Trial Outcomes & Findings for Study to Determine the Effectiveness of GSK1120212 in BRAF Mutation-positive Melanoma Previously Treated With or Without a BRAF Inhibitor (NCT NCT01037127)

Last Updated: 2014-03-31

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

97 participants

Primary outcome timeframe

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)

Results posted on

2014-03-31

Participant Flow

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.

Participant milestones

Participant milestones
Measure	Trametinib 2 mg: Prior BRAF Inhibitors 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.	Trametinib 2 mg: Prior Standard Therapy 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 Study STARTED	40	57
Overall Study COMPLETED	35	36
Overall Study NOT COMPLETED	5	21

Reasons for withdrawal

Reasons for withdrawal
Measure	Trametinib 2 mg: Prior BRAF Inhibitors 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.	Trametinib 2 mg: Prior Standard Therapy 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 Study Lost to Follow-up	2	4
Overall Study Physician Decision	1	0
Overall Study Study Closed Terminated	2	17

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Trametinib 2 mg: Prior BRAF Inhibitors n=40 Participants 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.	Trametinib 2 mg: Prior Standard Therapy n=57 Participants 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 n=97 Participants Total of all reporting groups
Age, Continuous	55.6 Years STANDARD_DEVIATION 14.52 • n=5 Participants	54.0 Years STANDARD_DEVIATION 12.60 • n=7 Participants	54.7 Years STANDARD_DEVIATION 13.37 • n=5 Participants
Sex: Female, Male Female	15 Participants n=5 Participants	14 Participants n=7 Participants	29 Participants n=5 Participants
Sex: Female, Male Male	25 Participants n=5 Participants	43 Participants n=7 Participants	68 Participants n=5 Participants
Race/Ethnicity, Customized White-Arabic/North African Heritage	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized White-White/Caucasian/European Heritage	40 Participants n=5 Participants	56 Participants n=7 Participants	96 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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)

Population: All Treated Population: all participants who received at least one dose of investigational product

Outcome measures

Outcome measures
Measure	Trametinib 2 mg: Prior BRAF Inhibitors n=40 Participants 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.	Trametinib 2 mg: Prior Standard Therapy n=57 Participants 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.	Participants With BRAF Mutation V600E 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 With BRAF Mutation V600E and no Prior Brain Mets 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 With BRAF Mutation V600K 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.
Number of Participants With Best Confirmed Response CR	0 Participants	1 Participants	—	—	—
Number of Participants With Best Confirmed Response PR	0 Participants	13 Participants	—	—	—

PRIMARY outcome

Timeframe: From Baseline (Day 1) until the time of the first documented evidence of a confirmed CR or PR (up to approximately 25 weeks)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Trametinib 2 mg: Prior BRAF Inhibitors n=12 Participants 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.	Trametinib 2 mg: Prior Standard Therapy n=45 Participants 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.	Participants With BRAF Mutation V600E n=46 Participants 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 With BRAF Mutation V600E and no Prior Brain Mets n=36 Participants 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 With BRAF Mutation V600K n=8 Participants 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.
Number of Participants With Best Confirmed Response in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors PR	2 Participants	11 Participants	11 Participants	9 Participants	0 Participants
Number of Participants With Best Confirmed Response in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors CR	0 Participants	1 Participants	1 Participants	1 Participants	0 Participants

PRIMARY outcome

Timeframe: Week 8

Population: All Treated Population

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.

Outcome measures

Outcome measures
Measure	Trametinib 2 mg: Prior BRAF Inhibitors n=30 Participants 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.	Trametinib 2 mg: Prior Standard Therapy n=30 Participants 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.	Participants With BRAF Mutation V600E 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 With BRAF Mutation V600E and no Prior Brain Mets 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 With BRAF Mutation V600K 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.
Number of Participants With Best Unconfirmed Response at the Time of the Interim Analysis (Week 8) CR	0 Participants	0 Participants	—	—	—
Number of Participants With Best Unconfirmed Response at the Time of the Interim Analysis (Week 8) PR	0 Participants	6 Participants	—	—	—

SECONDARY outcome

Timeframe: 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

Population: 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.

