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Study to Determine the Effectiveness of GSK1120212 in BRAF Mutation-positive Melanoma Previously Treated With or Without a BRAF Inhibitor

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ClinicalTrials.gov Identifier: NCT01037127
Recruitment Status : Completed
First Posted : December 21, 2009
Results First Posted : March 31, 2014
Last Update Posted : March 31, 2014
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Cancer
Intervention Drug: GSK1120212
Enrollment 97
Recruitment Details The study used a 2-stage, Green-Dahlberg design that permitted stopping the trial for futility if <3 objective responses were observed in the first 30 participants enrolled. If >=3 objective responses were observed, 55 participants could be enrolled in each cohort.
Pre-assignment Details  
Arm/Group Title Trametinib 2 mg: Prior BRAF Inhibitors Trametinib 2 mg: Prior Standard Therapy
Hide Arm/Group Description Participants who were previously treated (before the start of this study) with BRAF inhibitors received trametinib (GSK1120212) 2 milligram (mg) tablets orally once daily (qd) until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, enrollment in this cohort was stopped because, after enrollment of the first 30 participants, no objective responses were observed. Eligible participants who had been consented at the time the 30th participant was dosed were allowed to enroll, leading to overenrollment of 10 participants (total of 40 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks. Participants who were previously treated with standard therapy, but not with BRAF inhibitors, received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, 55 participants were enrolled in this cohort because objective responses occurred in 6 participants at the time of the interim analysis. Eligible participants who had been consented at the time the 55th participant was dosed were allowed to enroll. This led to the overenrollment of 2 participants (total of 57 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Period Title: Overall Study
Started 40 57
Completed 35 36
Not Completed 5 21
Reason Not Completed
Lost to Follow-up             2             4
Physician Decision             1             0
Study Closed Terminated             2             17
Arm/Group Title Trametinib 2 mg: Prior BRAF Inhibitors Trametinib 2 mg: Prior Standard Therapy Total
Hide Arm/Group Description Participants who were previously treated (before the start of this study) with BRAF (v-Raf murine sarcoma viral oncogene homolog B1) inhibitors received trametinib 2 milligram (mg) tablets orally once daily (qd) until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, enrollment in this cohort was stopped because, after enrollment of the first 30 participants, no objective responses were observed. Eligible participants who had been consented at the time the 30th participant was dosed were allowed to enroll, leading to overenrollment of 10 participants (total of 40 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks. Participants who were previously treated with standard therapy, but not with BRAF inhibitors, received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, 55 participants were enrolled in this cohort because objective responses occurred in 6 participants at the time of the interim analysis. Eligible participants who had been consented at the time the 55th participant was dosed were allowed to enroll. This led to the overenrollment of 2 participants (total of 57 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks. Total of all reporting groups
Overall Number of Baseline Participants 40 57 97
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 40 participants 57 participants 97 participants
55.6  (14.52) 54.0  (12.60) 54.7  (13.37)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 57 participants 97 participants
Female
15
  37.5%
14
  24.6%
29
  29.9%
Male
25
  62.5%
43
  75.4%
68
  70.1%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 40 participants 57 participants 97 participants
White-Arabic/North African Heritage 0 1 1
White-White/Caucasian/European Heritage 40 56 96
1.Primary Outcome
Title Number of Participants With Best Confirmed Response
Hide Description Best confirmed response was assessed by the Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Best response was measured either as a complete response (CR), defined as the disappearance of all target lesions and pathological lymph nodes <10 millimeters (mm), or a partial response (PR), defined as at least a 30% decrease in the sum of the diameters of target lesions. To be assigned a status of confirmed CR or PR, a confirmatory disease assessment was required no less than 28 days after the criteria for response were first met.
Time Frame From Baseline (Day 1) until the time of the first documented evidence of a confirmed complete response or partial response (up to approximately 25 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Population: all participants who received at least one dose of investigational product
Arm/Group Title Trametinib 2 mg: Prior BRAF Inhibitors Trametinib 2 mg: Prior Standard Therapy
Hide Arm/Group Description:
Participants who were previously treated (before the start of this study) with BRAF inhibitors received trametinib 2 milligram (mg) tablets orally once daily (qd) until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, enrollment in this cohort was stopped because, after enrollment of the first 30 participants, no objective responses were observed. Eligible participants who had been consented at the time the 30th participant was dosed were allowed to enroll, leading to overenrollment of 10 participants (total of 40 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Participants who were previously treated with standard therapy, but not with BRAF inhibitors, received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, 55 participants were enrolled in this cohort because objective responses occurred in 6 participants at the time of the interim analysis. Eligible participants who had been consented at the time the 55th participant was dosed were allowed to enroll. This led to the overenrollment of 2 participants (total of 57 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Overall Number of Participants Analyzed 40 57
Measure Type: Number
Unit of Measure: Participants
CR 0 1
PR 0 13
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trametinib 2 mg: Prior Standard Therapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter percentage of participants
Estimated Value 25
Confidence Interval (2-Sided) 95%
14.1 to 37.8
Estimation Comments The estimated value reflects the percentage of particpants with CR and PR.
