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Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212

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ClinicalTrials.gov Identifier: NCT01072175
Recruitment Status : Completed
First Posted : February 19, 2010
Results First Posted : November 21, 2013
Last Update Posted : July 5, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Non-Randomized;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Cancer
Interventions Drug: GSK2118436
Drug: GSK1120212
Enrollment 430
Recruitment Details This study was conducted in 16 sites: Australia (2) and USA (14)
Pre-assignment Details 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.
Arm/Group Title 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
Hide Arm/Group Description Participants received a single dose of dabrafenib 75 mg gelatin capsules with repeat dose trametinib (Day 15). 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. 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. 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. 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. Participants received dabrafenib 150 mg gelatin capsules BID. Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD. Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD. 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. 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. 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. Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD. Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Period Title: Part A (Drug-Drug Interaction)
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
Reason Not Completed
Death             1             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
Period Title: Part B (Dose Escalation and Expansion)
Started 0 6 23 27 94 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 94 0 0 0 0 0 0 0 0
Reason Not Completed
Death             0             4             18             21             68             0             0             0             0             0             0             0             0
Physician Decision             0             0             2             0             4             0             0             0             0             0             0             0             0
Lost to Follow-up             0             1             0             1             6             0             0             0             0             0             0             0             0
Study closed/terminated             0             0             3             2             10             0             0             0             0             0             0             0             0
Withdrawal by Subject             0             1             0             3             6             0             0             0             0             0             0             0             0
Period Title: Part C (Phase II: Randomized Phase)
Started 0 0 0 0 0 54 54 54 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
Reason Not Completed
Death             0             0             0             0             0             44             34             39             0             0             0             0             0
Physician Decision             0             0             0             0             0             1             1             1             0             0             0             0             0
Lost to Follow-up             0             0             0             0             0             0             3             3             0             0             0             0             0
Study closed/terminated             0             0             0             0             0             6             9             11             0             0             0             0             0
Withdrawal by Subject             0             0             0             0             0             3             7             0             0             0             0             0             0
Period Title: Part C (Phase II: Crossover Phase [CP])
Started 0 0 0 0 0 0 0 0 45 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 45 0 0 0 0
Reason Not Completed
Death             0             0             0             0             0             0             0             0             37             0             0             0             0
Physician Decision             0             0             0             0             0             0             0             0             1             0             0             0             0
Study closed/terminated             0             0             0             0             0             0             0             0             4             0             0             0             0
Withdrawal by Subject             0             0             0             0             0             0             0             0             3             0             0             0             0
Period Title: Part D (HPMC Capsules)
Started 0 0 0 0 0 0 0 0 0 12 16 43 39
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
Reason Not Completed
Death             0             0             0             0             0             0             0             0             0             10             12             28             26
Physician Decision             0             0             0             0             0             0             0             0             0             0             1             1             1
Lost to Follow-up             0             0             0             0             0             0             0             0             0             0             1             1             3
Study closed/terminated             0             0             0             0             0             0             0             0             0             2             1             10             9
Withdrawal by Subject             0             0             0             0             0             0             0             0             0             0             1             3             0
Arm/Group Title 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
Hide Arm/Group Description Participants received a single dose of dabrafenib 75 mg gelatin capsules with repeat dose trametinib (Day 15). 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. 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. 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. 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. Participants received dabrafenib 150 mg gelatin capsules BID. Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD. Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD. 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. 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. Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD. Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD. Total of all reporting groups
Overall Number of Baseline Participants 8 6 23 27 94 54 54 54 12 16 43 39 430
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 8 participants 6 participants 23 participants 27 participants 94 participants 54 participants 54 participants 54 participants 12 participants 16 participants 43 participants 39 participants 430 participants
52.8  (16.04) 48.2  (7.28) 54.2  (13.24) 52.2  (12.09) 52.4  (12.99) 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)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants 6 participants 23 participants 27 participants 94 participants 54 participants 54 participants 54 participants 12 participants 16 participants 43 participants 39 participants 430 participants
Female
2
  25.0%
2
  33.3%
10
  43.5%
12
  44.4%
56
  59.6%
25
  46.3%
24
  44.4%
20
  37.0%
6
  50.0%
8
  50.0%
18
  41.9%
14
  35.9%
197
  45.8%
Male
6
  75.0%
4
  66.7%
13
  56.5%
15
  55.6%
38
  40.4%
29
  53.7%
30
  55.6%
34
  63.0%
6
  50.0%
8
  50.0%
25
  58.1%
25
  64.1%
233
  54.2%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 8 participants 6 participants 23 participants 27 participants 94 participants 54 participants 54 participants 54 participants 12 participants 16 participants 43 participants 39 participants 430 participants
White 7 6 22 26 92 52 54 53 12 16 43 39 407
Asian 1 0 0 0 2 0 0 1 0 0 0 0 1
African American 0 0 0 1 0 0 0 0 0 0 0 0 1
Missing 0 0 1 0 0 2 0 0 0 0 0 0 3
1.Primary Outcome
Title Part A: Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Part A: Dabrafenib 75 mg Part A: Dabrafenib 75 mg + Trametinib 2 mg
Hide Arm/Group Description:
Participants received a single dose of dabrafenib 75 mg gelatin capsules alone on Day 1.
Participants received a single dose of dabrafenib 75 mg gelatin capsules with repeat dose trametinib (Day 15).
Overall Number of Participants Analyzed 8 8
Geometric Mean (95% Confidence Interval)
Unit of Measure: Nanograms per milliliter (ng/mL)
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)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part A: Dabrafenib 75 mg, Part A: Dabrafenib 75 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.03
Confidence Interval (2-Sided) 90%
0.79 to 1.34
Estimation Comments Geometric mean ratio (Day 15 Cmax/Day 1 Cmax) and 90% confidence interval for dabrafenib were calculated.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Part A: Dabrafenib 75 mg, Part A: Dabrafenib 75 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value .99
Confidence Interval (2-Sided) 90%
0.78 to 1.25
Estimation Comments Geometric mean ratio (Day 15 Cmax/Day 1 Cmax) and 90% confidence interval for GSK2285403 were calculated.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Part A: Dabrafenib 75 mg, Part A: Dabrafenib 75 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.03
Confidence Interval (2-Sided) 90%
0.84 to 1.27
Estimation Comments Geometric mean ratio (Day 15 Cmax/Day 1 Cmax) and 90% confidence interval for GSK2298683 were calculated.
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Part A: Dabrafenib 75 mg, Part A: Dabrafenib 75 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value .98
Confidence Interval (2-Sided) 90%
0.66 to 1.45
Estimation Comments Geometric mean ratio (Day 15 Cmax/Day 1 Cmax) and 90% confidence interval for GSK2167542 were calculated.
