, 39     1     0     1     0  
Direct bilirubin, High, n=15, 1, 1, 39     0     1     0     0  
Creatine kinaseMB mass,change to high,n=15,15,1,39     0     0     1     0  
Chloride, Low, n=15, 15, 40, 39     6     7     11     21  
Total protein, Low, n=15, 15, 40, 39     3     6     14     14  
Bicarbonate, Low, n=15, 15, 40, 39     3     3     7     5  
Uric acid, Low, n=15, 15, 40, 39     1     3     2     11  
Urea/BUN, Low, n=15, 15, 40, 39     2     1     8     4  
Creatine clearance, Low, n=4, 3, 3, 4     4     3     3     4  
Lactate dehydrogenase, Low, n=15, 15, 40, 39     2     2     0     0  

No statistical analysis provided for Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part D



23.  Primary:   Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part D   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks) ]

Measure Type Primary
Measure Title Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part D
Measure Description Hematology parameters were summarized according to NCI CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. For hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Hematology parameters included lymphocytes, total neutrophils, hemoglobin, white blood cell count, platelet count, monocytes, mean corpuscle hemoglobin concentration, eosinophils, basophils, mean corpuscle hemoglobin, mean corpuscle volume, red blood cell count, hematocrit, erythrocyte sedimentation, reticulocytes. Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ATP Population. Only those participants available at indicated timepoints were analyzed.

Reporting Groups
  Description
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  15     15     41     39  
Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part D  
[units: Participants]
       
Lymphocytes decreased, G3, n= 15, 15, 40, 39     1     4     8     7  
Total neutrophils, G3, n= 15, 15, 40, 39     0     1     2     4  
Hemoglobin (Hb) decreased, G3, n= 15, 15, 40, 39     0     1     1     1  
White blood cell count, G3, n= 15, 15, 40, 39     0     0     0     3  
Platelet count, G3, n= 15, 15, 40, 39     1     0     0     0  
Lymphocytes decreased, G4, n= 15, 15, 40, 39     0     1     0     1  
Platelet count, G4, n= 15, 15, 40, 39     0     0     1     0  
Monocytes, G4, n= 15, 15, 40, 39     5     7     15     9  
Mean corpuscle Hb concentration High,n=15,15,40,39     5     2     7     6  
Eosinophils, High, n= 15, 15, 40, 39     3     1     6     4  
Basophils, High, n= 15, 15, 40, 39     1     2     5     2  
Mean corpuscle Hb, High, n= 15, 15, 40, 39     1     0     4     3  
Mean corpuscle volume, High, n= 15, 15, 40, 39     1     0     4     3  
Red blood cell count, High, n= 15, 15, 40, 39     2     0     3     0  
Hematocrit, High, n= 15, 15, 40, 39     1     0     1     1  
Erythrocyte sedimentation, High, n= 15, 15, 40, 1     0     0     0     1  
Reticulocytes, High, n= 15, 15, 4, 39     0     0     1     0  
Red blood cell count, Low, n= 15, 15, 40, 39     5     8     21     13  
Hematocrit, Low, n= 15, 15, 40, 39     4     10     14     16  
Monocytes, Low, n= 15, 15, 40, 39     4     2     10     10  
Mean corpuscle Hb concentration Low, n=15,15,40,39     3     3     6     3  
Mean corpuscle volume, Low, n= 15, 15, 41, 39     2     3     3     5  
Mean corpuscle Hb, Low, n= 15, 15, 40, 39     0     3     5     3  
Eosinophils, Low, n= 15, 15, 41, 39     1     1     3     4  
Reticulocytes, Low, n= 15, 15, 4, 39     0     0     4     0  
Basophils, Low, n= 15, 15, 40, 39     0     0     1     0  

No statistical analysis provided for Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part D



24.  Primary:   Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part D   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks) ]

Measure Type Primary
Measure Title Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part D
Measure Description Blood pressure were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred.lood pressure measurement included systolic blood pressure (BP, milimeter of mercury [mmHg]) and diastolic BP (DBP). Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value. Heart Rate is the measure of heartbeats per minute (bpm). Changes in heart rate, either decrease to <60 bpm, change to normal or no change, or increase to >100 bpm are presented
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ATP Population

Reporting Groups
  Description
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  15     15     40     39  
Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part D  
[units: Participants]
       
Heart rate, Decrease to <60 bpm     2     3     12     14  
Heart rate, Change to normal or no change     9     8     18     17  
Heart rate, Increase to >100 bpm     5     5     12     12  
Systolic BP (mmHg) , increase to G3 or G4     3     1     5     6  
Diastolic BP (mmHg), increase to G3 or G4     4     0     2     3  

No statistical analysis provided for Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part D



25.  Secondary:   Steady State Concentration of Trametinib With Concomitant Administration of Dabrafenib in Part A   [ Time Frame: Day 15 and Day 16 ]

Measure Type Secondary
Measure Title Steady State Concentration of Trametinib With Concomitant Administration of Dabrafenib in Part A
Measure Description The steady state plasma concentration (Css) of trametinib with concomitant dabrafenib administration was assessed at Day 15 and Day 16. At steady state the amount of drug administered (in a given time period) is equal to the amount of drug eliminated.
Time Frame Day 15 and Day 16  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population

Reporting Groups
  Description
Part A: Dabrafenib 75 mg + Trametinib 2 mg Participants received a single dose of dabrafenib 75 mg gelatin capsules with repeat dose trametinib (Day 15).

