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

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01037127
• Collaborator: (none)
• Enrollment: 97
• Locations: 10
• Arms: 2
• Duration (Months): 38
• Patients Per Site: 9.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

MEK113583 is a Phase II open-label, multi-site study to investigate the objective response rate, safety, and pharmacokinetics of GSK1120212 in subjects with BRAF mutation-positive melanoma who were previously treated with or without a BRAF inhibitor. GSK1120212 is a potent and highly selective inhibitor of MEK activation and kinase activity.

Condition or Disease	Intervention/Treatment	Phase
Cancer	Drug: GSK1120212	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 97 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multi-Center Study to Investigate the Objective Response Rate, Safety, and Pharmacokinetics of GSK1120212, a MEK Inhibitor, in BRAF Mutation-positive Melanoma Subjects Previously Treated With or Without a BRAF Inhibitor
• Study Start Date: Nov 1, 2009
• Actual Primary Completion Date: Jul 1, 2011
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A Subjects who have had previous treatment with a BRAF inhibitor.	Drug: GSK1120212; Daily oral dosing
Experimental: Cohort B Subjects who have had previous chemotherapy or immunotherapy without a BRAF inhibitor.	Drug: GSK1120212; Daily oral dosing

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Best Confirmed Response [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)]

   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.

2. Number of Participants With Best Confirmed Response in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors [From Baseline (Day 1) until the time of the first documented evidence of a confirmed CR or PR (up to approximately 25 weeks)]

   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.

3. Number of Participants With Best Unconfirmed Response at the Time of the Interim Analysis (Week 8) [Week 8]

   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.

Secondary Outcome Measures

1. Mean Plasma Concentrations [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]

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

2. Number of Participants With Any Adverse Event (AE) [From the date of the first dose of study medication until 28 days after the last dose (up to 477 days)]

   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.

3. Duration of Tumor Response [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)]

   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.

4. Progression-free Survival (PFS) [Baseline (Day 1) until the time of disease progression or death due to any cause (up to approximately 57 weeks)]

   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.

5. PFS in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors [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.

6. Overall Survival [Baseline (Day 1) until death due to any cause (up to 134 weeks)]

   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.

7. Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline [Month 6, Month 12 and Month 24]

   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.

8. Number of Participants With Tumor Progression [Baseline (Day 1) until tumor progression (up to approximately 57 weeks)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Metastatic cutaneous melanoma that was previously treated with: (Cohort A) a BRAF inhibitor either with or without other prior therapy. (Cohort B) at least 1 prior chemotherapy or immunotherapy, without treatment with a BRAF inhibitor.

• Documented positive BRAF mutation (V600E, V600K, or V600D).

• Subjects must provide archived tumor tissue or undergo fresh tumor biopsy prior to enrollment.

• The subject must have a radiographically measurable tumor.

• The subject is able to carry out daily life activities without significant difficulty (ECOG performance status score of 0 or 1).

• Able to swallow and retain oral medication.

• Sexually active subjects must use acceptable methods of contraception during the course of the study.

• Adequate organ system function and blood cell counts.

Exclusion Criteria:

• The subject has had major surgery or received certain types of cancer therapy within 21 days before starting the study.

• Previous treatment with a MEK inhibitor.

• Current use of a prohibited medication listed in the protocol.

• Uncontrolled glaucoma.

• Brain metastasis, unless previously treated with surgery or stereotactic radiosurgery, and the disease has been stable for at least 2 months prior to enrollment.

• Current severe or uncontrolled systemic disease.

• History of clinically significant heart, lung, or eye/vision problems.

• Significant unresolved side effects from previous anti-cancer therapy.