2.Primary Outcome
Title Part A: AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
PK Population
Arm/Group Title Part A: Dabrafenib 75 mg Part A: Dabrafenib 75 mg + Trametinib 2 mg
Hide Arm/Group Description:
Participants received a single dose of dabrafenib 75 mg gelatin capsules alone on Day 1.
Participants received a single dose of dabrafenib 75 mg gelatin capsules with repeat dose trametinib (Day 15).
Overall Number of Participants Analyzed 8 8
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng*hour/mL (ng*hr/mL)
GSK2118436 AUC (0-t) Number Analyzed 8 participants 8 participants
2734
(2205 to 3390)
2751
(2219 to 3411)
GSK2118436 AUC (0-inf) Number Analyzed 8 participants 8 participants
3128
(2578 to 3797)
2949
(2445 to 3556)
GSK2285403 AUC (0-t) Number Analyzed 8 participants 8 participants
2232
(1684 to 2959)
2287
(1899 to 2753)
GSK2285403 AUC (0-inf) Number Analyzed 8 participants 8 participants
2819
(2231 to 3562)
2497
(2097 to 2974)
GSK2298683 AUC (0-t) Number Analyzed 8 participants 8 participants
12761
(10347 to 15738)
13053
(10475 to 16266)
GSK2298683 AUC (0-inf) Number Analyzed 0 participants 0 participants
GSK2167542 AUC (0-t) Number Analyzed 8 participants 8 participants
270
(188 to 390)
276
(230 to 332)
GSK2167542 AUC (0-inf) Number Analyzed 0 participants 0 participants
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part A: Dabrafenib 75 mg, Part A: Dabrafenib 75 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.01
Confidence Interval (2-Sided) 90%
0.85 to 1.19
Estimation Comments Geometric mean ratio (Day 15 AUC(0-inf)/ Day 1 AUC(0-inf)) and 90% confidence interval for dabrafenib were calculated.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Part A: Dabrafenib 75 mg, Part A: Dabrafenib 75 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 0.94
Confidence Interval (2-Sided) 90%
0.82 to 1.08
Estimation Comments Geometric mean ratio (Day 15 AUC(0-inf)/ Day 1 AUC(0-inf)) and 90% confidence interval for dabrafenib were calculated.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Part A: Dabrafenib 75 mg, Part A: Dabrafenib 75 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.02
Confidence Interval (2-Sided) 90%
0.84 to 1.25
Estimation Comments Geometric mean ratio (Day 15 AUC(0-t)/ Day 1 AUC(0-t)) and 90% confidence interval for GSK2285403 were calculated.
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Part A: Dabrafenib 75 mg, Part A: Dabrafenib 75 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 0.92
Confidence Interval (2-Sided) 90%
0.81 to 1.03
Estimation Comments Geometric mean ratio (Day 15 AUC(0-inf)/ Day 1 AUC(0-inf)) and 90% confidence interval for GSK2285403 were calculated.
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Part A: Dabrafenib 75 mg, Part A: Dabrafenib 75 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.02
Confidence Interval (2-Sided) 90%
0.81 to 1.29
Estimation Comments Geometric mean ratio (Day 15 AUC(0-t)/ Day 1 AUC(0-t)) and 90% confidence interval for GSK2298683 were calculated.
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Part A: Dabrafenib 75 mg, Part A: Dabrafenib 75 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.02
Confidence Interval (2-Sided) 90%
0.76 to 1.37
Estimation Comments Geometric mean ratio (Day 15 AUC(0-t)/ Day 1 AUC(0-t)) and 90% confidence interval for GSK2167542 were calculated.
3.Primary Outcome
Title Part B: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
Hide 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.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Participants (ATP) Population: all participants who received at least one dose of either dabrafenib or trametinib
Arm/Group Title 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
Hide Arm/Group Description:
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.
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.
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.
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.
Overall Number of Participants Analyzed 6 23 27 94
Measure Type: Count of Participants
Unit of Measure: Participants
Any AE
6
 100.0%
23
 100.0%
27
 100.0%
93
  98.9%
Any SAE
1
  16.7%
15
  65.2%
14
  51.9%
55
  58.5%
4.Primary Outcome
Title Part B: Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline
Hide 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. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.
Arm/Group Title 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
Hide Arm/Group Description:
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.
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.
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.
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.
Overall Number of Participants Analyzed 6 23 27 94
Measure Type: Count of Participants
Unit of Measure: Participants
Albumin Number Analyzed 0 participants 0 participants 1 participants 3 participants
Increase to Grade 3 0 0
1
 100.0%
3
 100.0%
Increase to Grade 4 0 0
0
   0.0%
0
   0.0%
Alkaline Phosphatase Number Analyzed 1 participants 2 participants 1 participants 10 participants
Increase to Grade 3
1
 100.0%
2
 100.0%
1
 100.0%
10
 100.0%
Increase to Grade 4
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Alanine Amino Transferase Number Analyzed 0 participants 0 participants 1 participants 2 participants
Increase to Grade 3 0 0
1
 100.0%
2
 100.0%
Increase to Grade 4 0 0
0
   0.0%
0
   0.0%
Amylase Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Aspartate Amino Transferase Number Analyzed 0 participants 0 participants 1 participants 5 participants
Increase to Grade 3 0 0
1
 100.0%
5
 100.0%
Increase to Grade 4 0 0
0
   0.0%
0
   0.0%
Total Bilirubin Number Analyzed 0 participants 0 participants 0 participants 2 participants
Increase to Grade 3 0 0 0
2
 100.0%
Increase to Grade 4 0 0 0
0
   0.0%
Calcium (Hypercalcemia) Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Calcium (Hypocalcemia) Number Analyzed 0 participants 0 participants 1 participants 2 participants
Increase to Grade 3 0 0
1
 100.0%
1
  50.0%
Increase to Grade 4 0 0
0
   0.0%
1
  50.0%
Creatine Kinase Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Creatinine Number Analyzed 0 participants 0 participants 1 participants 0 participants
Increase to Grade 3 0 0
0
   0.0%
0
Increase to Grade 4 0 0
1
 100.0%
0
Gamma Glutamyl Transferase Number Analyzed 1 participants 0 participants 3 participants 13 participants
Increase to Grade 3
1
 100.0%
0
3
 100.0%
13
 100.0%
Increase to Grade 4
0
   0.0%
0
0
   0.0%
0
   0.0%
Glucose (Hyperglycemia) Number Analyzed 0 participants 2 participants 2 participants 5 participants
Increase to Grade 3 0
2
 100.0%
2
 100.0%
5
 100.0%
Increase to Grade 4 0
0
   0.0%
0
   0.0%
0
   0.0%
Glucose (Hypoglycemia) Number Analyzed 0 participants 0 participants 0 participants 1 participants
Increase to Grade 3 0 0 0
1
 100.0%
Increase to Grade 4 0 0 0
0
   0.0%
Potassium (Hyperkalemia) Number Analyzed 0 participants 0 participants 0 participants 1 participants
Increase to Grade 3 0 0 0
1
 100.0%
Increase to Grade 4 0 0 0
0
   0.0%
Potassium (Hypokalemia) Number Analyzed 0 participants 0 participants 1 participants 4 participants
Increase to Grade 3 0 0
1
 100.0%
4
 100.0%
Increase to Grade 4 0 0
0
   0.0%
0
   0.0%
Lipase Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Magnesium (Hypermagnesemia) Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Magnesium (Hypomagnesemia) Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Sodium (Hypernatremia) Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Sodium (Hyponatremia) Number Analyzed 0 participants 2 participants 7 participants 12 participants
Increase to Grade 3 0
2
 100.0%
7
 100.0%
12
 100.0%
Increase to Grade 4 0
0
   0.0%
0
   0.0%
0
   0.0%
Blood pH Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Phosphorus inorganic Number Analyzed 0 participants 2 participants 6 participants 4 participants
Increase to Grade 3 0
2
 100.0%
6
 100.0%
4
 100.0%
Increase to Grade 4 0
0
   0.0%
0
   0.0%
0
   0.0%
Uric acid Number Analyzed 1 participants 0 participants 0 participants 1 participants
Increase to Grade 3
0
   0.0%
0 0
0
   0.0%
Increase to Grade 4
1
 100.0%
0 0
1
 100.0%
5.Primary Outcome
Title Part B: Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range
Hide Description For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.
