Cancer
Conditions
Keywords
GSK1120212, BRAF Inhibitor, melanoma, MEK Inhibitor
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.
Interventions
DRUGGSK1120212
Daily oral dosing
Sponsors
GlaxoSmithKline
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Australia, United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Trametinib 2 mg: Prior BRAF Inhibitors 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. | 40 |
| 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. | 57 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 4 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Study Closed Terminated | 2 | 17 |
Baseline characteristics
| Characteristic | Trametinib 2 mg: Prior Standard Therapy | Total | Trametinib 2 mg: Prior BRAF Inhibitors |
|---|---|---|---|
| Age, Continuous | 54.0 Years STANDARD_DEVIATION 12.6 | 54.7 Years STANDARD_DEVIATION 13.37 | 55.6 Years STANDARD_DEVIATION 14.52 |
| Race/Ethnicity, Customized White-Arabic/North African Heritage | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White-White/Caucasian/European Heritage | 56 Participants | 96 Participants | 40 Participants |
| Sex: Female, Male Female | 14 Participants | 29 Participants | 15 Participants |
| Sex: Female, Male Male | 43 Participants | 68 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 37 / 40 | 57 / 57 |
| serious Total, serious adverse events | 4 / 40 | 14 / 57 |
Outcome results
Primary
Number of Participants With Best Confirmed Response
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)
Population: All Treated Population: all participants who received at least one dose of investigational product
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants With Best Confirmed Response | CR | 0 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants With Best Confirmed Response | PR | 0 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants With Best Confirmed Response | CR | 1 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants With Best Confirmed Response | PR | 13 Participants |
95% CI: [14.1, 37.8]
Primary
Number of Participants With Best Confirmed Response in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors
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)
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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trametinib 2 mg: Prior BRAF Inhibitors | 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 |
| Trametinib 2 mg: Prior BRAF Inhibitors | 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 |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants With Best Confirmed Response in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors | CR | 1 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants With Best Confirmed Response in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors | PR | 11 Participants |
| Participants With BRAF Mutation V600E | Number of Participants With Best Confirmed Response in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors | CR | 1 Participants |
| Participants With BRAF Mutation V600E | Number of Participants With Best Confirmed Response in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors | PR | 11 Participants |
| Participants With BRAF Mutation V600E and no Prior Brain Mets | Number of Participants With Best Confirmed Response in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors | PR | 9 Participants |
| Participants With BRAF Mutation V600E and no Prior Brain Mets | Number of Participants With Best Confirmed Response in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors | CR | 1 Participants |
| Participants With BRAF Mutation V600K | 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 |
| Participants With BRAF Mutation V600K | Number of Participants With Best Confirmed Response in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors | PR | 0 Participants |
95% CI: [2.1, 48.4]
95% CI: [14.6, 41.9]
95% CI: [14.3, 41.4]
95% CI: [14.2, 45.2]
Primary
Number of Participants With Best Unconfirmed Response at the Time of the Interim Analysis (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.
Time frame: Week 8
Population: All Treated Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants With Best Unconfirmed Response at the Time of the Interim Analysis (Week 8) | CR | 0 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants With Best Unconfirmed Response at the Time of the Interim Analysis (Week 8) | PR | 0 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants With Best Unconfirmed Response at the Time of the Interim Analysis (Week 8) | CR | 0 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants With Best Unconfirmed Response at the Time of the Interim Analysis (Week 8) | PR | 6 Participants |
95% CI: [7.7, 38.6]
Secondary
Duration of Tumor 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.
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)
Population: All Treated Population. Only those participants who had a confirmed CR or PR were analyzed for duration of response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib 2 mg: Prior Standard Therapy | Duration of Tumor Response | 5.7 Months |
Secondary
Mean Plasma Concentrations
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
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Trametinib 2 mg: Prior BRAF Inhibitors | Mean Plasma Concentrations | Day 15, 2 to 4 hrs post-dose, n=23, 48 | 23.6 Nanograms (ng)/milliliter (mL) | Standard Deviation 8.29 |
| Trametinib 2 mg: Prior BRAF Inhibitors | Mean Plasma Concentrations | Week 4, pre-dose, n=23, 42 | 11.7 Nanograms (ng)/milliliter (mL) | Standard Deviation 3.82 |
| Trametinib 2 mg: Prior BRAF Inhibitors | 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 |
| Trametinib 2 mg: Prior BRAF Inhibitors | Mean Plasma Concentrations | Week 8, pre-dose, n=19, 31 | 11.6 Nanograms (ng)/milliliter (mL) | Standard Deviation 4.67 |
| Trametinib 2 mg: Prior BRAF Inhibitors | Mean Plasma Concentrations | Day 15, 4 to 8 hrs post-dose, n=22, 49 | 21.3 Nanograms (ng)/milliliter (mL) | Standard Deviation 6.14 |
| Trametinib 2 mg: Prior BRAF Inhibitors | Mean Plasma Concentrations | Week 12, pre-dose, n=7, 30 | 13.2 Nanograms (ng)/milliliter (mL) | Standard Deviation 3.75 |
| Trametinib 2 mg: Prior BRAF Inhibitors | Mean Plasma Concentrations | Day 15, pre-dose, n= 27, 44 | 12.3 Nanograms (ng)/milliliter (mL) | Standard Deviation 3.69 |
| Trametinib 2 mg: Prior Standard Therapy | Mean Plasma Concentrations | Week 12, pre-dose, n=7, 30 | 12.5 Nanograms (ng)/milliliter (mL) | Standard Deviation 6.29 |
| Trametinib 2 mg: Prior Standard Therapy | Mean Plasma Concentrations | Day 15, pre-dose, n= 27, 44 | 11.6 Nanograms (ng)/milliliter (mL) | Standard Deviation 5.54 |