Measured Values
    Part A: Dabrafenib 75 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  7  
Steady State Concentration of Trametinib With Concomitant Administration of Dabrafenib in Part A  
[units: ng/mL]
Median ( Full Range )
 
Day 15     9.7  
  ( 6 to 18 )  
Day 16     10.2  
  ( 6 to 17 )  

No statistical analysis provided for Steady State Concentration of Trametinib With Concomitant Administration of Dabrafenib in Part A



26.  Secondary:   The AUC [0-tau] of Dabrafenib (DAB) and Its Metabolite in Combination With Trametinib (T) in Part B   [ Time Frame: Day 15 and Day 21 ]

Measure Type Secondary
Measure Title The AUC [0-tau] of Dabrafenib (DAB) and Its Metabolite in Combination With Trametinib (T) in Part B
Measure Description Area under the concentration-time curve from time zero (predose) until the last time of quantifiable concentration (AUC [0-tau]) was assessed. Blood samples for PK analysis of dabrafenib and its the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
Time Frame Day 15 and Day 21  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population. Only those participants who were available at the indicated time point were analyzed.

Reporting Groups
  Description
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Measured Values
    Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  6     8     12     8  
The AUC [0-tau] of Dabrafenib (DAB) and Its Metabolite in Combination With Trametinib (T) in Part B  
[units: ng*hr/mL]
Geometric Mean ( 95% Confidence Interval )
       
DAB, Day 15, n=6, 4, 5, 4     2466  
  ( 1458 to 4171 )  
  3539  
  ( 1634 to 7666 )  
  5187  
  ( 3737 to 7199 )  
  4114  
  ( 1560 to 10848 )  
DAB, Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  4656  
  ( 3901 to 5557 )  
  4528  
  ( 3602 to 5692 )  
  5518  
  ( 3732 to 8158 )  
GSK2285403, Day 15, n=6, 4, 5, 4     2120  
  ( 1366 to 3290 )  
  2163  
  ( 1267 to 3694 )  
  3136  
  ( 2501 to 3932 )  
  3180  
  ( 1389 to 7283 )  
GSK2285403, Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  3257  
  ( 2162 to 4907 )  
  2989  
  ( 2545 to 3510 )  
  3632  
  ( 2364 to 5581 )  
GSK2298683, Day 15, n=6, 4, 5, 4     37159  
  ( 22389 to 61673 )  
  40634  
  ( 30329 to 54441 )  
  43727  
  ( 31486 to 60727 )  
  68528  
  ( 42444 to 110642 )  
GSK2298683 , Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  47911  
  ( 30643 to 74909 )  
  49939  
  ( 39219 to 63589 )  
  59965  
  ( 45117 to 79699 )  
GSK2167542, Day 15, n=6, 4, 5, 4     2859  
  ( 1568 to 5216 )  
  2961  
  ( 1206 to 7270 )  
  4156  
  ( 2802 to 6165 )  
  3746  
  ( 1992 to 7043 )  
GSK2167542, Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  3609  
  ( 2279 to 5714 )  
  2995  
  ( 1891 to 4743 )  
  3961  
  ( 2361 to 6645 )  
[1] No participants were analyzed in this treatment arm at this time point.

No statistical analysis provided for The AUC [0-tau] of Dabrafenib (DAB) and Its Metabolite in Combination With Trametinib (T) in Part B



27.  Secondary:   Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) and Maximum Plasma Concentration (Cmax) of Dabrafenib and Its Metabolite in Combination With Trametinib in Part B   [ Time Frame: Day 15 and Day 21 ]

Measure Type Secondary
Measure Title Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) and Maximum Plasma Concentration (Cmax) of Dabrafenib and Its Metabolite in Combination With Trametinib in Part B
Measure Description Pre-dose (trough) concentration at the end of the dosing interval (Ctau) and maximum plasma concentration (Cmax) were assessed for plasma dabrafenib (DAB) following repeat dosing of DAB administered in combination with trametinib (T). The trough concentration is defined as the plasma level of a pharmaceutical product measured just before the next dose. Blood samples for PK analysis of the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) of dabrafenib were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
Time Frame Day 15 and Day 21  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population. Only those participants who were available at the indicated time points were analyzed.

Reporting Groups
  Description
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Measured Values
    Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  6     8     12     8  
Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) and Maximum Plasma Concentration (Cmax) of Dabrafenib and Its Metabolite in Combination With Trametinib in Part B  
[units: ng/mL]
Geometric Mean ( 95% Confidence Interval )
       