Arm/Group Title 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
Hide Arm/Group Description:
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.
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.
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.
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.
Overall Number of Participants Analyzed 6 23 27 94
Measure Type: Count of Participants
Unit of Measure: Participants
Direct Bilirubin Number Analyzed 0 participants 0 participants 0 participants 0 participants
Decrease to Low 0 0 0 0
Increase to High 0 0 0 0
Indirect Bilirubin Number Analyzed 0 participants 0 participants 0 participants 0 participants
Decrease to Low 0 0 0 0
Increase to High 0 0 0 0
Creatine Kinase MB mass Number Analyzed 0 participants 0 participants 0 participants 0 participants
Decrease to Low 0 0 0 0
Increase to High 0 0 0 0
Chloride Number Analyzed 2 participants 15 participants 18 participants 55 participants
Decrease to Low
0
   0.0%
4
  26.7%
10
  55.6%
39
  70.9%
Increase to High
2
 100.0%
11
  73.3%
8
  44.4%
16
  29.1%
Carbon dioxide content/Bicarbonate Number Analyzed 4 participants 11 participants 17 participants 41 participants
Decrease to Low
1
  25.0%
4
  36.4%
6
  35.3%
16
  39.0%
Increase to High
3
  75.0%
7
  63.6%
11
  64.7%
25
  61.0%
Creatinine clearance Number Analyzed 4 participants 9 participants 15 participants 27 participants
Decrease to Low
2
  50.0%
4
  44.4%
10
  66.7%
19
  70.4%
Increase to High
2
  50.0%
5
  55.6%
5
  33.3%
8
  29.6%
Lactate dehydrogenase Number Analyzed 5 participants 11 participants 12 participants 39 participants
Decrease to Low
1
  20.0%
2
  18.2%
1
   8.3%
4
  10.3%
Increase to High
4
  80.0%
9
  81.8%
11
  91.7%
35
  89.7%
Total protein Number Analyzed 3 participants 12 participants 11 participants 37 participants
Decrease to Low
0
   0.0%
10
  83.3%
10
  90.9%
30
  81.1%
Increase to High
3
 100.0%
2
  16.7%
1
   9.1%
7
  18.9%
Troponin I Number Analyzed 0 participants 0 participants 0 participants 0 participants
Decrease to Low 0 0 0 0
Increase to High 0 0 0 0
Trponin T Number Analyzed 0 participants 0 participants 0 participants 0 participants
Decrease to Low 0 0 0 0
Increase to High 0 0 0 0
Urea/BUN Number Analyzed 3 participants 14 participants 19 participants 47 participants
Decrease to Low
2
  66.7%
4
  28.6%
3
  15.8%
17
  36.2%
Increase to High
1
  33.3%
10
  71.4%
16
  84.2%
30
  63.8%
6.Primary Outcome
Title Part B: Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline
Hide Description Hematology 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. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.
Arm/Group Title 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
Hide Arm/Group Description:
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.
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.
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.
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.
Overall Number of Participants Analyzed 6 23 27 94
Measure Type: Count of Participants
Unit of Measure: Participants
Hemoglobin (Increased) Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Hemoglobin (Anemia) Number Analyzed 0 participants 0 participants 3 participants 10 participants
Increase to Grade 3 0 0
3
 100.0%
10
 100.0%
Increase to Grade 4 0 0
0
   0.0%
0
   0.0%
Lymphocytes (Increased) Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Lymphocytes (Decreased) Number Analyzed 0 participants 8 participants 8 participants 24 participants
Increase to Grade 3 0
7
  87.5%
4
  50.0%
19
  79.2%
Increase to Grade 4 0
1
  12.5%
4
  50.0%
5
  20.8%
Total Neutrophils Number Analyzed 1 participants 3 participants 3 participants 10 participants
Increase to Grade 3
1
 100.0%
3
 100.0%
3
 100.0%
10
 100.0%
Increase to Grade 4
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Platelet Count Number Analyzed 0 participants 0 participants 2 participants 2 participants
Increase to Grade 3 0 0
2
 100.0%
1
  50.0%
Increase to Grade 4 0 0
0
   0.0%
1
  50.0%
White Blood Cell Count Number Analyzed 0 participants 2 participants 4 participants 8 participants
Increase to Grade 3 0
2
 100.0%
4
 100.0%
8
 100.0%
Increase to Grade 4 0
0
   0.0%
0
   0.0%
0
   0.0%
7.Primary Outcome
Title Part B: Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range
Hide Description For Hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.
Arm/Group Title 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
Hide Arm/Group Description:
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.
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.
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.
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.