Human plasma samples were analyzed for trametinib using a validated analytical method.

Outcome measures

Outcome measures
Measure	Trametinib 2 mg: Prior BRAF Inhibitors n=27 Participants 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.	Trametinib 2 mg: Prior Standard Therapy n=49 Participants 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.	Participants With BRAF Mutation V600E 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 With BRAF Mutation V600E and no Prior Brain Mets 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 With BRAF Mutation V600K 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.
Mean Plasma Concentrations Day 15, pre-dose, n= 27, 44	12.3 Nanograms (ng)/milliliter (mL) Standard Deviation 3.69	11.6 Nanograms (ng)/milliliter (mL) Standard Deviation 5.54	—	—	—
Mean Plasma Concentrations Day 15, 0.5 to 2 hrs post-dose, n=23, 49	18.6 Nanograms (ng)/milliliter (mL) Standard Deviation 7.23	15.2 Nanograms (ng)/milliliter (mL) Standard Deviation 8.93	—	—	—
Mean Plasma Concentrations Day 15, 2 to 4 hrs post-dose, n=23, 48	23.6 Nanograms (ng)/milliliter (mL) Standard Deviation 8.29	20.8 Nanograms (ng)/milliliter (mL) Standard Deviation 9.87	—	—	—
Mean Plasma Concentrations Day 15, 4 to 8 hrs post-dose, n=22, 49	21.3 Nanograms (ng)/milliliter (mL) Standard Deviation 6.14	19.0 Nanograms (ng)/milliliter (mL) Standard Deviation 8.39	—	—	—
Mean Plasma Concentrations Week 4, pre-dose, n=23, 42	11.7 Nanograms (ng)/milliliter (mL) Standard Deviation 3.82	11.6 Nanograms (ng)/milliliter (mL) Standard Deviation 4.19	—	—	—
Mean Plasma Concentrations Week 8, pre-dose, n=19, 31	11.6 Nanograms (ng)/milliliter (mL) Standard Deviation 4.67	11.8 Nanograms (ng)/milliliter (mL) Standard Deviation 6.24	—	—	—
Mean Plasma Concentrations Week 12, pre-dose, n=7, 30	13.2 Nanograms (ng)/milliliter (mL) Standard Deviation 3.75	12.5 Nanograms (ng)/milliliter (mL) Standard Deviation 6.29	—	—	—

SECONDARY outcome

Timeframe: From the date of the first dose of study medication until 28 days after the last dose (up to 477 days)

Population: All Treated Population

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.

Outcome measures

Outcome measures
Measure	Trametinib 2 mg: Prior BRAF Inhibitors n=40 Participants 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.	Trametinib 2 mg: Prior Standard Therapy n=57 Participants 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.	Participants With BRAF Mutation V600E 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 With BRAF Mutation V600E and no Prior Brain Mets 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 With BRAF Mutation V600K 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.
Number of Participants With Any Adverse Event (AE)	39 Participants	57 Participants	—	—	—

SECONDARY outcome

Timeframe: 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)

Population: All Treated Population. Only those participants who had a confirmed CR or PR were analyzed for duration of response.

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.

Outcome measures

Outcome measures
Measure	Trametinib 2 mg: Prior BRAF Inhibitors 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.	Trametinib 2 mg: Prior Standard Therapy n=14 Participants 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.	Participants With BRAF Mutation V600E 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 With BRAF Mutation V600E and no Prior Brain Mets 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 With BRAF Mutation V600K 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.
Duration of Tumor Response	—	5.7 Months Interval 3.7 to 9.2	—	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) until the time of disease progression or death due to any cause (up to approximately 57 weeks)

Population: All Treated Population

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.