DAB Ctau, Day 15, n=6, 4, 5, 4     59.8  
  ( 19.1 to 187 )  
  44.6  
  ( 17.1 to 117 )  
  115  
  ( 27.8 to 472 )  
  73.7  
  ( 10.3 to 528 )  
DAB Ctau, Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  185  
  ( 79.7 to 428 )  
  102  
  ( 57.1 to 184 )  
  79.9  
  ( 32.2 to 198 )  
DAB Cmax, Day 15, n=6, 4, 5, 4     640  
  ( 390 to 1048 )  
  906  
  ( 221 to 3717 )  
  1306  
  ( 700 to 2437 )  
  1046  
  ( 545 to 2011 )  
DAB Cmax, Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  1263  
  ( 863 to 1848 )  
  1346  
  ( 997 to 1817 )  
  1391  
  ( 1002 to 1932 )  
GSK2285403 Ctau, Day 15, n=6, 4, 5, 4     72.9  
  ( 25.2 to 211 )  
  47.8  
  ( 20.2 to 113 )  
  97.9  
  ( 32.2 to 297 )  
  74.4  
  ( 15.7 to 353 )  
GSK2285403 Ctau, Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  136  
  ( 62.4 to 299 )  
  92.9  
  ( 60.2 to 143 )  
  82.7  
  ( 37.6 to 182 )  
GSK2285403 Cmax, Day 15, n=6, 4, 5, 4     399  
  ( 265 to 601 )  
  418  
  ( 146 to 1201 )  
  597  
  ( 300 to 1186 )  
  630  
  ( 411 to 964 )  
GSK2285403 Cmax, Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  775  
  ( 441 to 1364 )  
  668  
  ( 507 to 882 )  
  722  
  ( 502 to 1039 )  
GSK2298683 Ctau, Day 15, n=6, 4, 5, 4     2345  
  ( 1237 to 4447 )  
  2360  
  ( 1134 to 4911 )  
  2792  
  ( 2069 to 3768 )  
  4372  
  ( 2589 to 7384 )  
GSK2298683 Ctau, Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  2920  
  ( 1674 to 5095 )  
  3221  
  ( 2619 to 3962 )  
  3740  
  ( 2564 to 5455 )  
GSK2298683 Cmax, Day 15, n=6, 4, 5, 4     3757  
  ( 2385 to 5916 )  
  4545  
  ( 3817 to 5411 )  
  4636  
  ( 3258 to 6598 )  
  7098  
  ( 4914 to 10254 )  
GSK2298683 Cmax, Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  5301  
  ( 3392 to 8286 )  
  5416  
  ( 4163 to 7048 )  
  6257  
  ( 4937 to 7931 )  
GSK2167542 Ctau, Day 15, n=6, 4, 5, 4     257  
  ( 140 to 473 )  
  249  
  ( 79.4 to 782 )  
  331  
  ( 185 to 590 )  
  318  
  ( 260 to 389 )  
GSK2167542 Ctau, Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  196  
  ( 90.8 to 425 )  
  248  
  ( 140 to 439 )  
  369  
  ( 191 to 714 )  
GSK2167542 Cmax, Day 15, n=6, 4, 5, 4     300  
  ( 157 to 572 )  
  355  
  ( 114 to 1108 )  
  523  
  ( 251 to 1091 )  
  460  
  ( 190 to 1113 )  
GSK2167542 Cmax, Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  543  
  ( 298 to 989 )  
  373  
  ( 248 to 562 )  
  430  
  ( 226 to 818 )  
[1] No participants were analyzed in this treatment arm at this time point.

No statistical analysis provided for Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) and Maximum Plasma Concentration (Cmax) of Dabrafenib and Its Metabolite in Combination With Trametinib in Part B



28.  Secondary:   The Tmax of Dabrafenib and Its Metabolite in Combination With Trametinib in Part B   [ Time Frame: Day 15 and Day 21 ]

Measure Type Secondary
Measure Title The Tmax of Dabrafenib and Its Metabolite in Combination With Trametinib in Part B
Measure Description The tmax is defined as the time of occurenceof Cmax. Tha tmax was assessed for plasma dabrafenib (DAB) following repeat dosing of dabrafenib 75 and 150 mg BID administered in combination with trametinib. Blood samples for PK analysis of the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) of dabrafenib were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
Time Frame Day 15 and Day 21  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population. Only those participants who were available at the indicated time points were analyzed.

Reporting Groups
  Description
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Measured Values
    Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  6     8     12     8  
The Tmax of Dabrafenib and Its Metabolite in Combination With Trametinib in Part B  
[units: Hours]
Median ( Full Range )
       
DAB Day 15, n=6, 4, 5, 4     2.00  
  ( 1.03 to 2.00 )  
  2.00  
  ( 1.03 to 6.00 )  
  2.00  
  ( 1.00 to 2.10 )  
  1.50  
  ( 1.00 to 2.00 )  
DAB Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  1.54  
  ( 1.00 to 2.00 )  
  1.53  
  ( 1.00 to 2.03 )  
  2.04  
  ( 1.00 to 4.03 )  
GSK2285403 Day 15, n=6, 4, 5, 4     2.00  
  ( 2.00 to 2.03 )  
  2.00  
  ( 1.03 to 8.00 )  
  2.00  
  ( 2.00 to 4.03 )  
  2.00  
  ( 2.00 to 2.00 )  
GSK2285403 Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  1.97  
  ( 0.00 to 2.00 )  
  2.00  
  ( 1.00 to 2.03 )  
  2.07  
  ( 1.00 to 6.00 )  
GSK2298683 Day 15, n=6, 4, 5, 4     6.00  
  ( 4.00 to 8.00 )  
  4.96  
  ( 0.00 to 6.30 )  
  4.17  
  ( 1.00 to 8.02 )  
  4.10  
  ( 4.00 to 8.00 )  
GSK2298683 Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  4.00  
  ( 1.00 to 6.00 )  
  4.00  
  ( 1.00 to 6.00 )  
  4.02  
  ( 2.00 to 8.07 )  
GSK2167542 Day 15, n=6, 4, 5, 4     0.00  
  ( 0.00 to 4.17 )  
  2.94  
  ( 0.00 to 8.00 )  
  4.17  
  ( 1.00 to 8.02 )  
  1.52  
  ( 0.00 to 2.00 )  
GSK2167542 Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  2.00  
  ( 1.00 to 2.32 )  
  1.01  
  ( 0.00 to 8.00 )  
  1.50  
  ( 0.00 to 8.15 )  
[1] No participants were analyzed in this treatment arm at this time point.

No statistical analysis provided for The Tmax of Dabrafenib and Its Metabolite in Combination With Trametinib in Part B



29.  Secondary:   The AUC (0-tau) Assessment of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212)   [ Time Frame: Day 15 and Day 21 ]

Measure Type Secondary
Measure Title The AUC (0-tau) Assessment of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212)
Measure Description AUC (0-tau) is defined as area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration. AUC (0-tau) was assessed for plasma trametinib following repeat dosing of trametinib in combination with dabrafenib. Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
Time Frame Day 15 and Day 21  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population. Only those participants who were available at the indicated time points were analyzed.

Reporting Groups
  Description
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Measured Values
    Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  6     8     12     8  
The AUC (0-tau) Assessment of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212)  
[units: ng*hr/mL]
Geometric Mean ( 95% Confidence Interval )
       
Day 15, n=6, 4, 5, 4     169  
  ( 113 to 252 )  
  147  
  ( 101 to 212 )  
  217  
  ( 139 to 338 )  
  394  
  ( 229 to 679 )  
Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  169  
  ( 146 to 194 )  
  269  
  ( 238 to 304 )  
  351  
  ( 284 to 432 )  
[1] No participants were analyzed in this treatment arm at this time point.