Overall Number of Participants Analyzed 6 23 27 94
Measure Type: Count of Participants
Unit of Measure: Participants
Basophils Number Analyzed 0 participants 2 participants 4 participants 9 participants
Decrease to Low 0
0
   0.0%
0
   0.0%
2
  22.2%
Increase to High 0
2
 100.0%
4
 100.0%
7
  77.8%
Eosinophils Number Analyzed 1 participants 10 participants 13 participants 39 participants
Decrease to Low
1
 100.0%
5
  50.0%
6
  46.2%
28
  71.8%
Increase to High
0
   0.0%
5
  50.0%
7
  53.8%
11
  28.2%
Hematocrit Number Analyzed 1 participants 5 participants 9 participants 26 participants
Decrease to Low
1
 100.0%
5
 100.0%
7
  77.8%
24
  92.3%
Increase to High
0
   0.0%
0
   0.0%
2
  22.2%
2
   7.7%
Mean Corpuscle Hemoglobin concentration Number Analyzed 2 participants 10 participants 16 participants 34 participants
Decrease to Low
0
   0.0%
6
  60.0%
11
  68.8%
21
  61.8%
Increase to High
2
 100.0%
4
  40.0%
5
  31.3%
13
  38.2%
Mean Corpuscle Hemoglobin Number Analyzed 0 participants 9 participants 14 participants 23 participants
Decrease to Low 0
6
  66.7%
8
  57.1%
12
  52.2%
Increase to High 0
3
  33.3%
6
  42.9%
11
  47.8%
Mean Corpuscle Volume Number Analyzed 2 participants 7 participants 10 participants 18 participants
Decrease to Low
1
  50.0%
5
  71.4%
6
  60.0%
13
  72.2%
Increase to High
1
  50.0%
2
  28.6%
4
  40.0%
5
  27.8%
Monocytes Number Analyzed 3 participants 12 participants 19 participants 51 participants
Decrease to Low
2
  66.7%
8
  66.7%
10
  52.6%
21
  41.2%
Increase to High
1
  33.3%
4
  33.3%
9
  47.4%
30
  58.8%
Red Blood Cell count Number Analyzed 1 participants 9 participants 6 participants 27 participants
Decrease to Low
1
 100.0%
9
 100.0%
5
  83.3%
25
  92.6%
Increase to High
0
   0.0%
0
   0.0%
1
  16.7%
2
   7.4%
Reticulocytes Number Analyzed 4 participants 8 participants 11 participants 9 participants
Decrease to Low
2
  50.0%
1
  12.5%
5
  45.5%
3
  33.3%
Increase to High
2
  50.0%
7
  87.5%
6
  54.5%
6
  66.7%
8.Primary Outcome
Title Part B: Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure
Hide 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 8 years)
Hide Outcome Measure Data
Hide Analysis Population Description
ATP Population
Arm/Group Title 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
Hide Arm/Group Description:
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.
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.
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.
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.
Overall Number of Participants Analyzed 6 23 27 78
Measure Type: Number
Unit of Measure: 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
9.Primary Outcome
Title Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator
Hide 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 7 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) Population: all randomized participants regardless of whether or not treatment was administered
Arm/Group Title Part C: Dabrafenib 150 mg Part C: Dabrafenib 150 mg + Trametinib 1 mg Part C: Dabrafenib 150 mg + Trametinib 2 mg
Hide Arm/Group Description:
Participants received dabrafenib 150 mg gelatin capsules BID.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 54 54 54
Measure Type: Count of Participants
Unit of Measure: Participants
CR
2
   3.7%
6
  11.1%
10
  18.5%
PR
27
  50.0%
21
  38.9%
31
  57.4%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part C: Dabrafenib 150 mg, Part C: Dabrafenib 150 mg + Trametinib 1 mg
Comments Difference in response rate Arm2 - Arm1
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Unconditional exact method
Estimated Value -4
Confidence Interval (2-Sided) 95%
-23.1 to 15.9
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Part C: Dabrafenib 150 mg, Part C: Dabrafenib 150 mg + Trametinib 2 mg
Comments Difference in response rate Arm3 - Arm1
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Unconditional exact method
Estimated Value 22
Confidence Interval (2-Sided) 95%
2.5 to 40.7
Estimation Comments [Not Specified]
10.Primary Outcome
Title Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR)
Hide 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 19 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title Part C: Dabrafenib 150 mg Part C: Dabrafenib 150 mg + Trametinib 1 mg Part C: Dabrafenib 150 mg + Trametinib 2 mg
Hide Arm/Group Description:
Participants received dabrafenib 150 mg gelatin capsules BID.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 54 54 54
Measure Type: Count of Participants
Unit of Measure: Participants
CR
4
   7.4%
4
   7.4%
7
  13.0%
PR
21
  38.9%
18
  33.3%
26
  48.1%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part C: Dabrafenib 150 mg, Part C: Dabrafenib 150 mg + Trametinib 1 mg
Comments Difference in response rate Arm2- Arm1
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Unconditional exact method
Estimated Value -6
Confidence Interval (2-Sided) 95%
-24.9 to 14.1
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Part C: Dabrafenib 150 mg, Part C: Dabrafenib 150 mg + Trametinib 2 mg
Comments Difference in response rate Arm3 - Arm1
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Unconditional exact method
Estimated Value 15
Confidence Interval (2-Sided) 95%
-4.9 to 33.7
Estimation Comments [Not Specified]
11.Primary Outcome
Title Part C (Crossover): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator
Hide 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 7 years)
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 45
Measure Type: Count of Participants
Unit of Measure: Participants
CR
1
   2.2%
PR
5
  11.1%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Response rate
Estimated Value 6
Confidence Interval (2-Sided) 95%
5.1 to 26.8
Estimation Comments [Not Specified]
12.Primary Outcome
Title Part C (Randomized): Progression-free Survival (PFS) as Assessed by the Investigator
Hide Description PFS is defined as the interval between the date of randomization 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 date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 7 years)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title Part C: Dabrafenib 150 mg Part C: Dabrafenib 150 mg + Trametinib 1 mg Part C: Dabrafenib 150 mg + Trametinib 2 mg
Hide Arm/Group Description:
Participants received dabrafenib 150 mg gelatin capsules BID.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 54 54 54
Median (Full Range)
Unit of Measure: Months
5.8
(4.3 to 7.4)
9.2
(5.7 to 11.0)
9.4
(7.6 to 16.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part C: Dabrafenib 150 mg, Part C: Dabrafenib 150 mg + Trametinib 1 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0048
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.58
Confidence Interval (2-Sided) 95%
0.38 to 0.87
Estimation Comments HRs were estimated using the Pike estimator.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Part C: Dabrafenib 150 mg, Part C: Dabrafenib 150 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.44
Confidence Interval (2-Sided) 95%
0.29 to 0.68
Estimation Comments HRs were estimated using the Pike estimator.