2.Primary Outcome
Title Number of Participants With Best Confirmed Response in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors
Hide Description The number of participants with best confirmed response was analyzed for the following subgroups of participants previously treated with standard therapy but not BRAF inhibitors: (1) participants with prior (before the start of this study) brain metastases (mets); (2) participants without prior brain mets; (3) participants with BRAF mutation V600E; (4) participants with BRAF mutation V600E and no prior brain mets; and (5) participants with BRAF mutation V600K. Objective response was assessed per RECIST version 1.1. Objective response was measured either as CR, defined as the disappearance of all target lesions and pathological lymph nodes <10 mm, or PR, defined as at least a 30% decrease in the sum of the diameters of target lesions. To be assigned a status of confirmed CR or PR, a confirmatory disease assessment was required no less than 28 days after the criteria for response were first met. Brain metastasis is a cancer that has spread to the brain from another location of the body.
Time Frame From Baseline (Day 1) until the time of the first documented evidence of a confirmed CR or PR (up to approximately 25 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Population. A single participant could have been included in more than one subgroup. Subgroup analysis was not conducted in participants previously treated with BRAF inhibitors because there were no CRs or PRs among these participants.
Arm/Group Title Participants With Prior Brain Mets Participants Without Prior Brain Mets Participants With BRAF Mutation V600E Participants With BRAF Mutation V600E and no Prior Brain Mets Participants With BRAF Mutation V600K
Hide Arm/Group Description:
Participants in this arm were those with prior (before the start of this study) brain metastasis, who were previously treated with standard therapy but not BRAF inhibitors. Participants received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met.
Participants in this arm were those without prior brain metastasis, who were previoulsy treated with standard thearpy but not BRAF inhibitors. Participants received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met.
Participants in this arm were those with a positive BRAF mutation at V600E, who were previously treated with standard therapy but not with BRAF inhibitors. Participants received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met.
Participants in this arm were those with a positive BRAF mutation at V600E but no prior brain metastasis, who were previously treated with standard therapy but not with BRAF inhibitors. Participants received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met.
Participants in this arm were those with a positive BRAF mutation at V600K, who were previously treated with standard therapy but not with BRAF inhibitors. Participants received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met.
Overall Number of Participants Analyzed 12 45 46 36 8
Measure Type: Number
Unit of Measure: Participants
CR 0 1 1 1 0
PR 2 11 11 9 0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Participants With Prior Brain Mets
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter percentage of participants
Estimated Value 17
Confidence Interval (2-Sided) 95%
2.1 to 48.4
Estimation Comments The estimated value reflects the percentage of particpants with CR and PR.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Participants Without Prior Brain Mets
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter percentage of participants
Estimated Value 27
Confidence Interval (2-Sided) 95%
14.6 to 41.9
Estimation Comments The estimated value reflects the percentage of particpants with CR and PR.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Participants With BRAF Mutation V600E
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter percentage of participants
Estimated Value 26
Confidence Interval (2-Sided) 95%
14.3 to 41.4
Estimation Comments The estimated value reflects the percentage of particpants with CR and PR.
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Participants With BRAF Mutation V600E and no Prior Brain Mets
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter percentage of participants
Estimated Value 28
Confidence Interval (2-Sided) 95%
14.2 to 45.2
Estimation Comments The estimated value reflects the percentage of particpants with CR and PR.
3.Primary Outcome
Title Number of Participants With Best Unconfirmed Response at the Time of the Interim Analysis (Week 8)
Hide Description An interim analysis was performed using data collected approximately 12 and 13 weeks after the 30th participant was enrolled in the prior BRAF inhibitor and prior standard therapy groups, respectively. The best unconfirmed response by the investigator per RECIST version 1.1 was assessed. The study design permitted stopping the study for futility if <3 best confirmed responses were observed in the first 30 participants of each treatment arm after completing the first post-dose assessment at Week 8. Best response was measured as either a CR, defined as the disappearance of all target lesions and pathological lymph nodes <10 millimeters, or a PR, defined as at least a 30% decrease in the sum of the diameters of target lesions.