No statistical analysis provided for The AUC (0-tau) Assessment of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212)



30.  Secondary:   The Ctau and Cmax Assessments of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212)   [ Time Frame: Day 15 and Day 21 ]

Measure Type Secondary
Measure Title The Ctau and Cmax Assessments of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212)
Measure Description Pre-dose (trough) concentration at the end of the dosing interval (Ctau) and maximum plasma concentration (Cmax) were assessed for plasma trametinib following repeat dosing of trametinib in combination with dabrafenib. Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 15 pre-dose or Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
Time Frame Day 15 and Day 21  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population. Only those participants who were available at the indicated time point were analyzed.

Reporting Groups
  Description
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Measured Values
    Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  6     8     12     8  
The Ctau and Cmax Assessments of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212)  
[units: ng/mL]
Geometric Mean ( 95% Confidence Interval )
       
Ctau, Day 15, n=6, 4, 5, 4     5.56  
  ( 3.74 to 8.28 )  
  5.05  
  ( 3.81 to 6.69 )  
  7.62  
  ( 5.38 to 10.8 )  
  12.4  
  ( 6.50 to 23.6 )  
Ctau, Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  5.57  
  ( 4.80 to 6.45 )  
  8.51  
  ( 7.65 to 9.48 )  
  10.8  
  ( 8.75 to 13.3 )  
Cmax, Day 15, n=6, 4, 5, 4     10.2  
  ( 7.18 to 14.4 )  
  8.08  
  ( 5.06 to 12.9 )  
  11.5  
  ( 6.16 to 21.5 )  
  22.4  
  ( 14.0 to 35.6 )  
Cmax, Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  10.2  
  ( 8.50 to 12.1 )  
  18.0  
  ( 14.9 to 21.7 )  
  22.6  
  ( 18.1 to 28.2 )  
[1] No participants were analyzed in this treatment arm at this time point.

No statistical analysis provided for The Ctau and Cmax Assessments of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212)



31.  Secondary:   The Tmax Assessment of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212)   [ Time Frame: Day 15 and Day 21 ]

Measure Type Secondary
Measure Title The Tmax Assessment of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212)
Measure Description The tmax is defined as the time of occurrence of Cmax. The PK parameter for tmax was assessed for plasma trametinib following repeat dosing of trametinib in combination with dabrafenib. Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 15 pre-dose or Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
Time Frame Day 15 and Day 21  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population. Only those participants who were available at the indicated time point were analyzed.

Reporting Groups
  Description
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Measured Values
    Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  6     8     12     8  
The Tmax Assessment of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212)  
[units: Hours]
Median ( Full Range )
       
Day 15, n=6, 4, 5, 4     2.00  
  ( 1.03 to 4.00 )  
  2.00  
  ( 1.00 to 8.00 )  
  2.00  
  ( 1.00 to 8.00 )  
  1.52  
  ( 1.00 to 2.00 )  
Day 21, n=0, 8, 12, 8     NA  
  ( NA to NA ) [1]
  2.00  
  ( 0.93 to 8.00 )  
  2.00  
  ( 1.00 to 2.00 )  
  2.00  
  ( 1.00 to 8.15 )  
[1] No participants were analyzed in this treatment arm at this time point.

No statistical analysis provided for The Tmax Assessment of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212)



32.  Secondary:   Number of Participants With BRAFi-naïve Mutant Metastatic Melanoma With the Best Overall Response as Assessed by Investigator in Part B   [ Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to 103 weeks) ]

Measure Type Secondary
Measure Title Number of Participants With BRAFi-naïve Mutant Metastatic Melanoma With the Best Overall Response as Assessed by Investigator in Part B
Measure Description Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be <10 milimeter [mm] in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Participants with unknown or missing response were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by an investigator as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. BRAFi-naïve participants were those with BRAF-mutation-positive melanoma who had not received prior therapy with a BRAF inhibitor.
Time Frame From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to 103 weeks)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All Treated Population

Reporting Groups
  Description
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Measured Values
    Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  6     22     25     24  
Number of Participants With BRAFi-naïve Mutant Metastatic Melanoma With the Best Overall Response as Assessed by Investigator in Part B  
[units: Participants]
       
CR     0     4     0     2  
PR     4     10     11     13  

No statistical analysis provided for Number of Participants With BRAFi-naïve Mutant Metastatic Melanoma With the Best Overall Response as Assessed by Investigator in Part B



33.  Secondary:   Duration of Response as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma in Part B   [ Time Frame: First documented evidence of PR or CR until the earlier of date of disease progression or date of death due to any cause (up to approximately 22 months) ]

Measure Type Secondary
Measure Title Duration of Response as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma in Part B
Measure Description Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. BRAFi-naïve participants were those with BRAF-mutation-positive melanoma who had not received prior therapy with a BRAF inhibitor.
Time Frame First documented evidence of PR or CR until the earlier of date of disease progression or date of death due to any cause (up to approximately 22 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All Treated Population. Only those participants who had a CR or PR were analyzed.

Reporting Groups
  Description
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Measured Values
    Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  4     14     11     15  
Duration of Response as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma in Part B  
[units: Months]
Median ( 95% Confidence Interval )
  12.4  
  ( 3.7 to 14.9 )  
  8.4  
  ( 5.5 to NA ) [1]
  12.6  
  ( 6.5 to NA ) [1]
  11.3  
  ( 9.1 to 16.9 )  
[1] At the time of this report, the data was not yet mature; therefore, the upper limit (UL) of the CI could not be estimated.