• The subject is pregnant or breastfeeding.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Los Angeles	California	United States	90024
2	GSK Investigational Site	Aurora	Colorado	United States	80045
3	GSK Investigational Site	New York	New York	United States	10016
4	GSK Investigational Site	Philadelphia	Pennsylvania	United States	19104
5	GSK Investigational Site	Nashville	Tennessee	United States	37203
6	GSK Investigational Site	Nashville	Tennessee	United States	37232-6307
7	GSK Investigational Site	Houston	Texas	United States	77030-4009
8	GSK Investigational Site	Westmead	New South Wales	Australia	2145
9	GSK Investigational Site	East Melbourne	Victoria	Australia	3002
10	GSK Investigational Site	Nedlands	Western Australia	Australia	6009

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01037127
• Other Study ID Numbers: 113583
• First Posted: Dec 21, 2009
• Last Update Posted: Mar 31, 2014
• Last Verified: Jan 1, 2014

• Keywords provided by GlaxoSmithKline: GSK1120212; BRAF Inhibitor; melanoma; MEK Inhibitor
• Additional relevant MeSH terms: Melanoma; Trametinib

Study Results

Participant Flow

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.

Arm/Group Title	Trametinib 2 mg: Prior BRAF Inhibitors	Trametinib 2 mg: Prior Standard Therapy
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

Baseline Characteristics

Arm/Group Title	Trametinib 2 mg: Prior BRAF Inhibitors	Trametinib 2 mg: Prior Standard Therapy	Total
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 Participants	40	57	97
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	55.6 (14.52)	54.0 (12.60)	54.7 (13.37)
Sex: Female, Male (Count of Participants)
Female	15 37.5%	14 24.6%	29 29.9%
Male	25 62.5%	43 75.4%	68 70.1%
Race/Ethnicity, Customized (Number) [Number]
White-Arabic/North African Heritage	0 0%	1 1.8%	1 1%
White-White/Caucasian/European Heritage	40 100%	56 98.2%	96 99%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Best Confirmed Response
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)

Outcome Measure Data

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
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.
Measure Participants	40	57
CR	0 0%	1 1.8%
PR	0 0%	13 22.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trametinib 2 mg: Prior Standard Therapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percentage of participants
	Estimated Value	25
	Confidence Interval	(2-Sided) 95%; 14.1 to 37.8
	Parameter Dispersion	Type: Value:
	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
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)

Outcome Measure Data

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
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.
Measure Participants	12	45	46	36	8
CR	0 0%	1 1.8%	1 1%	1 NaN	0 NaN
PR	2 5%	11 19.3%	11 11.3%	9 NaN	0 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trametinib 2 mg: Prior BRAF Inhibitors
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percentage of participants
	Estimated Value	17
	Confidence Interval	(2-Sided) 95%; 2.1 to 48.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated value reflects the percentage of particpants with CR and PR.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trametinib 2 mg: Prior Standard Therapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percentage of participants
	Estimated Value	27
	Confidence Interval	(2-Sided) 95%; 14.6 to 41.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated value reflects the percentage of particpants with CR and PR.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Participants With BRAF Mutation V600E
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percentage of participants
	Estimated Value	26
	Confidence Interval	(2-Sided) 95%; 14.3 to 41.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated value reflects the percentage of particpants with CR and PR.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Participants With BRAF Mutation V600E and no Prior Brain Mets
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percentage of participants
	Estimated Value	28
	Confidence Interval	(2-Sided) 95%; 14.2 to 45.2
	Parameter Dispersion	Type: Value:
	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)
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

Outcome Measure Data

Analysis Population Description

All Treated Population

Arm/Group Title	Trametinib 2 mg: Prior BRAF Inhibitors	Trametinib 2 mg: Prior Standard Therapy
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.
Measure Participants	30	30
CR	0 0%	0 0%
PR	0 0%	6 10.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trametinib 2 mg: Prior Standard Therapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percentage of participants
	Estimated Value	20
	Confidence Interval	() 95%; 7.7 to 38.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated value reflects the percentage of particpants with CR and PR.