Time Frame Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Population
Arm/Group Title Trametinib 2 mg: Prior BRAF Inhibitors Trametinib 2 mg: Prior Standard Therapy
Hide Arm/Group Description:
Participants who were previously treated (before the start of this study) with BRAF inhibitors received trametinib 2 milligram (mg) tablets orally once daily (qd) until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, enrollment in this cohort was stopped because, after enrollment of the first 30 participants, no objective responses were observed. Eligible participants who had been consented at the time the 30th participant was dosed were allowed to enroll, leading to overenrollment of 10 participants (total of 40 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Participants who were previously treated with standard therapy, but not with BRAF inhibitors, received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, 55 participants were enrolled in this cohort because objective responses occurred in 6 participants at the time of the interim analysis. Eligible participants who had been consented at the time the 55th participant was dosed were allowed to enroll. This led to the overenrollment of 2 participants (total of 57 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Overall Number of Participants Analyzed 30 30
Measure Type: Number
Unit of Measure: Participants
CR 0 0
PR 0 6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trametinib 2 mg: Prior Standard Therapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter percentage of participants
Estimated Value 20
Confidence Interval 95%
7.7 to 38.6
Estimation Comments The estimated value reflects the percentage of particpants with CR and PR.
4.Secondary Outcome
Title Mean Plasma Concentrations
Hide Description Human plasma samples were analyzed for trametinib using a validated analytical method.
Time Frame Day 15, pre-dose, 0.5-2 hours (hrs) post-dose, 2-4 hrs post-dose, and 4-8 hrs post-dose; Week 4, pre-dose; Week 8, pre-dose; Week 12, pre-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) Population: all participants in the All Treated Population for whom PK samples were obtained and analyzed. Only those participants available at the indicated time points were analyzed.
Arm/Group Title Trametinib 2 mg: Prior BRAF Inhibitors Trametinib 2 mg: Prior Standard Therapy
Hide Arm/Group Description:
Participants who were previously treated (before the start of this study) with BRAF inhibitors received trametinib 2 milligram (mg) tablets orally once daily (qd) until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, enrollment in this cohort was stopped because, after enrollment of the first 30 participants, no objective responses were observed. Eligible participants who had been consented at the time the 30th participant was dosed were allowed to enroll, leading to overenrollment of 10 participants (total of 40 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Participants who were previously treated with standard therapy, but not with BRAF inhibitors, received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, 55 participants were enrolled in this cohort because objective responses occurred in 6 participants at the time of the interim analysis. Eligible participants who had been consented at the time the 55th participant was dosed were allowed to enroll. This led to the overenrollment of 2 participants (total of 57 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Overall Number of Participants Analyzed 27 49
Mean (Standard Deviation)
Unit of Measure: Nanograms (ng)/milliliter (mL)
Day 15, pre-dose, n= 27, 44 12.3  (3.69) 11.6  (5.54)
Day 15, 0.5 to 2 hrs post-dose, n=23, 49 18.6  (7.23) 15.2  (8.93)
Day 15, 2 to 4 hrs post-dose, n=23, 48 23.6  (8.29) 20.8  (9.87)
Day 15, 4 to 8 hrs post-dose, n=22, 49 21.3  (6.14) 19.0  (8.39)
Week 4, pre-dose, n=23, 42 11.7  (3.82) 11.6  (4.19)
Week 8, pre-dose, n=19, 31 11.6  (4.67) 11.8  (6.24)
Week 12, pre-dose, n=7, 30 13.2  (3.75) 12.5  (6.29)
5.Secondary Outcome
Title Number of Participants With Any Adverse Event (AE)
Hide Description An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. AE and serious AE (SAE) data were collected from the start of the investigational product and continued until the End of Treatment Visit. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.
Time Frame From the date of the first dose of study medication until 28 days after the last dose (up to 477 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Population
Arm/Group Title Trametinib 2 mg: Prior BRAF Inhibitors Trametinib 2 mg: Prior Standard Therapy
Hide Arm/Group Description:
Participants who were previously treated (before the start of this study) with BRAF inhibitors received trametinib 2 milligram (mg) tablets orally once daily (qd) until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, enrollment in this cohort was stopped because, after enrollment of the first 30 participants, no objective responses were observed. Eligible participants who had been consented at the time the 30th participant was dosed were allowed to enroll, leading to overenrollment of 10 participants (total of 40 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Participants who were previously treated with standard therapy, but not with BRAF inhibitors, received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, 55 participants were enrolled in this cohort because objective responses occurred in 6 participants at the time of the interim analysis. Eligible participants who had been consented at the time the 55th participant was dosed were allowed to enroll. This led to the overenrollment of 2 participants (total of 57 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Overall Number of Participants Analyzed 40 57
Measure Type: Number
Unit of Measure: Participants
39 57
6.Secondary Outcome
Title Duration of Tumor Response
Hide Description Duration of tumor response is defined as the time from the first documented evidence of a CR or PR to disease progression (at least a 20 percent increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; unequivocal progression of non-target lesions, or the appearance of a new lesion) or death due to any cause. No participants who were previously treated with BRAF inhibitors had a CR, defined as the disappearance of all target lesions and pathological lymph nodes <10 millimeters, or a PR, defined as at least a 30% decrease in the sum of the diameters of target lesions; thus, no duration of response data can be presented.
