Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01072175
First received: February 12, 2010
Last updated: July 18, 2016
Last verified: July 2016
Results First Received: June 27, 2013  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Endpoint Classification: Pharmacokinetics/Dynamics Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Cancer
Interventions: Drug: GSK2118436
Drug: GSK1120212

  Participant Flow
  Hide Participant Flow

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

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

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

Participant Flow for 5 periods

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

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

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

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

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



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

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

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



  Outcome Measures
  Show All Outcome Measures

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

36.  Secondary:   Pre- and Post-dose H-scores for Individual Participants in Part B   [ Time Frame: Screening and at disease progression (up to approximately 8 months) ]
  Hide Outcome Measure 36

Measure Type Secondary
Measure Title Pre- and Post-dose H-scores for Individual Participants in Part B
Measure Description p-ERK and p-AKT, biomarkers in tumor biopsies, were assessed for participants with BRAF mutant colorectal cancer. The H-score, which is a composite score that comprises intensity and percentage of staining, is a method of assessing the amount of protein or phospho-protein present in a biopsy sample. The score is obtained by the formula: (3 * percentage of strongly staining nuclei) + (2 * percentage of moderately staining nuclei) + (percentage of weakly staining nuclei). The H-score ranges from 0 to 300, with a score of 0 representing the absence of any of the target protein and an H-score of 300 representing maximum staining and intensity of the target protein.
Time Frame Screening and at disease progression (up to approximately 8 months)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Biomarker Population: participants with H-score data for pre- and post-biopsy pairs

Reporting Groups
  Description
Part B: Dabrafenib + Trametinib Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib (75 mg or 150 mg) gelatin capsules BID and trametinib (1 mg, 1.5 mg, or 2 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.

Measured Values
    Part B: Dabrafenib + Trametinib  
Number of Participants Analyzed  
[units: participants]
  10  
Pre- and Post-dose H-scores for Individual Participants in Part B  
[units: scores on a scale]
 
p-ERK: Participant 1, pre-dose score     135  
p-ERK: Participant 1, post-dose score     109  
p-ERK: Participant 2, pre-dose score     193  
p-ERK: Participant 2, post-dose score     138  
p-ERK: Participant 3, pre-dose score     148  
p-ERK: Participant 3, post-dose score     65  
p-ERK: Participant 4, pre-dose score     80  
p-ERK: Participant 4, post-dose score     20  
p-ERK: Participant 5, pre-dose score     130  
p-ERK: Participant 5, post-dose score     99  
p-ERK: Participant 6, pre-dose score     68  
p-ERK: Participant 6, post-dose score     7  
p-ERK: Participant 7, pre-dose score     128  
p-ERK: Participant 7, post-dose score     81  
p-ERK: Participant 8, pre-dose score     196  
p-ERK: Participant 8, post-dose score     75  
p-ERK: Participant 9, pre-dose score     164  
p-ERK: Participant 9, post-dose score     109  
p-ERK: Participant 10, pre-dose score     239  
p-ERK: Participant 10, post-dose score     78  
p-AKT: Participant 1, pre-dose score     130  
p-AKT, Participant 1, post-dose score     180  
p-AKT: Participant 2, pre-dose score     76  
p-AKT, Participant 2, post-dose score     50  
p-AKT: Participant 3, pre-dose score     192  
p-AKT, Participant 3, post-dose score     277  
p-AKT: Participant 4, pre-dose score     25  
p-AKT, Participant 4, post-dose score     135  
p-AKT: Participant 5, pre-dose score     55  
p-AKT, Participant 5, post-dose score     2  
p-AKT: Participant 6, pre-dose score     145  
p-AKT, Participant 6, post-dose score     20  
p-AKT: Participant 7, pre-dose score     22  
p-AKT, Participant 7, post-dose score     7  
p-AKT: Participant 8, pre-dose score     183  
p-AKT, Participant 8, post-dose score     123  
p-AKT: Participant 9, pre-dose score     278  
p-AKT, Participant 9, post-dose score     289  
p-AKT: Participant 10, pre-dose score     73  
p-AKT, Participant 10, post-dose score     0  

No statistical analysis provided for Pre- and Post-dose H-scores for Individual Participants in Part B



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

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

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

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

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

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

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

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

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

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

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

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

49.  Secondary:   Duration of Response as Assessed by the Investigator in Part D   [ Time Frame: First documented evidence of PR or CR until the earlier of date of disease progression or date of death due to any cause (up to approximately 13 months) ]

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

51.  Secondary:   Overall Survival in Part D   [ Time Frame: From the date of first dose until date of death due to any cause (up to approximately 14 months) ]
Results not yet reported.   Anticipated Reporting Date:   06/2017   Safety Issue:   No


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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