13.Primary Outcome
Title Part C (Crossover): Progression-free Survival (PFS) as Assessed by the Investigator
Hide 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 7 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Crossover Population
Arm/Group Title Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 45
Median (95% Confidence Interval)
Unit of Measure: Months
3.6
(1.8 to 3.9)
14.Primary Outcome
Title Part C (Randomized): Progression-free Survival (PFS) as Assessed by the Blinded Independent Central Review (BICR)
Hide Description PFS is defined as the interval between the date of randomization 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 date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 19 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title Part C: Dabrafenib 150 mg Part C: Dabrafenib 150 mg + Trametinib 1 mg Part C: Dabrafenib 150 mg + Trametinib 2 mg
Hide Arm/Group Description:
Participants received dabrafenib 150 mg gelatin capsules BID.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 54 54 54
Median (95% Confidence Interval)
Unit of Measure: Months
7.3
(5.5 to 9.4)
8.3
(5.6 to 11.3)
9.2 [1] 
(7.6 to NA)
[1]
NA: Not estimable due to insufficient number of participants with events
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part C: Dabrafenib 150 mg, Part C: Dabrafenib 150 mg + Trametinib 1 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1667
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.73
Confidence Interval (2-Sided) 95%
0.45 to 1.18
Estimation Comments HRs were estimated using the Pike estimator.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Part C: Dabrafenib 150 mg, Part C: Dabrafenib 150 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0119
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.54
Confidence Interval (2-Sided) 95%
0.32 to 0.90
Estimation Comments HRs were estimated using the Pike estimator.
15.Primary Outcome
Title Part C (Randomized): Duration of Response as Assessed by the Investigator and Blinded Independent Central Review (BICR)
Hide 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 19 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Only those participants who had a CR or PR were analyzed for duration of response.
Arm/Group Title Part C: Dabrafenib 150 mg Part C: Dabrafenib 150 mg + Trametinib 1 mg Part C: Dabrafenib 150 mg + Trametinib 2 mg
Hide Arm/Group Description:
Participants received dabrafenib 150 mg gelatin capsules BID.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 54 54 54
Median (95% Confidence Interval)
Unit of Measure: Months
Investigator assessed Number Analyzed 29 participants 27 participants 41 participants
5.6
(3.9 to 7.4)
11.1
(7.4 to 13.2)
10.5
(7.4 to 19.2)
BICR assessed Number Analyzed 25 participants 22 participants 33 participants
7.6 [1] 
(4.7 to NA)
9.5 [1] 
(5.6 to NA)
NA [1] 
(6.7 to NA)
[1]
NA: Not estimable due to insufficient number of participants with events
16.Primary Outcome
Title Part C (Randomized): Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
Hide 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.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Hide Outcome Measure Data
Hide Analysis Population Description
ATP Population
Arm/Group Title Part C: Dabrafenib 150 mg Part C: Dabrafenib 150 mg + Trametinib 1 mg Part C: Dabrafenib 150 mg + Trametinib 2 mg
Hide Arm/Group Description:
Participants received dabrafenib 150 mg gelatin capsules BID.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 53 54 55
Measure Type: Count of Participants
Unit of Measure: Participants
Any AE
53
 100.0%
53
  98.1%
55
 100.0%
Any SAE
15
  28.3%
24
  44.4%
39
  70.9%
17.Primary Outcome
Title Part C (Randomized): Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline
Hide 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. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.
Arm/Group Title Part C: Dabrafenib 150 mg Part C: Dabrafenib 150 mg + Trametinib 1 mg Part C: Dabrafenib 150 mg + Trametinib 2 mg
Hide Arm/Group Description:
Participants received dabrafenib 150 mg gelatin capsules BID.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 53 54 55
Measure Type: Count of Participants
Unit of Measure: Participants
Albumin Number Analyzed 0 participants 1 participants 1 participants
Increase to Grade 3 0
1
 100.0%
1
 100.0%
Increase to Grade 4 0
0
   0.0%
0
   0.0%
Alkaline Phosphatase Number Analyzed 0 participants 3 participants 2 participants
Increase to Grade 3 0
3
 100.0%
2
 100.0%
Increase to Grade 4 0
0
   0.0%
0
   0.0%
Alanine Amino Transferase Number Analyzed 0 participants 2 participants 2 participants
Increase to Grade 3 0
2
 100.0%
2
 100.0%
Increase to Grade 4 0
0
   0.0%
0
   0.0%
Aspartate Amino Transferase Number Analyzed 0 participants 1 participants 3 participants
Increase to Grade 3 0
1
 100.0%
3
 100.0%
Increase to Grade 4 0
0
   0.0%
0
   0.0%
Total Bilirubin Number Analyzed 0 participants 2 participants 0 participants
Increase to Grade 3 0
2
 100.0%
0
Increase to Grade 4 0
0
   0.0%
0
Calcium (Hypercalcemia) Number Analyzed 0 participants 1 participants 0 participants
Increase to Grade 3 0
0
   0.0%
0
Increase to Grade 4 0
1
 100.0%
0
Calcium (Hypocalcemia) Number Analyzed 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0
Increase to Grade 4 0 0 0
Cholesterol Number Analyzed 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0
Increase to Grade 4 0 0 0
Creatine Kinase Number Analyzed 0 participants 1 participants 0 participants
Increase to Grade 3 0
0
   0.0%
0
Increase to Grade 4 0
1
 100.0%
0
Creatinine Number Analyzed 0 participants 1 participants 3 participants
Increase to Grade 3 0
1
 100.0%
2
  66.7%
Increase to Grade 4 0
0
   0.0%
1
  33.3%
Gamma Glutamyl Transferase Number Analyzed 1 participants 11 participants 8 participants
Increase to Grade 3
1
 100.0%
11
 100.0%
7
  87.5%
Increase to Grade 4
0
   0.0%
0
   0.0%
1
  12.5%
Glucose (Hyperglycemia) Number Analyzed 1 participants 4 participants 6 participants
Increase to Grade 3
1
 100.0%
4
 100.0%
6
 100.0%
Increase to Grade 4
0
   0.0%
0
   0.0%
0
   0.0%
Glucose (Hypoglycemia) Number Analyzed 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0
Increase to Grade 4 0 0 0
Potassium (Hyperkalemia) Number Analyzed 2 participants 0 participants 1 participants
Increase to Grade 3
2
 100.0%
0
1
 100.0%
Increase to Grade 4
0
   0.0%
0
0
   0.0%
Potassium (Hypokalemia) Number Analyzed 3 participants 1 participants 2 participants
Increase to Grade 3
3
 100.0%
1
 100.0%
1
  50.0%
Increase to Grade 4
0
   0.0%
0
   0.0%
1
  50.0%
Magnesium (Hypermagnesemia) Number Analyzed 0 participants 2 participants 1 participants
Increase to Grade 3 0
2
 100.0%
1
 100.0%
Increase to Grade 4 0
0
   0.0%
0
   0.0%
Magnesium (Hypomagnesemia) Number Analyzed 0 participants 0 participants 1 participants
Increase to Grade 3 0 0
1
 100.0%
Increase to Grade 4 0 0
0
   0.0%
Sodium (Hypernatremia) Number Analyzed 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0
Increase to Grade 4 0 0 0
Sodium (Hyponatremia) Number Analyzed 0 participants 10 participants 6 participants
Increase to Grade 3 0
10
 100.0%
6
 100.0%
Increase to Grade 4 0
0
   0.0%
0
   0.0%
Phosphorus inorganic Number Analyzed 0 participants 6 participants 4 participants
Increase to Grade 3 0
6
 100.0%
4
 100.0%
Increase to Grade 4 0
0
   0.0%
0
   0.0%
Triglycerides Number Analyzed 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0
Increase to Grade 4 0 0 0
18.Primary Outcome
Title Part C (Randomized): Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range
Hide Description For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Hide Outcome Measure Data
Hide Analysis Population Description
ATP Population. Only those participants who were available at the indicated time points were analyzed.