Time Frame From the time of the first documented evidence of a confirmed CR or PR until disease progression or death due to any cause (up to approximately 40 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Population. Only those participants who had a confirmed CR or PR were analyzed for duration of response.
Arm/Group Title Trametinib 2 mg: Prior BRAF Inhibitors Trametinib 2 mg: Prior Standard Therapy
Hide Arm/Group Description:
Participants who were previously treated (before the start of this study) with BRAF inhibitors received trametinib 2 milligram (mg) tablets orally once daily (qd) until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, enrollment in this cohort was stopped because, after enrollment of the first 30 participants, no objective responses were observed. Eligible participants who had been consented at the time the 30th participant was dosed were allowed to enroll, leading to overenrollment of 10 participants (total of 40 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Participants who were previously treated with standard therapy, but not with BRAF inhibitors, received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, 55 participants were enrolled in this cohort because objective responses occurred in 6 participants at the time of the interim analysis. Eligible participants who had been consented at the time the 55th participant was dosed were allowed to enroll. This led to the overenrollment of 2 participants (total of 57 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Overall Number of Participants Analyzed 0 14
Median (95% Confidence Interval)
Unit of Measure: Months
5.7
(3.7 to 9.2)
7.Secondary Outcome
Title Progression-free Survival (PFS)
Hide Description PFS is defined as the interval between the treatment start date and the earliest date of disease progression (at least a 20 percent increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; unequivocal progression of non-target lesions, or the appearance of a new lesion) or death due to any cause, whichever occurred first. Participants who had not progressed or died were censored at the date of the last adequate tumor assessment at the time of the cut-off.
Time Frame Baseline (Day 1) until the time of disease progression or death due to any cause (up to approximately 57 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Population
Arm/Group Title Trametinib 2 mg: Prior BRAF Inhibitors Trametinib 2 mg: Prior Standard Therapy
Hide Arm/Group Description:
Participants who were previously treated (before the start of this study) with BRAF inhibitors received trametinib 2 milligram (mg) tablets orally once daily (qd) until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, enrollment in this cohort was stopped because, after enrollment of the first 30 participants, no objective responses were observed. Eligible participants who had been consented at the time the 30th participant was dosed were allowed to enroll, leading to overenrollment of 10 participants (total of 40 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Participants who were previously treated with standard therapy, but not with BRAF inhibitors, received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, 55 participants were enrolled in this cohort because objective responses occurred in 6 participants at the time of the interim analysis. Eligible participants who had been consented at the time the 55th participant was dosed were allowed to enroll. This led to the overenrollment of 2 participants (total of 57 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Overall Number of Participants Analyzed 40 57
Median (95% Confidence Interval)
Unit of Measure: Months
1.8
(1.8 to 2.0)
4.0
(3.6 to 5.6)
8.Secondary Outcome
Title PFS in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors
Hide Description PFS was analyzed for the following subgroups of participants previously treated with standard therapy but not BRAF inhibitors: (1) participants with prior (before the start of this study) brain metastases (mets); (2) participants without prior brain mets; (3) participants with BRAF mutation V600E; (4) participants with BRAF mutation V600E and no prior brain mets; and (5) participants with BRAF mutation V600K. Per RECIST version 1.1, PFS is defined as the interval between the treatment start date and the earliest date of disease progression (at least a 20 percent increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; unequivocal progression of non-target lesions, or the appearance of a new lesion) or death due to any cause, whichever occurred earliest. Brain metastasis is a cancer that has spread to the brain from another location of the body.
Time Frame Baseline (Day 1) until the time of disease progression or death due to any cause (up to approximately 57 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Population. A single participant could have been included in more than one subgroup. Subgroup analysis was not conducted in participants previously treated with BRAF inhibitors because this subgroup was stopped for futility and nearly all the participants progressed before 4 months.
Arm/Group Title Participants With Prior Brain Mets Participants Without Prior Brain Mets Participants With BRAF Mutation V600E Paticipants With BRAF Mutation V600E and no Prior Brain Mets Participants With BRAF Mutation V600K
Hide Arm/Group Description:
Participants in this arm were those with prior (before the start of this study) brain metastasis who were previously treated with standard therapy but not with BRAF inhibitors received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met.
Participants in this arm were those without prior brain metastasis who were previously treated with standard therapy but not with BRAF inhibitors. Participants received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met.