| Trametinib 2 mg: Prior Standard Therapy | Mean Plasma Concentrations | Day 15, 0.5 to 2 hrs post-dose, n=23, 49 | 15.2 Nanograms (ng)/milliliter (mL) | Standard Deviation 8.93 |
| Trametinib 2 mg: Prior Standard Therapy | Mean Plasma Concentrations | Day 15, 2 to 4 hrs post-dose, n=23, 48 | 20.8 Nanograms (ng)/milliliter (mL) | Standard Deviation 9.87 |
| Trametinib 2 mg: Prior Standard Therapy | Mean Plasma Concentrations | Day 15, 4 to 8 hrs post-dose, n=22, 49 | 19.0 Nanograms (ng)/milliliter (mL) | Standard Deviation 8.39 |
| Trametinib 2 mg: Prior Standard Therapy | Mean Plasma Concentrations | Week 4, pre-dose, n=23, 42 | 11.6 Nanograms (ng)/milliliter (mL) | Standard Deviation 4.19 |
| Trametinib 2 mg: Prior Standard Therapy | Mean Plasma Concentrations | Week 8, pre-dose, n=19, 31 | 11.8 Nanograms (ng)/milliliter (mL) | Standard Deviation 6.24 |
Secondary
Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline
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
Population: All Treated Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Censored, less than 12 months follow-up | 3 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Censored, more than 6 months follow-up | 2 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Censored, more than 12 months follow-up | 2 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Died at or prior to 6 months | 20 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Died at or prior to 24 months | 35 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Died at or prior to 12 months | 30 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Died after 24 months | 0 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Censored, less than 6 months follow-up | 3 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Censored, less than 24 months follow-up | 3 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Died after 12 months | 5 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Censored, more than 24 months follow-up | 2 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Died after 6 months | 15 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Censored, more than 24 months follow-up | 19 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Died after 6 months | 24 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Censored, less than 6 months follow-up | 1 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Censored, more than 6 months follow-up | 20 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Died at or prior to 12 months | 23 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Died after 12 months | 13 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Censored, less than 12 months follow-up | 1 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Censored, more than 12 months follow-up | 20 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Died at or prior to 24 months | 34 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Died after 24 months | 2 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Censored, less than 24 months follow-up | 2 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants Who Survived Until 6 Months, 12 Months and 24 Months From Baseline | Died at or prior to 6 months | 12 Participants |
Secondary
Number of Participants With Any Adverse Event (AE)
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)
Population: All Treated Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants With Any Adverse Event (AE) | 39 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants With Any Adverse Event (AE) | 57 Participants |
Secondary
Number of Participants With Tumor Progression
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)
Population: All Treated Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants With Tumor Progression | Number of par. with DP in target lesions | 21 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants With Tumor Progression | Number of par. with a new lesion | 22 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants With Tumor Progression | Number of par. with DP in non-target lesions | 8 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants With Tumor Progression | Number of par. with clinical progression | 3 Participants |
| Trametinib 2 mg: Prior BRAF Inhibitors | Number of Participants With Tumor Progression | Number of participants (par.) with DP | 35 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants With Tumor Progression | Number of par. with clinical progression | 0 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants With Tumor Progression | Number of participants (par.) with DP | 43 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants With Tumor Progression | Number of par. with DP in target lesions | 22 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants With Tumor Progression | Number of par. with DP in non-target lesions | 11 Participants |
| Trametinib 2 mg: Prior Standard Therapy | Number of Participants With Tumor Progression | Number of par. with a new lesion | 23 Participants |
Secondary
Overall Survival
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)
Population: All Treated Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib 2 mg: Prior BRAF Inhibitors | Overall Survival | 5.5 Months |
| Trametinib 2 mg: Prior Standard Therapy | Overall Survival | 14.3 Months |
Secondary
PFS in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors
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)
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 this subgroup was stopped for futility and nearly all the participants progressed before 4 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib 2 mg: Prior BRAF Inhibitors | PFS in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors | 3.0 Months |
| Trametinib 2 mg: Prior Standard Therapy | PFS in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors | 4.6 Months |
| Participants With BRAF Mutation V600E | PFS in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors | 4.6 Months |
| Participants With BRAF Mutation V600E and no Prior Brain Mets | PFS in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors | 5.3 Months |
| Participants With BRAF Mutation V600K | PFS in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors | 3.7 Months |
Secondary
Progression-free Survival (PFS)
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)
Population: All Treated Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib 2 mg: Prior BRAF Inhibitors | Progression-free Survival (PFS) | 1.8 Months |
| Trametinib 2 mg: Prior Standard Therapy | Progression-free Survival (PFS) | 4.0 Months |