No statistical analysis provided for Duration of Response as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma in Part B



34.  Secondary:   Progression-free Survival (PFS) as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma in Part B   [ Time Frame: From the date of first dose to the earliest date of disease progression (PD) or death due to any cause (up to approximately 22 months) ]

Measure Type Secondary
Measure Title Progression-free Survival (PFS) as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma in Part B
Measure Description PFS is defined as the interval between the first dose of study medication and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. BRAFi-naïve were the participants with BRAF-mutation positive melanoma who had not received prior therapy with a BRAF-inhibitor..
Time Frame From the date of first dose to the earliest date of disease progression (PD) or death due to any cause (up to approximately 22 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All Treated Population.

Reporting Groups
  Description
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Measured Values
    Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  6     22     25     24  
Progression-free Survival (PFS) as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma in Part B  
[units: Months]
Median ( 95% Confidence Interval )
  8.7  
  ( 5.3 to 16.6 )  
  8.2  
  ( 5.4 to 11.0 )  
  5.4  
  ( 3.5 to 12.8 )  
  10.8  
  ( 5.3 to 14.4 )  

No statistical analysis provided for Progression-free Survival (PFS) as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma in Part B



35.  Secondary:   Overall Survival (OS) in Part B BRAFi Naïve Melanoma Participants   [ Time Frame: From the date of first dose until date of death due to any cause (up to approximately 22 months) ]

Measure Type Secondary
Measure Title Overall Survival (OS) in Part B BRAFi Naïve Melanoma Participants
Measure Description OS is defined as the interval of time between the date of randomization until the date of death due to any cause. For the participants who did not die, overall survival was censored at the date of last contact.
Time Frame From the date of first dose until date of death due to any cause (up to approximately 22 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All Treated Population.

Reporting Groups
  Description
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Measured Values
    Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  6     22     25     24  
Overall Survival (OS) in Part B BRAFi Naïve Melanoma Participants  
[units: Months]
Median ( 95% Confidence Interval )
  21.4  
  ( 8.0 to NA ) [1]
  16.4  
  ( 14.5 to NA ) [1]
  13.3  
  ( 6.3 to NA ) [1]
  NA  
  ( 12.9 to NA ) [2]
[1] At the time of this report, the data was not yet mature; therefore, the upper limit (UL) of the CI could not be estimated.
[2] At the time of this report, the data was not yet mature; therefore, the median and the upper limit (UL) of the CI could not be estimated.

No statistical analysis provided for Overall Survival (OS) in Part B BRAFi Naïve Melanoma Participants



36.  Secondary:   Overall Survival (OS) in Part C   [ Time Frame: From the date of randomization until date of death due to any cause (up to approximately 17 months) ]

Measure Type Secondary
Measure Title Overall Survival (OS) in Part C
Measure Description OS is defined as the interval of time between the date of randomization until the date of death due to any cause. For the participants who did not die, overall survival was censored at the date of last contact. When calculating overall survival, deaths following crossover were included.
Time Frame From the date of randomization until date of death due to any cause (up to approximately 17 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population

Reporting Groups
  Description
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part C: Dabrafenib 150 mg     Part C: Dabrafenib 150 mg + Trametinib 1 mg     Part C: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  54     54     54  
Overall Survival (OS) in Part C  
[units: Months]
Median ( 95% Confidence Interval )
  NA  
  ( 13.4 to NA ) [1]
  NA  
  ( 14.5 to NA ) [1]
  NA  
  ( NA to NA ) [1]
[1] The data cut-off date was triggered by at least 70% PFS events in Part C. At the time of data cut, the OS data was not yet mature.

No statistical analysis provided for Overall Survival (OS) in Part C



37.  Secondary:   Plasma Concentrations of Dabrafenib and Its Metabolites in Part C   [ Time Frame: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56 ]

Measure Type Secondary
Measure Title Plasma Concentrations of Dabrafenib and Its Metabolites in Part C
Measure Description Plasma concentrations of dabrafenib and its metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were assesed following daily dose of dabrafenib and trametinib.
Time Frame Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population. Only those participants who were available at the indicated time points were analyzed.

Reporting Groups
  Description
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part C: Dabrafenib 150 mg     Part C: Dabrafenib 150 mg + Trametinib 1 mg     Part C: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  49     53     50  
Plasma Concentrations of Dabrafenib and Its Metabolites in Part C  
[units: ng/mL]
Median ( Full Range )
     