Participants in this arm were those with positive BRAF mutation at V600E, who were previously treated with standard therapy but not with BRAF inhibitors. Participants received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met.
Participants in this arm were those with positive BRAF mutation at V600E but no prior brain metastasis, who were previously treated with standard therapy but not with BRAF inhibitors. Participants received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met.
Participants in this arm were those with positive BRAF mutation at V600K, who were previously treated with standard therapy but not with BRAF inhibitors. Participants received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met.
Overall Number of Participants Analyzed 12 45 46 36 8
Median (95% Confidence Interval)
Unit of Measure: Months
3.0
(1.8 to 5.3)
4.6
(3.6 to 7.2)
4.6
(3.6 to 5.7)
5.3
(3.6 to 7.4)
3.7
(1.8 to 4.6)
9.Secondary Outcome
Title Overall Survival
Hide Description Overall survival is defined as the time from the treatment start date until death due to any cause. Participants who had not died were censored at the date of the last adequate tumor assessment at the time of the cut-off.
Time Frame Baseline (Day 1) until death due to any cause (up to 134 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Population
Arm/Group Title Trametinib 2 mg: Prior BRAF Inhibitors Trametinib 2 mg: Prior Standard Therapy
Hide Arm/Group Description:
Participants who were previously treated (before the start of this study) with BRAF inhibitors received trametinib 2 milligram (mg) tablets orally once daily (qd) until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, enrollment in this cohort was stopped because, after enrollment of the first 30 participants, no objective responses were observed. Eligible participants who had been consented at the time the 30th participant was dosed were allowed to enroll, leading to overenrollment of 10 participants (total of 40 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Participants who were previously treated with standard therapy, but not with BRAF inhibitors, received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, 55 participants were enrolled in this cohort because objective responses occurred in 6 participants at the time of the interim analysis. Eligible participants who had been consented at the time the 55th participant was dosed were allowed to enroll. This led to the overenrollment of 2 participants (total of 57 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Overall Number of Participants Analyzed 40 57
Median (95% Confidence Interval)
Unit of Measure: Months
5.5
(3.5 to 9.0)
14.3
(11.3 to 24.4)
10.Secondary Outcome
Title Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline
Hide Description Overall survival (defined as the time from the treatment start date until death due to any cause) data data are presented as the number of participants who were alive 6 months, 12 months and 24 months after Baseline. Participants who had not died were censored at the date of the last adequate tumor assessment at the time of the cut-off.
Time Frame Month 6, Month 12 and Month 24
Hide Outcome Measure Data
Hide Analysis Population Description
All Treated Population
Arm/Group Title Trametinib 2 mg: Prior BRAF Inhibitors Trametinib 2 mg: Prior Standard Therapy
Hide Arm/Group Description:
Participants who were previously treated (before the start of this study) with BRAF inhibitors received trametinib 2 milligram (mg) tablets orally once daily (qd) until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, enrollment in this cohort was stopped because, after enrollment of the first 30 participants, no objective responses were observed. Eligible participants who had been consented at the time the 30th participant was dosed were allowed to enroll, leading to overenrollment of 10 participants (total of 40 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Participants who were previously treated with standard therapy, but not with BRAF inhibitors, received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, 55 participants were enrolled in this cohort because objective responses occurred in 6 participants at the time of the interim analysis. Eligible participants who had been consented at the time the 55th participant was dosed were allowed to enroll. This led to the overenrollment of 2 participants (total of 57 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Overall Number of Participants Analyzed 40 57
Measure Type: Number
Unit of Measure: Participants
Died at or prior to 6 months 20 12
Died after 6 months 15 24
Censored, less than 6 months follow-up 3 1
Censored, more than 6 months follow-up 2 20
Died at or prior to 12 months 30 23
Died after 12 months 5 13
Censored, less than 12 months follow-up 3 1
Censored, more than 12 months follow-up 2 20
Died at or prior to 24 months 35 34
Died after 24 months 0 2
Censored, less than 24 months follow-up 3 2
Censored, more than 24 months follow-up 2 19
11.Secondary Outcome
Title Number of Participants With Tumor Progression
Hide Description Tumor progression was assessed as disease progression (DP), defined as at least a 20 percent increase in the sum of diameters of target lesions (representative of all involved organs), taking as reference the smallest sum on study; unequivocal progression of non-target lesions; or the appearance of a new lesion. Because melanoma often progresses to the brain/central nervous system (CNS) and this study enrolled approximately 20% participants with prior brain metastases, tumor progression in the brain/CNS was summarized. Paticipants could have been included in more than one category.