Outcome measures

Outcome measures
Measure	Trametinib 2 mg: Prior BRAF Inhibitors n=40 Participants 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.	Trametinib 2 mg: Prior Standard Therapy n=57 Participants 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.	Participants With BRAF Mutation V600E 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 With BRAF Mutation V600E and no Prior Brain Mets 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 With BRAF Mutation V600K 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.
Progression-free Survival (PFS)	1.8 Months Interval 1.8 to 2.0	4.0 Months Interval 3.6 to 5.6	—	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) until the time of disease progression or death due to any cause (up to approximately 57 weeks)

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.

Outcome measures

Outcome measures
Measure	Trametinib 2 mg: Prior BRAF Inhibitors n=12 Participants 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.	Trametinib 2 mg: Prior Standard Therapy n=45 Participants 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.	Participants With BRAF Mutation V600E n=46 Participants 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 With BRAF Mutation V600E and no Prior Brain Mets n=36 Participants 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 With BRAF Mutation V600K n=8 Participants 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.
PFS in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors	3.0 Months Interval 1.8 to 5.3	4.6 Months Interval 3.6 to 7.2	4.6 Months Interval 3.6 to 5.7	5.3 Months Interval 3.6 to 7.4	3.7 Months Interval 1.8 to 4.6

SECONDARY outcome

Timeframe: Baseline (Day 1) until death due to any cause (up to 134 weeks)

Population: All Treated Population

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.

Outcome measures

Outcome measures
Measure	Trametinib 2 mg: Prior BRAF Inhibitors n=40 Participants 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.	Trametinib 2 mg: Prior Standard Therapy n=57 Participants 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.	Participants With BRAF Mutation V600E 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 With BRAF Mutation V600E and no Prior Brain Mets 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 With BRAF Mutation V600K 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 Survival	5.5 Months Interval 3.5 to 9.0	14.3 Months Interval 11.3 to 24.4	—	—	—

SECONDARY outcome

Timeframe: Month 6, Month 12 and Month 24

Population: All Treated Population

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.

Outcome measures

Outcome measures
Measure	Trametinib 2 mg: Prior BRAF Inhibitors n=40 Participants 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.	Trametinib 2 mg: Prior Standard Therapy n=57 Participants 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.	Participants With BRAF Mutation V600E 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 With BRAF Mutation V600E and no Prior Brain Mets 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 With BRAF Mutation V600K 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.
Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline Died after 12 months	5 Participants	13 Participants	—	—	—
Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline Censored, less than 12 months follow-up	3 Participants	1 Participants	—	—	—
Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline Died at or prior to 6 months	20 Participants	12 Participants	—	—	—
Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline Died after 6 months	15 Participants	24 Participants	—	—	—
Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline Censored, less than 6 months follow-up	3 Participants	1 Participants	—	—	—
Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline Censored, more than 6 months follow-up	2 Participants	20 Participants	—	—	—
Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline Died at or prior to 12 months	30 Participants	23 Participants	—	—	—
Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline Censored, more than 12 months follow-up	2 Participants	20 Participants	—	—	—
Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline Died at or prior to 24 months	35 Participants	34 Participants	—	—	—
Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline Died after 24 months	0 Participants	2 Participants	—	—	—
Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline Censored, less than 24 months follow-up	3 Participants	2 Participants	—	—	—
Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline Censored, more than 24 months follow-up	2 Participants	19 Participants	—	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1) until tumor progression (up to approximately 57 weeks)

Population: All Treated Population

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.