Day 15, GSK2118436, n=49, 53, 49     59.3  
  ( 9 to 2420 )  
  68.2  
  ( 0 to 1555 )  
  66.3  
  ( 7 to 1804 )  
Week 8, GSK2118436, n=41, 47, 50     45.6  
  ( 3 to 1841 )  
  69.8  
  ( 0 to 946 )  
  50.5  
  ( 0 to 1696 )  
Week 16, GSK2118436, n= 46, 46, 45     84.4  
  ( 0 to 1865 )  
  66.7  
  ( 0 to 1774 )  
  82.9  
  ( 2 to 3033 )  
Week 24, GSK2118436, n=28, 36, 42     66.3  
  ( 4 to 594 )  
  66.2  
  ( 1 to 2684 )  
  93.3  
  ( 7 to 741 )  
Week 32, GSK2118436, n=18, 30, 34     40.6  
  ( 1 to 500 )  
  57.1  
  ( 0 to 1424 )  
  66.4  
  ( 0 to 2042 )  
Week 40, GSK2118436, n=11, 27, 26     229  
  ( 5 to 714 )  
  97.6  
  ( 19 to 2597 )  
  150.9  
  ( 0 to 1624 )  
Week 48, GSK2118436, n=5, 14, 19     44.7  
  ( 13 to 132 )  
  105.6  
  ( 0 to 1322 )  
  107.7  
  ( 3 to 806 )  
Week 56, GSK2118436, n=2, 10, 8     46.4  
  ( 25 to 68 )  
  44.5  
  ( 0 to 6646 )  
  193.8  
  ( 3 to 413 )  
Day 15, GSK2285403, n=49, 53, 49     92.7  
  ( 14 to 1337 )  
  71.8  
  ( 2 to 1220 )  
  90.5  
  ( 10 to 995 )  
Week 8, GSK2285403, n=41, 47, 50     65.2  
  ( 3 to 2041 )  
  80.4  
  ( 0 to 769 )  
  90.6  
  ( 0 to 757 )  
Week 16, GSK2285403, n=46, 46, 45     113.4  
  ( 0 to 2090 )  
  81.9  
  ( 0 to 995 )  
  114.7  
  ( 3 to 2563 )  
Week 24, GSK2285403, n= 28, 36, 42     95.0  
  ( 4 to 616 )  
  88.1  
  ( 0 to 1689 )  
  130.2  
  ( 9 to 529 )  
Week 32, GSK2285403, n=18, 30, 34     62.5  
  ( 3 to 890 )  
  86.7  
  ( 0 to 808 )  
  87.4  
  ( 0 to 973 )  
Week 40, GSK2285403, n=11, 27, 26     263.8  
  ( 7 to 693 )  
  143.5  
  ( 16 to 870 )  
  136.2  
  ( 0 to 1665 )  
Week 48, GSK2285403, n=5, 14, 19     43.3  
  ( 32 to 241 )  
  93.6  
  ( 0 to 898 )  
  146.4  
  ( 2 to 418 )  
Week 56, GSK2285403, n=2, 10, 8     48.3  
  ( 45 to 51 )  
  92.9  
  ( 0 to 1841 )  
  141.5  
  ( 7 to 755 )  
Day 15, GSK2298683, n=49, 53, 49     3493  
  ( 1381 to 16820 )  
  3043.3  
  ( 199 to 8562 )  
  3145.8  
  ( 428 to 16240 )  
Week 8, GSK2298683, n=41, 43, 50     3149.7  
  ( 238 to 13330 )  
  3238.4  
  ( 20 to 7686 )  
  3010  
  ( 31 to 13130 )  
Week 16, GSK2298683, n= 46, 46, 45     3497.9  
  ( 21 to 9952 )  
  2946.1  
  ( 0 to 8782 )  
  2756.5  
  ( 44 to 14004 )  
Week 24, GSK2298683, n=28, 36, 42     2876.5  
  ( 500 to 8635 )  
  3365.4  
  ( 25 to 7482 )  
  3193.7  
  ( 133 to 6531 )  
Week 32, GSK2298683, n=18, 30, 34     2699.9  
  ( 447 to 14341 )  
  3267.1  
  ( 0 to 9278 )  
  3046.8  
  ( 50 to 9077 )  
Week 40, GSK2298683, n=11, 27, 26     4410.6  
  ( 1023 to 14258 )  
  3694.7  
  ( 1900 to 7663 )  
  3492.8  
  ( 0 to 12550 )  
Week 48, GSK2298683, n=5, 14, 19     3554.9  
  ( 1889 to 7148 )  
  4146.9  
  ( 0 to 8351 )  
  3936.1  
  ( 464 to 12239 )  
Week 56, GSK2298683, n=2, 10, 8     2032.2  
  ( 1102 to 2963 )  
  3843.5  
  ( 374 to 6866 )  
  2904.9  
  ( 1305 to 4673 )  
Day 15, GSK2167542, n=49, 53, 49     247.9  
  ( 95 to 955 )  
  288  
  ( 49 to 1164 )  
  289.3  
  ( 72 to 1140 )  
Week 8, GSK2167542, n=41, 47, 50     239.5  
  ( 19 to 1092 )  
  275.2  
  ( 3 to 983 )  
  262.4  
  ( 0 to 9876 )  
Week 16, GSK2167542, n=46, 46, 45     244  
  ( 1 to 772 )  
  204.4  
  ( 0 to 922 )  
  243.8  
  ( 3 to 1049 )  
Week 24, GSK2167542, n=28, 36, 42     225.6  
  ( 48 to 899 )  
  247.2  
  ( 4 to 990 )  
  254.6  
  ( 3 to 846 )  
Week 32, GSK2167542, n=18, 30, 34     171  
  ( 19 to 544 )  
  255.4  
  ( 0 to 698 )  
  289.3  
  ( 2 to 962 )  
Week 40, GSK2167542, n=11, 27, 26     222.2  
  ( 95 to 639 )  
  249.3  
  ( 55 to 674 )  
  268.9  
  ( 0 to 910 )  
Week 48, GSK2167542, n=5, 14, 19     204.5  
  ( 145 to 286 )  
  232  
  ( 0 to 915 )  
  260.9  
  ( 81 to 886 )  
Week 56, GSK2167542, n=5, 10, 8     171.8  
  ( 116 to 228 )  
  250  
  ( 28 to 851 )  
  462.1  
  ( 107 to 663 )  

No statistical analysis provided for Plasma Concentrations of Dabrafenib and Its Metabolites in Part C



38.  Secondary:   Plasma Concentrations of Trametinib in Part C   [ Time Frame: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56 ]

Measure Type Secondary
Measure Title Plasma Concentrations of Trametinib in Part C
Measure Description Plasma concentrations of trametinib was assessed following daily dose of dabrafenib and trametinib.
Time Frame Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population. Only those participants who were available at the indicated time points were analyzed.