Time Frame Baseline (Day 1) until tumor progression (up to approximately 57 weeks)
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Hide Analysis Population Description
All Treated Population
Arm/Group Title Trametinib 2 mg: Prior BRAF Inhibitors Trametinib 2 mg: Prior Standard Therapy
Hide Arm/Group Description:
Participants who were previously treated (before the start of this study) with BRAF inhibitors received trametinib 2 milligram (mg) tablets orally once daily (qd) until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, enrollment in this cohort was stopped because, after enrollment of the first 30 participants, no objective responses were observed. Eligible participants who had been consented at the time the 30th participant was dosed were allowed to enroll, leading to overenrollment of 10 participants (total of 40 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Participants who were previously treated with standard therapy, but not with BRAF inhibitors, received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, 55 participants were enrolled in this cohort because objective responses occurred in 6 participants at the time of the interim analysis. Eligible participants who had been consented at the time the 55th participant was dosed were allowed to enroll. This led to the overenrollment of 2 participants (total of 57 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
Overall Number of Participants Analyzed 40 57
Measure Type: Number
Unit of Measure: Participants
Number of participants (par.) with DP 35 43
Number of par. with DP in target lesions 21 22
Number of par. with DP in non-target lesions 8 11
Number of par. with a new lesion 22 23
Number of par. with clinical progression 3 0
Time Frame Serious AEs and non-serious AEs are presented from the date of the first dose of study medication until the last participant's last visit (up to 1130 days).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Trametinib 2 mg: Prior BRAF Inhibitors Trametinib 2 mg: Prior Standard Therapy
Hide Arm/Group Description Participants who were previously treated (before the start of this study) with BRAF (v-Raf murine sarcoma viral oncogene homolog B1) inhibitors received trametinib 2 milligram (mg) tablets orally once daily (qd) until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, enrollment in this cohort was stopped because, after enrollment of the first 30 participants, no objective responses were observed. Eligible participants who had been consented at the time the 30th participant was dosed were allowed to enroll, leading to overenrollment of 10 participants (total of 40 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks. Participants who were previously treated with standard therapy, but not with BRAF inhibitors, received trametinib 2 mg tablets orally qd until treatment discontinuation criteria were met. Per the pre-specified study design, enrollment could have been stopped if objective response was observed in fewer than 3 participants among the first 30 participants enrolled. Per this criterion, 55 participants were enrolled in this cohort because objective responses occurred in 6 participants at the time of the interim analysis. Eligible participants who had been consented at the time the 55th participant was dosed were allowed to enroll. This led to the overenrollment of 2 participants (total of 57 participants in this cohort). An interim analysis was performed after 30 participants had completed the first target post-dose disease assessment at 8 weeks.
All-Cause Mortality
Trametinib 2 mg: Prior BRAF Inhibitors Trametinib 2 mg: Prior Standard Therapy
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
