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
  Show All Outcome Measures

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 ]

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

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 ) ]

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) ]

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) ]

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) ]

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) ]

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) ]

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) ]

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) ]

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) ]

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) ]

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) ]

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) ]

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) ]

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) ]

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) ]

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 ]

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 ]

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 ]

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) ]

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) ]

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) ]

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) ]

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

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 ]

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 ]

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

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 ]

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 ]

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

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) ]

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) ]

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) ]

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) ]

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) ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

44.  Secondary:   The Cmax Assessment of Trametinib 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 ]

45.  Secondary:   The Tmax Assessment of Trametinib 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 ]

46.  Secondary:   Area Under the Concentration-time Curve Assessment of Trametinib 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 ]

47.  Secondary:   Number of Participants With the Best Overall Response as Assessed by the Investigator in Participants in Part D   [ Time Frame: From the date of first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 280 days ) ]

48.  Secondary:   Duration of Response as Assessed by the Investigator in Part D   [ 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 13 months) ]

49.  Secondary:   Progression-free Survival (PFS) as Assessed by the Investigator in Part D   [ Time Frame: From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 13 months) ]

50.  Secondary:   Change From Baseline in p-ERK and Other Biomarkers in Tumor Biopsies in Participants With BRAF Mutant Colorectal Cancer in Part B   [ Time Frame: Screening and at disease progression (up to approximately 8 months) ]
Results not yet posted.   Anticipated Posting Date:   06/2014   Safety Issue:   No

51.  Secondary:   Overall Survival in Part D   [ Time Frame: From the date of first dose until date of death due to any cause (up to approximately 14 months) ]
Results not yet posted.   Anticipated Posting Date:   10/2014   Safety Issue:   No


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


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