Arm/Group Title Part C: Dabrafenib 150 mg Part C: Dabrafenib 150 mg + Trametinib 1 mg Part C: Dabrafenib 150 mg + Trametinib 2 mg
Hide Arm/Group Description:
Participants received dabrafenib 150 mg gelatin capsules BID.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 53 54 55
Measure Type: Count of Participants
Unit of Measure: Participants
Direct Bilirubin Number Analyzed 0 participants 0 participants 0 participants
Decrease to Low 0 0 0
Increase to High 0 0 0
Creatine Kinase MB mass Number Analyzed 0 participants 1 participants 0 participants
Decrease to Low 0
0
   0.0%
0
Increase to High 0
1
 100.0%
0
Chloride Number Analyzed 18 participants 38 participants 36 participants
Decrease to Low
7
  38.9%
24
  63.2%
24
  66.7%
Increase to High
11
  61.1%
14
  36.8%
12
  33.3%
Carbon dioxide content/Bicarbonate Number Analyzed 13 participants 22 participants 28 participants
Decrease to Low
5
  38.5%
8
  36.4%
12
  42.9%
Increase to High
8
  61.5%
14
  63.6%
16
  57.1%
C-Reactive protein Number Analyzed 0 participants 0 participants 3 participants
Decrease to Low 0 0
0
   0.0%
Increase to High 0 0
3
 100.0%
Creatinine Clearance Number Analyzed 14 participants 27 participants 20 participants
Decrease to Low
7
  50.0%
16
  59.3%
10
  50.0%
Increase to High
7
  50.0%
11
  40.7%
10
  50.0%
High Density Lipids, Cholesterol Number Analyzed 0 participants 0 participants 0 participants
Decrease to Low 0 0 0
Increase to High 0 0 0
Lactate Dehydrogenase Number Analyzed 5 participants 27 participants 34 participants
Decrease to Low
2
  40.0%
3
  11.1%
2
   5.9%
Increase to High
3
  60.0%
24
  88.9%
32
  94.1%
Low Density Lipids, Cholesterol Number Analyzed 0 participants 0 participants 0 participants
Decrease to Low 0 0 0
Increase to High 0 0 0
Total Protein Number Analyzed 5 participants 18 participants 22 participants
Decrease to Low
4
  80.0%
10
  55.6%
19
  86.4%
Increase to High
1
  20.0%
8
  44.4%
3
  13.6%
Troponin I Number Analyzed 0 participants 0 participants 0 participants
Decrease to Low 0 0 0
Increase to High 0 0 0
Urea/BUN Number Analyzed 13 participants 27 participants 29 participants
Decrease to Low
5
  38.5%
4
  14.8%
9
  31.0%
Increase to High
8
  61.5%
23
  85.2%
20
  69.0%
19.Primary Outcome
Title Part C (Randomized): Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline
Hide 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 Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.
Arm/Group Title Part C: Dabrafenib 150 mg Part C: Dabrafenib 150 mg + Trametinib 1 mg Part C: Dabrafenib 150 mg + Trametinib 2 mg
Hide Arm/Group Description:
Participants received dabrafenib 150 mg gelatin capsules BID.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 53 54 55
Measure Type: Count of Participants
Unit of Measure: Participants
Hemoglobin (Increased) Number Analyzed 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0
Increase to Grade 4 0 0 0
Hemoglobin (Anemia) Number Analyzed 0 participants 4 participants 2 participants
Increase to Grade 3 0
4
 100.0%
2
 100.0%
Increase to Grade 4 0
0
   0.0%
0
   0.0%
Lymphocytes (Increased) Number Analyzed 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0
Increase to Grade 4 0 0 0
Lymphocytes (Decreased) Number Analyzed 3 participants 11 participants 15 participants
Increase to Grade 3
3
 100.0%
10
  90.9%
12
  80.0%
Increase to Grade 4
0
   0.0%
1
   9.1%
3
  20.0%
Total Neutrophils Number Analyzed 1 participants 2 participants 8 participants
Increase to Grade 3
1
 100.0%
2
 100.0%
4
  50.0%
Increase to Grade 4
0
   0.0%
0
   0.0%
4
  50.0%
Platelet Count Number Analyzed 0 participants 2 participants 4 participants
Increase to Grade 3 0
2
 100.0%
3
  75.0%
Increase to Grade 4 0
0
   0.0%
1
  25.0%
White Blood Cell count Number Analyzed 0 participants 3 participants 5 participants
Increase to Grade 3 0
3
 100.0%
5
 100.0%
Increase to Grade 4 0
0
   0.0%
0
   0.0%
20.Primary Outcome
Title Part C (Randomized): Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range
Hide Description For Hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.