Trametinib 2 mg: Prior BRAF Inhibitors Trametinib 2 mg: Prior Standard Therapy
Affected / at Risk (%) Affected / at Risk (%)
Total   4/40 (10.00%)   14/57 (24.56%) 
Gastrointestinal disorders     
Vomiting  1  2/40 (5.00%)  0/57 (0.00%) 
Diarrhea  1  1/40 (2.50%)  0/57 (0.00%) 
Gastrointestinal fistula  1  0/40 (0.00%)  1/57 (1.75%) 
Gastrointestinal hemorrhage  1  1/40 (2.50%)  0/57 (0.00%) 
Nausea  1  1/40 (2.50%)  0/57 (0.00%) 
General disorders     
Pneumatosis  1  0/40 (0.00%)  1/57 (1.75%) 
Pyrexia  1  0/40 (0.00%)  1/57 (1.75%) 
Infections and infestations     
Cellulitis  1  0/40 (0.00%)  5/57 (8.77%) 
Pneumonia  1  1/40 (2.50%)  2/57 (3.51%) 
Endocarditis  1  1/40 (2.50%)  0/57 (0.00%) 
Sepsis syndrome  1  0/40 (0.00%)  1/57 (1.75%) 
Upper respiratory tract infection  1  0/40 (0.00%)  1/57 (1.75%) 
Urinary tract infection  1  0/40 (0.00%)  1/57 (1.75%) 
Injury, poisoning and procedural complications     
Compression fracture  1  0/40 (0.00%)  1/57 (1.75%) 
Investigations     
Blood amylase increased  1  0/40 (0.00%)  1/57 (1.75%) 
Lipase increased  1  0/40 (0.00%)  1/57 (1.75%) 
Metabolism and nutrition disorders     
Decreased appetite  1  1/40 (2.50%)  0/57 (0.00%) 
Dehydration  1  1/40 (2.50%)  0/57 (0.00%) 
Hypoglycemia  1  0/40 (0.00%)  1/57 (1.75%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Tumor hemorrhage  1  1/40 (2.50%)  0/57 (0.00%) 
Nervous system disorders     
Cerebral hemorrhage  1  0/40 (0.00%)  1/57 (1.75%) 
Lethargy  1  1/40 (2.50%)  0/57 (0.00%) 
Seizure  1  0/40 (0.00%)  1/57 (1.75%) 
Respiratory, thoracic and mediastinal disorders     
Pulmonary embolism  1  1/40 (2.50%)  1/57 (1.75%) 
Hypoxia  1  1/40 (2.50%)  0/57 (0.00%) 
Skin and subcutaneous tissue disorders     
Rash erythematous  1  0/40 (0.00%)  1/57 (1.75%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Trametinib 2 mg: Prior BRAF Inhibitors Trametinib 2 mg: Prior Standard Therapy
Affected / at Risk (%) Affected / at Risk (%)
Total   37/40 (92.50%)   57/57 (100.00%) 
Blood and lymphatic system disorders     
Anemia  1  5/40 (12.50%)  10/57 (17.54%) 
Cardiac disorders     
Left ventricular dysfunction  1  0/40 (0.00%)  7/57 (12.28%) 
Endocrine disorders     
Hypothyroidism  1  0/40 (0.00%)  3/57 (5.26%) 
Eye disorders     
Vision blurred  1  6/40 (15.00%)  4/57 (7.02%) 
Eye edema  1  2/40 (5.00%)  0/57 (0.00%) 
Visual impairment  1  0/40 (0.00%)  3/57 (5.26%) 
Gastrointestinal disorders     
Diarrhea  1  19/40 (47.50%)  33/57 (57.89%) 
Nausea  1  19/40 (47.50%)  23/57 (40.35%) 
Vomiting  1  11/40 (27.50%)  16/57 (28.07%) 
Constipation  1  13/40 (32.50%)  11/57 (19.30%) 
Abdominal pain  1  7/40 (17.50%)  13/57 (22.81%) 
Dry mouth  1  8/40 (20.00%)  6/57 (10.53%) 
Dyspepsia  1  4/40 (10.00%)  4/57 (7.02%) 
Stomatitis  1  4/40 (10.00%)  4/57 (7.02%) 
Abdominal distension  1  2/40 (5.00%)  3/57 (5.26%) 
Abdominal pain upper  1  2/40 (5.00%)  4/57 (7.02%) 
Flatulence  1  2/40 (5.00%)  3/57 (5.26%) 
Gastrooesophageal reflux disease  1  1/40 (2.50%)  4/57 (7.02%) 
Ascites  1  3/40 (7.50%)  0/57 (0.00%) 
Hemorrhoids  1  0/40 (0.00%)  4/57 (7.02%) 
Mouth ulceration  1  2/40 (5.00%)  1/57 (1.75%) 
General disorders     
Fatigue  1  14/40 (35.00%)  24/57 (42.11%) 
Edema peripheral  1  13/40 (32.50%)  24/57 (42.11%) 
Pyrexia  1  7/40 (17.50%)  14/57 (24.56%) 
Face edema  1  2/40 (5.00%)  8/57 (14.04%) 
Chills  1  3/40 (7.50%)  7/57 (12.28%) 
Mucosal inflammation  1  1/40 (2.50%)  7/57 (12.28%) 
Pain  1  1/40 (2.50%)  4/57 (7.02%) 
Asthenia  1  3/40 (7.50%)  1/57 (1.75%) 
Infections and infestations     
Cellulitis  1  4/40 (10.00%)  3/57 (5.26%) 
Folliculitis  1  1/40 (2.50%)  6/57 (10.53%) 
Localized infection  1  3/40 (7.50%)  4/57 (7.02%) 
Urinary tract infection  1  5/40 (12.50%)  3/57 (5.26%) 