4. Secondary Outcome

Title	Mean Plasma Concentrations
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

Outcome Measure Data

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
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.
Measure Participants	27	49
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)
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)

Outcome Measure Data

Analysis Population Description

All Treated Population

Arm/Group Title	Trametinib 2 mg: Prior BRAF Inhibitors	Trametinib 2 mg: Prior Standard Therapy
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.
Measure Participants	40	57
Number [Participants]	39 97.5%	57 100%

6. Secondary Outcome

Title	Duration of Tumor Response
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)

Outcome Measure Data

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
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.
Measure Participants	0	14
Median (95% Confidence Interval) [Months]	5.7

7. Secondary Outcome

Title	Progression-free Survival (PFS)
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)

Outcome Measure Data

Analysis Population Description

All Treated Population

Arm/Group Title	Trametinib 2 mg: Prior BRAF Inhibitors	Trametinib 2 mg: Prior Standard Therapy
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.
Measure Participants	40	57
Median (95% Confidence Interval) [Months]	1.8	4.0

8. Secondary Outcome

Title	PFS in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors
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)

Outcome Measure Data

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
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.
Measure Participants	12	45	46	36	8
Median (95% Confidence Interval) [Months]	3.0	4.6	4.6	5.3	3.7

9. Secondary Outcome

Title	Overall Survival
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)

Outcome Measure Data

Analysis Population Description

All Treated Population

Arm/Group Title	Trametinib 2 mg: Prior BRAF Inhibitors	Trametinib 2 mg: Prior Standard Therapy
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.
Measure Participants	40	57
Median (95% Confidence Interval) [Months]	5.5	14.3

10. Secondary Outcome

Title	Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline
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

Outcome Measure Data

Analysis Population Description

All Treated Population

Arm/Group Title	Trametinib 2 mg: Prior BRAF Inhibitors	Trametinib 2 mg: Prior Standard Therapy
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.
Measure Participants	40	57
Died at or prior to 6 months	20 50%	12 21.1%
Died after 6 months	15 37.5%	24 42.1%
Censored, less than 6 months follow-up	3 7.5%	1 1.8%
Censored, more than 6 months follow-up	2 5%	20 35.1%
Died at or prior to 12 months	30 75%	23 40.4%
Died after 12 months	5 12.5%	13 22.8%
Censored, less than 12 months follow-up	3 7.5%	1 1.8%
Censored, more than 12 months follow-up	2 5%	20 35.1%
Died at or prior to 24 months	35 87.5%	34 59.6%
Died after 24 months	0 0%	2 3.5%
Censored, less than 24 months follow-up	3 7.5%	2 3.5%
Censored, more than 24 months follow-up	2 5%	19 33.3%

11. Secondary Outcome

Title	Number of Participants With Tumor Progression
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)

Outcome Measure Data

Analysis Population Description

All Treated Population

Arm/Group Title	Trametinib 2 mg: Prior BRAF Inhibitors	Trametinib 2 mg: Prior Standard Therapy
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.
Measure Participants	40	57
Number of participants (par.) with DP	35 87.5%	43 75.4%
Number of par. with DP in target lesions	21 52.5%	22 38.6%
Number of par. with DP in non-target lesions	8 20%	11 19.3%
Number of par. with a new lesion	22 55%	23 40.4%
Number of par. with clinical progression	3 7.5%	0 0%