Reporting Groups
  Description
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part C: Dabrafenib 150 mg     Part C: Dabrafenib 150 mg + Trametinib 1 mg     Part C: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  59     53     50  
Plasma Concentrations of Trametinib in Part C  
[units: ng/mL]
Median ( Full Range )
     
Day 15, n=49, 53, 49     0  
  ( 0 to 0 )  
  5.86  
  ( 3.4 to 11.3 )  
  9.35  
  ( 4.8 to 26.00 )  
Week 8, n=41, 45, 50     0  
  ( 0 to 13.9 )  
  6.70  
  ( 2.0 to 9.6 )  
  10.3  
  ( 0 to 25.8 )  
Week 16, n=46, 43, 45     0  
  ( 0 to 9.8 )  
  6.99  
  ( 0 to 20.7 )  
  9.87  
  ( 1.1 to 25.4 )  
Week 24, n=29, 35, 41     0  
  ( 0 to 19.7 )  
  5.99  
  ( 0 to 11.2 )  
  9.54  
  ( 0.5 to 27.4 )  
Week 32, n=18, 30, 33     0  
  ( 0 to 0 )  
  5.77  
  ( 0.7 to 11.6 )  
  9.74  
  ( 0 to 51.5 )  
Week 40, n=11, 26, 27     0  
  ( 0 to 0 )  
  7.11  
  ( 2.2 to 16.7 )  
  10.1  
  ( 0 to 26.4 )  
Week 48, n=5, 14, 19     0  
  ( 0 to 0 )  
  5.62  
  ( 0 to 14.3 )  
  10.3  
  ( 0 to 35.6 )  
Week 56, n=2, 10, 8     0  
  ( 0 to 0 )  
  9.90  
  ( 3.4 to 16.9 )  
  8.60  
  ( 0 to 15.4 )  

No statistical analysis provided for Plasma Concentrations of Trametinib in Part C



39.  Secondary:   Oral Clearance (CL/F) of Dabrafenib and Trametinib   [ Time Frame: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48 ]

Measure Type Secondary
Measure Title Oral Clearance (CL/F) of Dabrafenib and Trametinib
Measure Description Oral clearance (CL/F) of dabrafenib and trametinib were assessed using a population approach. Oral clearance (CL/F) is defined as the apparent volume of plasma in the vascular compartment cleared of drug per unit time by the processes of metabolism and excretion. For dabrafenib, population CL/F is defined as inducible and non-inducible CL/F. As dabrafenib induces its own metabolism, total oral clearance at steady state includes a non-induced (Day 1) component and an induced component, as estimated by a population PK model.
Time Frame Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population

Reporting Groups
  Description
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Trametinib Participants received Trametinib 1 mg or 2 mg tablets QD.

Measured Values
    Part C: Dabrafenib 150 mg     Part C: Trametinib  
Number of Participants Analyzed  
[units: participants]
  53     109  
Oral Clearance (CL/F) of Dabrafenib and Trametinib  
[units: Liters per hour (L/hr)]
Mean ( 95% Confidence Interval )
   
Non-inducible     19.4  
  ( 17.6 to 21.2 )  
  5.07  
  ( 4.83 to 5.31 )  
Inducible     20.0  
  ( 19.2 to 20.8 )  
  NA  
  ( NA to NA ) [1]
[1] CL/F is not induced for trametinib.

No statistical analysis provided for Oral Clearance (CL/F) of Dabrafenib and Trametinib



40.  Secondary:   Oral Volume of Distribution (V/F) of Dabrafenib and Trametinib   [ Time Frame: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48 ]

Measure Type Secondary
Measure Title Oral Volume of Distribution (V/F) of Dabrafenib and Trametinib
Measure Description Oral volume of distribution (V/F) of dabrafenib and trametinib were assessed using a population approach. Oral volume of distribution (V/F) is defined as the apparent volume of distribution in the central compartment.
Time Frame Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population

Reporting Groups
  Description
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Trametinib Participants received Trametinib 1 mg or 2 mg tablets QD.

Measured Values
    Part C: Dabrafenib 150 mg     Part C: Trametinib  
Number of Participants Analyzed  
[units: participants]
  53     109  
Oral Volume of Distribution (V/F) of Dabrafenib and Trametinib  
[units: Liters (L)]
Mean ( 95% Confidence Interval )
  80.8  
  ( 73.9 to 87.7 )  
  184  
  ( 158 to 210 )  

No statistical analysis provided for Oral Volume of Distribution (V/F) of Dabrafenib and Trametinib



41.  Secondary:   Cmax of Dabrafenib Metabolites in Part D   [ Time Frame: Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose ]

Measure Type Secondary
Measure Title Cmax of Dabrafenib Metabolites in Part D
Measure Description The maximum concentration (Cmax) of dabrafenib metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) after single and repeat doses of DAB alone and in combination with trametinib was measured at Day 1 and Day 21.
Time Frame Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population. Only participants who were available at the indicated timepoints were analyzed.

Reporting Groups
  Description
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  15     14     15     15  
Cmax of Dabrafenib Metabolites in Part D  
[units: ng/mL]
Geometric Mean ( 95% Confidence Interval )
       
GSK2285403, Day 1,n=15, 14, 15, 15     525  
  ( 429 to 643 )  
  1055  
  ( 705 to 1579 )  
  597  
  ( 474 to 752 )  
  1363  
  ( 300 to 2066 )  
GSK2285403, Day 21, n=14, 11, 14, 12     596  
  ( 501 to 709 )  
  1203  
  ( 906 to 1599 )  
  696  
  ( 551 to 880 )  
  1120  
  ( 725 to 1730 )  
GSK2298683, Day 1, n=15, 14, 15, 15     1475  
  ( 1249 to 1741 )  
  2268  
  ( 1595 to 3223 )  
  1478  
  ( 1197 to 1824 )  
  2551  
  ( 1756 to 3707 )  
GSK2298683, Day 21, n=14, 11, 14, 12     3637  
  ( 3119 to 4242 )  
  6743  
  ( 5133 to 8859 )  
  4158  
  ( 3136 to 5514 )  
  6319  
  ( 4725 to 8450 )  
GSK2167542, Day 1, n=13, 13, 15, 15     50.1  
  ( 30 to 84 )  
  68.6  
  ( 36 to 129 )  
  61.2  
  ( 41 to 91 )  
  86.3  
  ( 48 to 155 )  
GSK2167542, Day 21, n=14, 11, 14, 12     210  
  ( 154 to 285 )  
  355  
  ( 268 to 470 )  
  289  
  ( 201 to 416 )  
  440  
  ( 303 to 637 )  