Outcome measures

Outcome measures
Measure	Trametinib 2 mg: Prior BRAF Inhibitors n=40 Participants 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.	Trametinib 2 mg: Prior Standard Therapy n=57 Participants 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.	Participants With BRAF Mutation V600E 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 With BRAF Mutation V600E and no Prior Brain Mets 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 With BRAF Mutation V600K 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.
Number of Participants With Tumor Progression Number of participants (par.) with DP	35 Participants	43 Participants	—	—	—
Number of Participants With Tumor Progression Number of par. with DP in target lesions	21 Participants	22 Participants	—	—	—
Number of Participants With Tumor Progression Number of par. with DP in non-target lesions	8 Participants	11 Participants	—	—	—
Number of Participants With Tumor Progression Number of par. with a new lesion	22 Participants	23 Participants	—	—	—
Number of Participants With Tumor Progression Number of par. with clinical progression	3 Participants	0 Participants	—	—	—

Adverse Events

Trametinib 2 mg: Prior BRAF Inhibitors

Serious events: 4 serious events

Other events: 37 other events

Deaths: 0 deaths

Trametinib 2 mg: Prior Standard Therapy

Serious events: 14 serious events

Other events: 57 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Trametinib 2 mg: Prior BRAF Inhibitors n=40 participants at risk 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.	Trametinib 2 mg: Prior Standard Therapy n=57 participants at risk 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.
Infections and infestations Cellulitis	0.00% 0/40 • 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).	8.8% 5/57 • 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).
Infections and infestations Pneumonia	2.5% 1/40 • 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).	3.5% 2/57 • 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).
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	2.5% 1/40 • 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).	1.8% 1/57 • 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).
Gastrointestinal disorders Vomiting	5.0% 2/40 • 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).	0.00% 0/57 • 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).
Investigations Blood amylase increased	0.00% 0/40 • 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).	1.8% 1/57 • 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).
Nervous system disorders Cerebral hemorrhage	0.00% 0/40 • 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).	1.8% 1/57 • 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).
Metabolism and nutrition disorders Decreased appetite	2.5% 1/40 • 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).	0.00% 0/57 • 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).
Metabolism and nutrition disorders Dehydration	2.5% 1/40 • 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).	0.00% 0/57 • 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).
Gastrointestinal disorders Diarrhea	2.5% 1/40 • 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).	0.00% 0/57 • 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).
Infections and infestations Endocarditis	2.5% 1/40 • 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).	0.00% 0/57 • 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).
Gastrointestinal disorders Gastrointestinal fistula	0.00% 0/40 • 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).	1.8% 1/57 • 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).
Gastrointestinal disorders Gastrointestinal hemorrhage	2.5% 1/40 • 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).	0.00% 0/57 • 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).
Metabolism and nutrition disorders Hypoglycemia	0.00% 0/40 • 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).	1.8% 1/57 • 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).
Respiratory, thoracic and mediastinal disorders Hypoxia	2.5% 1/40 • 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).	0.00% 0/57 • 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).
Nervous system disorders Lethargy	2.5% 1/40 • 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).	0.00% 0/57 • 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).
Investigations Lipase increased	0.00% 0/40 • 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).	1.8% 1/57 • 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).
Gastrointestinal disorders Nausea	2.5% 1/40 • 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).	0.00% 0/57 • 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).
General disorders Pneumatosis	0.00% 0/40 • 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).	1.8% 1/57 • 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).
General disorders Pyrexia	0.00% 0/40 • 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).	1.8% 1/57 • 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).
Skin and subcutaneous tissue disorders Rash erythematous	0.00% 0/40 • 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).	1.8% 1/57 • 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).
Infections and infestations Sepsis syndrome	0.00% 0/40 • 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).	1.8% 1/57 • 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).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor hemorrhage	2.5% 1/40 • 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).	0.00% 0/57 • 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).
Infections and infestations Upper respiratory tract infection	0.00% 0/40 • 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).	1.8% 1/57 • 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).
Nervous system disorders Seizure	0.00% 0/40 • 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).	1.8% 1/57 • 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).
Injury, poisoning and procedural complications Compression fracture	0.00% 0/40 • 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).	1.8% 1/57 • 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).
Infections and infestations Urinary tract infection	0.00% 0/40 • 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).	1.8% 1/57 • 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).