Adverse Events

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).
Arm/Group Title	Trametinib 2 mg: Prior BRAF Inhibitors		Trametinib 2 mg: Prior Standard Therapy
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Trametinib 2 mg: Prior BRAF Inhibitors		Trametinib 2 mg: Prior Standard Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/40 (10%)		14/57 (24.6%)
Gastrointestinal disorders
Vomiting	2/40 (5%)		0/57 (0%)
Diarrhea	1/40 (2.5%)		0/57 (0%)
Gastrointestinal fistula	0/40 (0%)		1/57 (1.8%)
Gastrointestinal hemorrhage	1/40 (2.5%)		0/57 (0%)
Nausea	1/40 (2.5%)		0/57 (0%)
General disorders
Pneumatosis	0/40 (0%)		1/57 (1.8%)
Pyrexia	0/40 (0%)		1/57 (1.8%)
Infections and infestations
Cellulitis	0/40 (0%)		5/57 (8.8%)
Pneumonia	1/40 (2.5%)		2/57 (3.5%)
Endocarditis	1/40 (2.5%)		0/57 (0%)
Sepsis syndrome	0/40 (0%)		1/57 (1.8%)
Upper respiratory tract infection	0/40 (0%)		1/57 (1.8%)
Urinary tract infection	0/40 (0%)		1/57 (1.8%)
Injury, poisoning and procedural complications
Compression fracture	0/40 (0%)		1/57 (1.8%)
Investigations
Blood amylase increased	0/40 (0%)		1/57 (1.8%)
Lipase increased	0/40 (0%)		1/57 (1.8%)
Metabolism and nutrition disorders
Decreased appetite	1/40 (2.5%)		0/57 (0%)
Dehydration	1/40 (2.5%)		0/57 (0%)
Hypoglycemia	0/40 (0%)		1/57 (1.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor hemorrhage	1/40 (2.5%)		0/57 (0%)
Nervous system disorders
Cerebral hemorrhage	0/40 (0%)		1/57 (1.8%)
Lethargy	1/40 (2.5%)		0/57 (0%)
Seizure	0/40 (0%)		1/57 (1.8%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	1/40 (2.5%)		1/57 (1.8%)
Hypoxia	1/40 (2.5%)		0/57 (0%)
Skin and subcutaneous tissue disorders
Rash erythematous	0/40 (0%)		1/57 (1.8%)
Other (Not Including Serious) Adverse Events
	Trametinib 2 mg: Prior BRAF Inhibitors		Trametinib 2 mg: Prior Standard Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/40 (92.5%)		57/57 (100%)
Blood and lymphatic system disorders
Anemia	5/40 (12.5%)		10/57 (17.5%)
Cardiac disorders
Left ventricular dysfunction	0/40 (0%)		7/57 (12.3%)
Endocrine disorders
Hypothyroidism	0/40 (0%)		3/57 (5.3%)
Eye disorders
Vision blurred	6/40 (15%)		4/57 (7%)
Eye edema	2/40 (5%)		0/57 (0%)
Visual impairment	0/40 (0%)		3/57 (5.3%)
Gastrointestinal disorders
Diarrhea	19/40 (47.5%)		33/57 (57.9%)
Nausea	19/40 (47.5%)		23/57 (40.4%)
Vomiting	11/40 (27.5%)		16/57 (28.1%)
Constipation	13/40 (32.5%)		11/57 (19.3%)
Abdominal pain	7/40 (17.5%)		13/57 (22.8%)
Dry mouth	8/40 (20%)		6/57 (10.5%)
Dyspepsia	4/40 (10%)		4/57 (7%)
Stomatitis	4/40 (10%)		4/57 (7%)
Abdominal distension	2/40 (5%)		3/57 (5.3%)
Abdominal pain upper	2/40 (5%)		4/57 (7%)
Flatulence	2/40 (5%)		3/57 (5.3%)
Gastrooesophageal reflux disease	1/40 (2.5%)		4/57 (7%)
Ascites	3/40 (7.5%)		0/57 (0%)
Hemorrhoids	0/40 (0%)		4/57 (7%)
Mouth ulceration	2/40 (5%)		1/57 (1.8%)
General disorders
Fatigue	14/40 (35%)		24/57 (42.1%)
Edema peripheral	13/40 (32.5%)		24/57 (42.1%)
Pyrexia	7/40 (17.5%)		14/57 (24.6%)
Face edema	2/40 (5%)		8/57 (14%)
Chills	3/40 (7.5%)		7/57 (12.3%)