Oral herpes  1  1/40 (2.50%)  3/57 (5.26%) 
Postoperative wound infection  1  2/40 (5.00%)  0/57 (0.00%) 
Sinus congestion  1  0/40 (0.00%)  3/57 (5.26%) 
Injury, poisoning and procedural complications     
Laceration  1  0/40 (0.00%)  3/57 (5.26%) 
Investigations     
Aspartate aminotransferase increased  1  3/40 (7.50%)  8/57 (14.04%) 
Alanine aminotransferase increased  1  1/40 (2.50%)  6/57 (10.53%) 
Weight decreased  1  2/40 (5.00%)  5/57 (8.77%) 
Blood alkaline phosphatase increased  1  2/40 (5.00%)  1/57 (1.75%) 
Ejection fraction decreased  1  0/40 (0.00%)  4/57 (7.02%) 
Hemoglobin decreased  1  2/40 (5.00%)  1/57 (1.75%) 
Metabolism and nutrition disorders     
Decreased appetite  1  7/40 (17.50%)  10/57 (17.54%) 
Hypokalemia  1  3/40 (7.50%)  6/57 (10.53%) 
Hypoalbuminemia  1  8/40 (20.00%)  4/57 (7.02%) 
Hyponatremia  1  4/40 (10.00%)  3/57 (5.26%) 
Dehydration  1  2/40 (5.00%)  4/57 (7.02%) 
Hypocalcemia  1  1/40 (2.50%)  6/57 (10.53%) 
Hypomagnesemia  1  0/40 (0.00%)  4/57 (7.02%) 
Musculoskeletal and connective tissue disorders     
Pain in extremity  1  7/40 (17.50%)  5/57 (8.77%) 
Arthralgia  1  3/40 (7.50%)  9/57 (15.79%) 
Muscle spasms  1  0/40 (0.00%)  9/57 (15.79%) 
Back pain  1  0/40 (0.00%)  5/57 (8.77%) 
Joint swelling  1  0/40 (0.00%)  3/57 (5.26%) 
Musculoskeletal chest pain  1  2/40 (5.00%)  1/57 (1.75%) 
Neck pain  1  0/40 (0.00%)  3/57 (5.26%) 
Nervous system disorders     
Dizziness  1  5/40 (12.50%)  8/57 (14.04%) 
Headache  1  3/40 (7.50%)  5/57 (8.77%) 
Dysgeusia  1  1/40 (2.50%)  5/57 (8.77%) 
Neuropathy peripheral  1  2/40 (5.00%)  2/57 (3.51%) 
Hypoaesthesia  1  2/40 (5.00%)  0/57 (0.00%) 
Amnesia  1  0/40 (0.00%)  3/57 (5.26%) 
Psychiatric disorders     
Insomnia  1  2/40 (5.00%)  8/57 (14.04%) 
Depression  1  1/40 (2.50%)  4/57 (7.02%) 
Mood altered  1  2/40 (5.00%)  0/57 (0.00%) 
Anxiety  1  2/40 (5.00%)  1/57 (1.75%) 
Renal and urinary disorders     
Proteinuria  1  0/40 (0.00%)  3/57 (5.26%) 
Pollakiuria  1  0/40 (0.00%)  3/57 (5.26%) 
Reproductive system and breast disorders     
Breast enlargement  1  2/40 (5.00%)  0/57 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Dyspnea  1  6/40 (15.00%)  9/57 (15.79%) 
Cough  1  2/40 (5.00%)  7/57 (12.28%) 
Epistaxis  1  2/40 (5.00%)  7/57 (12.28%) 
Oropharyngeal pain  1  0/40 (0.00%)  6/57 (10.53%) 
Rhinitis allergic  1  2/40 (5.00%)  1/57 (1.75%) 
Skin and subcutaneous tissue disorders     
Rash  1  20/40 (50.00%)  32/57 (56.14%) 
Dermatitis acneiform  1  8/40 (20.00%)  21/57 (36.84%) 
Pruritus  1  7/40 (17.50%)  20/57 (35.09%) 
Dry skin  1  8/40 (20.00%)  17/57 (29.82%) 
Alopecia  1  3/40 (7.50%)  8/57 (14.04%) 
Rash erythematous  1  2/40 (5.00%)  4/57 (7.02%) 
Erythema  1  2/40 (5.00%)  6/57 (10.53%) 
Photosensitivity reaction  1  0/40 (0.00%)  5/57 (8.77%) 
Rash pruritic  1  2/40 (5.00%)  2/57 (3.51%) 
Nail disorder  1  0/40 (0.00%)  3/57 (5.26%) 
Swelling face  1  2/40 (5.00%)  1/57 (1.75%) 
Skin erosion  1  2/40 (5.00%)  0/57 (0.00%) 
Skin fissures  1  3/40 (7.50%)  3/57 (5.26%) 
Skin ulcer  1  0/40 (0.00%)  3/57 (5.26%) 
Vascular disorders     
Hypertension  1  0/40 (0.00%)  12/57 (21.05%) 
Flushing  1  2/40 (5.00%)  3/57 (5.26%) 
Lymphedema  1  3/40 (7.50%)  2/57 (3.51%) 
Hypotension  1  1/40 (2.50%)  3/57 (5.26%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: GSK Response Center
Organization: GlaxoSmithKline
Phone: 866-435-7343
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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01037127    
Other Study ID Numbers: 113583
First Submitted: November 25, 2009
First Posted: December 21, 2009
Results First Submitted: June 12, 2013
Results First Posted: March 31, 2014
Last Update Posted: March 31, 2014