Arm/Group Title Part C: Dabrafenib 150 mg Part C: Dabrafenib 150 mg + Trametinib 1 mg Part C: Dabrafenib 150 mg + Trametinib 2 mg
Hide Arm/Group Description:
Participants received dabrafenib 150 mg gelatin capsules BID.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 53 54 55
Measure Type: Count of Participants
Unit of Measure: Participants
Basophils Number Analyzed 4 participants 7 participants 13 participants
Decrease to Low
1
  25.0%
1
  14.3%
3
  23.1%
Increase to High
3
  75.0%
6
  85.7%
10
  76.9%
Eosinophils Number Analyzed 5 participants 22 participants 17 participants
Decrease to Low
3
  60.0%
11
  50.0%
8
  47.1%
Increase to High
2
  40.0%
11
  50.0%
9
  52.9%
Hematocrit Number Analyzed 17 participants 24 participants 29 participants
Decrease to Low
15
  88.2%
23
  95.8%
27
  93.1%
Increase to High
2
  11.8%
1
   4.2%
2
   6.9%
Mean Corpuscle Hemoglobin concentration Number Analyzed 13 participants 24 participants 21 participants
Decrease to Low
11
  84.6%
16
  66.7%
12
  57.1%
Increase to High
2
  15.4%
8
  33.3%
9
  42.9%
Mean Corpuscle Hemoglobin Number Analyzed 10 participants 17 participants 16 participants
Decrease to Low
6
  60.0%
11
  64.7%
8
  50.0%
Increase to High
4
  40.0%
6
  35.3%
8
  50.0%
Mean Corpuscle Volume Number Analyzed 9 participants 10 participants 11 participants
Decrease to Low
8
  88.9%
5
  50.0%
7
  63.6%
Increase to High
1
  11.1%
5
  50.0%
4
  36.4%
Monocytes Number Analyzed 22 participants 34 participants 26 participants
Decrease to Low
5
  22.7%
14
  41.2%
12
  46.2%
Increase to High
17
  77.3%
20
  58.8%
14
  53.8%
Red Blood Cell count Number Analyzed 12 participants 26 participants 29 participants
Decrease to Low
11
  91.7%
22
  84.6%
25
  86.2%
Increase to High
1
   8.3%
4
  15.4%
4
  13.8%
Reticulocytes Number Analyzed 0 participants 1 participants 7 participants
Decrease to Low 0
1
 100.0%
2
  28.6%
Increase to High 0
0
   0.0%
5
  71.4%
21.Primary Outcome
Title Part C (Randomized): Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure
Hide 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 approximately 7 years)
Hide Outcome Measure Data
Hide Analysis Population Description
ATP Population
Arm/Group Title Part C: Dabrafenib 150 mg Part C: Dabrafenib 150 mg + Trametinib 1 mg Part C: Dabrafenib 150 mg + Trametinib 2 mg
Hide Arm/Group Description:
Participants received dabrafenib 150 mg gelatin capsules BID.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 53 54 55
Measure Type: Number
Unit of Measure: 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
22.Primary Outcome
Title Part D (Analyte=GSK2118436): Maximum Plasma Concentration (Cmax) of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title 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
Hide Arm/Group Description:
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.
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.
Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 15 14 15 15
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng/mL
Day 1
1117
(914 to 1365)
1669
(1059 to 2631)
1227
(924 to 1764)
2289
(1622 to 3231)
Day 21
1050
(811 to 1358)
1746
(1344 to 2269)
1217
(895 to 1654)
2052
(1472 to 2860)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg, Part D: Dabrafenib 150 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.51
Confidence Interval (2-Sided) 90%
1.10 to 2.08
Estimation Comments Geometric mean ratio (HPMC/Gelatin) and the corresponding 90% CI were provided for BRAF dose level 150 mg BID.
23.Primary Outcome
Title Part D (Analyte=GSK2118436): Tmax of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
PK Population. Only participants available at the indicated timepoints were analyzed.
Arm/Group Title 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
Hide Arm/Group Description:
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.
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.
Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 15 14 15 15
Median (Full Range)
Unit of Measure: Hours
Day 1
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
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)
24.Primary Outcome
Title Part D (Analyte=GSK2118436): AUC (0-tau) and AUC (0-inf) of Single and Repeat Doses of Dabrafenib Alone and in Combination With Trametinib
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
PK Population. Only participants available at the indicated timepoints were analyzed.
Arm/Group Title 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
Hide Arm/Group Description:
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.
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.
Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 15 14 15 15
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng*hr/mL
AUC (0-tau), Day 1 Number Analyzed 15 participants 14 participants 15 participants 15 participants
3593
(3008 to 4293)
6507
(4288 to 9872)
4618
(3525 to 6051)
7331
(5355 to 10037)
AUC (0-tau), Day 21 Number Analyzed 15 participants 14 participants 15 participants 15 participants
3020
(2390 to 3816)
4663
(3511 to 6194)
3434
(2679 to 4403)
5886
(4608 to 7517)
AUC (0-inf), Day 1 Number Analyzed 15 participants 14 participants 15 participants 15 participants
3982
(3325 to 4770)
7291
(4830 to 11005)
5321
(4192 to 6755)
8152
(5860 to 11341)
AUC (0-inf), Day 21 Number Analyzed 0 participants 0 participants 0 participants 0 participants
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg, Part D: Dabrafenib 150 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.23
Confidence Interval (2-Sided) 90%
0.89 to 1.69
Estimation Comments 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.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg, Part D: Dabrafenib 150 mg + Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 1.10
Confidence Interval (2-Sided) 90%
0.84 to 1.44
Estimation Comments Geometric mean ratio (HPMC/Gelatin) and the corresponding 90% CI were provided for BRAF dose level 150 mg BID.
25.Primary Outcome
Title Part D: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
Hide 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.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Hide Outcome Measure Data
Hide Analysis Population Description
ATP Population
Arm/Group Title 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
Hide Arm/Group Description:
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.
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.
Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 15 15 41 39
Measure Type: Count of Participants
Unit of Measure: Participants
Any AE
15
 100.0%
15
 100.0%
41
 100.0%
38
  97.4%
Any SAE
8
  53.3%
11
  73.3%
29
  70.7%
30
  76.9%
26.Primary Outcome
Title Part D: Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline
Hide 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. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.
Arm/Group Title 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
Hide Arm/Group Description:
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.
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.
Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 15 15 41 39
Measure Type: Count of Participants
Unit of Measure: Participants
Albumin Number Analyzed 0 participants 2 participants 1 participants 0 participants
Increase to Grade 3 0
2
 100.0%
1
 100.0%
0
Increase to Grade 4 0
0
   0.0%
0
   0.0%
0
Alkaline Phosphatase Number Analyzed 1 participants 2 participants 0 participants 3 participants
Increase to Grade 3
1
 100.0%
2
 100.0%
0
3
 100.0%
Increase to Grade 4
0
   0.0%
0
   0.0%
0
0
   0.0%
Alanine Amino Transferase Number Analyzed 2 participants 0 participants 2 participants 1 participants
Increase to Grade 3
2
 100.0%
0
2
 100.0%
1
 100.0%
Increase to Grade 4
0
   0.0%
0
0
   0.0%
0
   0.0%
Amylase Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Aspartate Amino Transferase Number Analyzed 2 participants 0 participants 3 participants 3 participants
Increase to Grade 3
2
 100.0%
0
3
 100.0%
3
 100.0%
Increase to Grade 4
0
   0.0%
0
0
   0.0%
0
   0.0%
Total Bilirubin Number Analyzed 1 participants 0 participants 0 participants 1 participants
Increase to Grade 3
1
 100.0%
0 0
1
 100.0%
Increase to Grade 4
0
   0.0%
0 0
0
   0.0%
Calcium (Hypercalcemia) Number Analyzed 0 participants 0 participants 0 participants 1 participants
Increase to Grade 3 0 0 0
1
 100.0%
Increase to Grade 4 0 0 0
0
   0.0%
Calcium (Hypocalcemia) Number Analyzed 0 participants 1 participants 1 participants 1 participants
Increase to Grade 3 0
1
 100.0%
0
   0.0%
1
 100.0%
Increase to Grade 4 0
0
   0.0%
1
 100.0%
0
   0.0%
Cholesterol Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Creatine Kinase Number Analyzed 0 participants 1 participants 2 participants 0 participants
Increase to Grade 3 0
1
 100.0%
2
 100.0%
0
Increase to Grade 4 0
0
   0.0%
0
   0.0%
0
Creatinine Number Analyzed 0 participants 0 participants 1 participants 0 participants
Increase to Grade 3 0 0
1
 100.0%
0
Increase to Grade 4 0 0
0
   0.0%
0
Gamma Glutamyl Transferase Number Analyzed 4 participants 3 participants 6 participants 5 participants
Increase to Grade 3
3
  75.0%
1
  33.3%
6
 100.0%
5
 100.0%
Increase to Grade 4
1
  25.0%
2
  66.7%
0
   0.0%
0
   0.0%
Glucose (Hyperglycemia) Number Analyzed 1 participants 2 participants 4 participants 1 participants
Increase to Grade 3
1
 100.0%
2
 100.0%
4
 100.0%
1
 100.0%
Increase to Grade 4
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Glucose (Hypoglycemia) Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Potassium (Hyperkalemia) Number Analyzed 0 participants 0 participants 1 participants 0 participants
Increase to Grade 3 0 0
1
 100.0%
0
Increase to Grade 4 0 0
0
   0.0%
0
Potassium (Hypokalemia) Number Analyzed 0 participants 1 participants 2 participants 2 participants
Increase to Grade 3 0
1
 100.0%
1
  50.0%
2
 100.0%
Increase to Grade 4 0
0
   0.0%
1
  50.0%
0
   0.0%
Lipase Number Analyzed 0 participants 2 participants 0 participants 1 participants
Increase to Grade 3 0
0
   0.0%
0
0
   0.0%
Increase to Grade 4 0
2
 100.0%
0
1
 100.0%
Magnesium (Hypermagnesemia) Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Magnesium (Hypomagnesemia) Number Analyzed 0 participants 0 participants 1 participants 0 participants
Increase to Grade 3 0 0
1
 100.0%
0
Increase to Grade 4 0 0
0
   0.0%
0
Sodium (Hypernatremia) Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Sodium (Hyponatremia) Number Analyzed 1 participants 4 participants 6 participants 6 participants
Increase to Grade 3
1
 100.0%
4
 100.0%
5
  83.3%
5
  83.3%
Increase to Grade 4
0
   0.0%
0
   0.0%
1
  16.7%
1
  16.7%
Phosphorus inorganic Number Analyzed 0 participants 0 participants 3 participants 2 participants
Increase to Grade 3 0 0
3
 100.0%
2
 100.0%
Increase to Grade 4 0 0
0
   0.0%
0
   0.0%
Triglycerides Number Analyzed 0 participants 0 participants 0 participants 0 participants
Increase to Grade 3 0 0 0 0
Increase to Grade 4 0 0 0 0
Uric acid Number Analyzed 0 participants 0 participants 2 participants 0 participants
Increase to Grade 3 0 0
0
   0.0%
0
Increase to Grade 4 0 0
2
 100.0%
0
27.Primary Outcome
Title Part D: Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range
Hide Description For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.
Time Frame From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Participants (ATP) Population. Only participants with lab values at the specified planned time were considered.
Arm/Group Title 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
Hide Arm/Group Description:
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.
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.
Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Overall Number of Participants Analyzed 15 15 41 39
Measure Type: Count of Participants
Unit of Measure: Participants
Direct Bilirubin Number Analyzed 0 participants 0 participants 0 participants 0 participants
Decrease Low 0 0 0 0
Increase to High 0 0 0 0
Creatine Kinase MB mass Number Analyzed 0 participants 0 participants 1 participants 0 participants
Decrease Low 0 0
0
   0.0%
0
Increase to High 0 0
1
 100.0%
0
Chloride Number Analyzed 9 participants 11 participants 25 participants 34 participants
Decrease Low
7
  77.8%
9
  81.8%
18
  72.0%
25
  73.5%
Increase to High
2
  22.2%
2
  18.2%
7
  28.0%
9
  26.5%
Carbon dioxide content/Bicarbonate Number Analyzed 7 participants 8 participants 24 participants 18 participants
Decrease Low
3
  42.9%
5
  62.5%
12
  50.0%
8
  44.4%
Increase to High
4
  57.1%
3
  37.5%
12
  50.0%
10
  55.6%
C-Reactive protein Number Analyzed 2 participants 0 participants 3 participants 3 participants
Decrease Low
0
   0.0%
0
0
   0.0%
0
   0.0%
Increase to High
2
 100.0%
0
3
 100.0%
3
 100.0%
Creatinine Clearance Number Analyzed 7 participants 6 participants 18 participants 11 participants
Decrease Low
5
  71.4%
5
  83.3%
7
  38.9%
7
  63.6%
Increase to High
2
  28.6%
1
  16.7%
11
  61.1%
4
  36.4%
High Density Lipids cholesterol Number Analyzed 0 participants 0 participants 1 participants 0 participants
Decrease Low 0 0
1
 100.0%
0
Increase to High 0 0
0
   0.0%
0
Lactate Dehydrogenase Number Analyzed 9 participants 10 participants 21 participants 24 participants
Decrease Low
2
  22.2%
3
  30.0%
1
   4.8%
4
  16.7%
Increase to High
7
  77.8%
7
  70.0%
20
  95.2%
20
  83.3%
Low Density Lipids cholesterol Number Analyzed 0 participants 0 participants 1 participants 0 participants
Decrease Low 0 0
0
   0.0%
0
Increase to High 0 0
1
 100.0%
0
Total Protein Number Analyzed 7 participants 8 participants 23 participants 22 participants
Decrease Low
5
  71.4%
7
  87.5%
17
  73.9%
15
  68.2%
Increase to High
2
  28.6%
1
  12.5%
6
  26.1%