No statistical analysis provided for Cmax of Dabrafenib Metabolites in Part D



42.  Secondary:   The Tmax of Dabrafenib Metabolites in Part D   [ Time Frame: Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose ]

Measure Type Secondary
Measure Title The Tmax of Dabrafenib Metabolites in Part D
Measure Description The time to Cmax (tmax) of DAB metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) after single and repeat doses of DAB alone and in combination with trametinib was measuered at Day 1 and Day 21.
Time Frame Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population. Only participants who were available at the indicated timepoints were analyzed.

Reporting Groups
  Description
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  15     14     15     15  
The Tmax of Dabrafenib Metabolites in Part D  
[units: Hours]
Median ( Full Range )
       
GSK2285403, Day 1, n=15, 14, 15, 15     3.00  
  ( 1.50 to 4.00 )  
  3.51  
  ( 2.00 to 6.18 )  
  3.00  
  ( 2.00 to 6.02 )  
  2.07  
  ( 1.50 to 10.00 )  
GSK2285403, Day 21, n=14, 11, 14, 12     2.00  
  ( 1.50 to 3.00 )  
  2.00  
  ( 1.42 to 3.00 )  
  2.00  
  ( 1.47 to 4.00 )  
  2.00  
  ( 1.00 to 3.98 )  
GSK2298683, Day 1, n=15, 14, 15, 15     10.0  
  ( 5.98 to 10.1 )  
  8.93  
  ( 4.00 to 24.0 )  
  10.0  
  ( 6.00 to 24.0 )  
  8.00  
  ( 4.07 to 24.0 )  
GSK2298683, Day 21, n=14, 11, 14, 12     5.00  
  ( 3.00 to 8.00 )  
  4.00  
  ( 3.00 to 6.00 )  
  5.98  
  ( 2.00 to 10.00 )  
  4.00  
  ( 3.00 to 6.08 )  
GSK2167542, Day 1, n=13, 13, 15, 15     24.0  
  ( 8.00 to 24.1 )  
  24.0  
  ( 6.00 to 24.6 )  
  24.0  
  ( 23.5 to 25.0 )  
  24.0  
  ( 10.0 to 24.3 )  
GSK2167542, Day 21, n=14, 11, 14, 12     0.75  
  ( 0 to 10.0 )  
  2.00  
  ( 0.50 to 10.0 )  
  2.00  
  ( 1.00 to 10.00 )  
  1.75  
  ( 0 to 9.92 )  

No statistical analysis provided for The Tmax of Dabrafenib Metabolites in Part D



43.  Secondary:   Area Under the Concentration-time Curve (AUC) of Dabrafenib Metabolites in Part D   [ Time Frame: Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose ]

Measure Type Secondary
Measure Title Area Under the Concentration-time Curve (AUC) of Dabrafenib Metabolites in Part D
Measure Description Area under the concentration-time curve (AUC) from pre-dose to dosing interval (AUC[0-tau]), from pre-dose to the last time of quantifable concentration (AUC[0-tau]), and from pre-dose extrapolated to infinity (AUC[0-inf]) of DAB metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) after single and repeat doses of DAB alone and in combination with trametinib was measured at Day 1 and Day 21.
Time Frame Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK Population. Only participants who were available at the indicated timepoints were analyzed.

Reporting Groups
  Description
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.

Measured Values
    Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
Number of Participants Analyzed  
[units: participants]
  15     14     15     15  
Area Under the Concentration-time Curve (AUC) of Dabrafenib Metabolites in Part D  
[units: ng*hr/mL]
Geometric Mean ( 95% Confidence Interval )
       
GSK2285403, AUC(0-tau), Day 1, n=15, 14, 15, 15     3134  
  ( 2533 to 3877 )  
  5950  
  ( 4045 to 8753 )  
  3694  
  ( 2903 to 4700 )  
  6524  
  ( 4520 to 9416 )  
GSK2285403, AUC(0-inf), Day 1, n=15, 14, 15, 15     3963  
  ( 3147 to 4990 )  
  7415  
  ( 4991 to 11015 )  
  5026  
  ( 3934 to 6422 )  
  7907  
  ( 5434 to 11506 )  
GSK2285403, AUC (0-tau), Day 21, n=14, 11, 14, 12     2568  
  ( 2099 to 3143 )  
  4262  
  ( 3007 to 6040 )  
  2919  
  ( 2296 to 3711 )  
  4216  
  ( 2986 to 5951 )  
GSK2298683, AUC, (0-tau), Day 1, n=15, 14, 15, 15     10396  
  ( 8388 to 12885 )  
  15952  
  ( 10532 to 24160 )  
  9575  
  ( 7143 to 12835 )  
  20935  
  ( 12430 to 35259 )  
GSK2298683, AUC (0-t), Day 1, n=15, 14, 15, 15     20047  
  ( 15384 to 26125 )  
  35206  
  ( 24970 to 49639 )  
  22692  
  ( 18398 to 27988 )  
  31666  
  ( 18474 to 54277 )  
GSK2298683, AUC (0-tau), Day 21, n = 14, 11, 14,     34283  
  ( 29189 to 40266 )  
  59340  
  ( 44595 to 78960 )  
  39672  
  ( 29504 to 53343 )  
  52712  
  ( 40084 to 69318 )  
GSK2167542, AUC(0-tau), Day 1, n=13, 13, 15, 15     132  
  ( 79 to 219 )  
  190  
  ( 101 to 356 )