Mucosal inflammation	1/40 (2.5%)		7/57 (12.3%)
Pain	1/40 (2.5%)		4/57 (7%)
Asthenia	3/40 (7.5%)		1/57 (1.8%)
Infections and infestations
Cellulitis	4/40 (10%)		3/57 (5.3%)
Folliculitis	1/40 (2.5%)		6/57 (10.5%)
Localized infection	3/40 (7.5%)		4/57 (7%)
Urinary tract infection	5/40 (12.5%)		3/57 (5.3%)
Oral herpes	1/40 (2.5%)		3/57 (5.3%)
Postoperative wound infection	2/40 (5%)		0/57 (0%)
Sinus congestion	0/40 (0%)		3/57 (5.3%)
Injury, poisoning and procedural complications
Laceration	0/40 (0%)		3/57 (5.3%)
Investigations
Aspartate aminotransferase increased	3/40 (7.5%)		8/57 (14%)
Alanine aminotransferase increased	1/40 (2.5%)		6/57 (10.5%)
Weight decreased	2/40 (5%)		5/57 (8.8%)
Blood alkaline phosphatase increased	2/40 (5%)		1/57 (1.8%)
Ejection fraction decreased	0/40 (0%)		4/57 (7%)
Hemoglobin decreased	2/40 (5%)		1/57 (1.8%)
Metabolism and nutrition disorders
Decreased appetite	7/40 (17.5%)		10/57 (17.5%)
Hypokalemia	3/40 (7.5%)		6/57 (10.5%)
Hypoalbuminemia	8/40 (20%)		4/57 (7%)
Hyponatremia	4/40 (10%)		3/57 (5.3%)
Dehydration	2/40 (5%)		4/57 (7%)
Hypocalcemia	1/40 (2.5%)		6/57 (10.5%)
Hypomagnesemia	0/40 (0%)		4/57 (7%)
Musculoskeletal and connective tissue disorders
Pain in extremity	7/40 (17.5%)		5/57 (8.8%)
Arthralgia	3/40 (7.5%)		9/57 (15.8%)
Muscle spasms	0/40 (0%)		9/57 (15.8%)
Back pain	0/40 (0%)		5/57 (8.8%)
Joint swelling	0/40 (0%)		3/57 (5.3%)
Musculoskeletal chest pain	2/40 (5%)		1/57 (1.8%)
Neck pain	0/40 (0%)		3/57 (5.3%)
Nervous system disorders
Dizziness	5/40 (12.5%)		8/57 (14%)
Headache	3/40 (7.5%)		5/57 (8.8%)
Dysgeusia	1/40 (2.5%)		5/57 (8.8%)
Neuropathy peripheral	2/40 (5%)		2/57 (3.5%)
Hypoaesthesia	2/40 (5%)		0/57 (0%)
Amnesia	0/40 (0%)		3/57 (5.3%)
Psychiatric disorders
Insomnia	2/40 (5%)		8/57 (14%)
Depression	1/40 (2.5%)		4/57 (7%)
Mood altered	2/40 (5%)		0/57 (0%)
Anxiety	2/40 (5%)		1/57 (1.8%)
Renal and urinary disorders
Proteinuria	0/40 (0%)		3/57 (5.3%)
Pollakiuria	0/40 (0%)		3/57 (5.3%)
Reproductive system and breast disorders
Breast enlargement	2/40 (5%)		0/57 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	6/40 (15%)		9/57 (15.8%)
Cough	2/40 (5%)		7/57 (12.3%)
Epistaxis	2/40 (5%)		7/57 (12.3%)
Oropharyngeal pain	0/40 (0%)		6/57 (10.5%)
Rhinitis allergic	2/40 (5%)		1/57 (1.8%)
Skin and subcutaneous tissue disorders
Rash	20/40 (50%)		32/57 (56.1%)
Dermatitis acneiform	8/40 (20%)		21/57 (36.8%)
Pruritus	7/40 (17.5%)		20/57 (35.1%)
Dry skin	8/40 (20%)		17/57 (29.8%)
Alopecia	3/40 (7.5%)		8/57 (14%)
Rash erythematous	2/40 (5%)		4/57 (7%)
Erythema	2/40 (5%)		6/57 (10.5%)
Photosensitivity reaction	0/40 (0%)		5/57 (8.8%)
Rash pruritic	2/40 (5%)		2/57 (3.5%)
Nail disorder	0/40 (0%)		3/57 (5.3%)
Swelling face	2/40 (5%)		1/57 (1.8%)
Skin erosion	2/40 (5%)		0/57 (0%)
Skin fissures	3/40 (7.5%)		3/57 (5.3%)
Skin ulcer	0/40 (0%)		3/57 (5.3%)
Vascular disorders
Hypertension	0/40 (0%)		12/57 (21.1%)
Flushing	2/40 (5%)		3/57 (5.3%)
Lymphedema	3/40 (7.5%)		2/57 (3.5%)
Hypotension	1/40 (2.5%)		3/57 (5.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.