A Phase 2 interventional study of GSK1120212 in Cancer, sponsored by GlaxoSmithKline. Completed at 10 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2014-03-31.
Sponsored by GlaxoSmithKline · Phase 2, Interventional, and Treatment
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.
3,006 studies on the registry are indexed under Melanoma; 520 are open to participants now.
This study's enrollment of 97 is above the median of 38 across 2,351 interventional studies indexed under Melanoma.
Browse Melanoma studies →GlaxoSmithKline is the lead sponsor of 3,562 studies on the registry; 117 are open to participants now.
Of its 258 completed or terminated interventional studies of FDA-regulated products, 232 (90%) have results posted.
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Exclusion Criteria:
Subjects who have had previous treatment with a BRAF inhibitor.
Drug: GSK1120212
Subjects who have had previous chemotherapy or immunotherapy without a BRAF inhibitor.
Drug: GSK1120212
Daily oral dosing
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)
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)
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
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
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)
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)
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)
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)
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)
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
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)
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.
| Milestone | Trametinib 2 mg: Prior BRAF Inhibitors | Trametinib 2 mg: Prior Standard Therapy |
|---|---|---|
| Started | 40 | 57 |
| Completed | 35 | 36 |
| Not completed | 5 | 21 |
| Withdrew: Lost to follow-up | 2 | 4 |
| Withdrew: Physician decision | 1 | 0 |
| Withdrew: Study closed terminated | 2 | 17 |
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.
| Participants | Trametinib 2 mg: Prior BRAF Inhibitors | Trametinib 2 mg: Prior Standard Therapy |
|---|---|---|
| CR | 0 | 1 |
| PR | 0 | 13 |
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.
| Participants | 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 |
|---|---|---|---|---|---|
| CR | 0 | 1 | 1 | 1 | 0 |
| PR | 2 | 11 | 11 | 9 | 0 |
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.
| Participants | Trametinib 2 mg: Prior BRAF Inhibitors | Trametinib 2 mg: Prior Standard Therapy |
|---|---|---|
| CR | 0 | 0 |
| PR | 0 | 6 |
Human plasma samples were analyzed for trametinib using a validated analytical method.
| Nanograms (ng)/milliliter (mL) | Trametinib 2 mg: Prior BRAF Inhibitors | Trametinib 2 mg: Prior Standard Therapy |
|---|---|---|
| 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 |
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.
| Participants | Trametinib 2 mg: Prior BRAF Inhibitors | Trametinib 2 mg: Prior Standard Therapy |
|---|---|---|
| Number of Participants With Any Adverse Event (AE) | 39 | 57 |
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.
| Months | Trametinib 2 mg: Prior BRAF Inhibitors | Trametinib 2 mg: Prior Standard Therapy |
|---|---|---|
| Duration of Tumor Response | — | 5.7 (3.7 to 9.2) |
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.
| Months | Trametinib 2 mg: Prior BRAF Inhibitors | Trametinib 2 mg: Prior Standard Therapy |
|---|---|---|
| Progression-free Survival (PFS) | 1.8 (1.8 to 2.0) | 4.0 (3.6 to 5.6) |
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.
| Months | 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 |
|---|---|---|---|---|---|
| PFS in the Indicated Subgroups of Participants Previously Treated With Standard Therapy But Not BRAF Inhibitors | 3.0 (1.8 to 5.3) | 4.6 (3.6 to 7.2) | 4.6 (3.6 to 5.7) | 5.3 (3.6 to 7.4) | 3.7 (1.8 to 4.6) |
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.
| Months | Trametinib 2 mg: Prior BRAF Inhibitors | Trametinib 2 mg: Prior Standard Therapy |
|---|---|---|
| Overall Survival | 5.5 (3.5 to 9.0) | 14.3 (11.3 to 24.4) |
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.
| Participants | Trametinib 2 mg: Prior BRAF Inhibitors | Trametinib 2 mg: Prior Standard Therapy |
|---|---|---|
| Died at or prior to 6 months | 20 | 12 |
| Died after 6 months | 15 | 24 |
| Censored, less than 6 months follow-up | 3 | 1 |
| Censored, more than 6 months follow-up | 2 | 20 |
| Died at or prior to 12 months | 30 | 23 |
| Died after 12 months | 5 | 13 |
| Censored, less than 12 months follow-up | 3 | 1 |
| Censored, more than 12 months follow-up | 2 | 20 |
| Died at or prior to 24 months | 35 | 34 |
| Died after 24 months | 0 | 2 |
| Censored, less than 24 months follow-up | 3 | 2 |
| Censored, more than 24 months follow-up | 2 | 19 |
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.
| Participants | Trametinib 2 mg: Prior BRAF Inhibitors | Trametinib 2 mg: Prior Standard Therapy |
|---|---|---|
| Number of participants (par.) with DP | 35 | 43 |
| Number of par. with DP in target lesions | 21 | 22 |
| Number of par. with DP in non-target lesions | 8 | 11 |
| Number of par. with a new lesion | 22 | 23 |
| Number of par. with clinical progression | 3 | 0 |
Collected over 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).. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Trametinib 2 mg: Prior BRAF Inhibitors | — | 4/40 (10%) | 37/40 (92.5%) |
| Trametinib 2 mg: Prior Standard Therapy | — | 14/57 (24.6%) | 57/57 (100%) |
| Event | Trametinib 2 mg: Prior BRAF Inhibitors | Trametinib 2 mg: Prior Standard Therapy |
|---|---|---|
| CellulitisInfections and infestations | 0/40 | 5/57 |
| VomitingGastrointestinal disorders | 2/40 | 0/57 |
| PneumoniaInfections and infestations | 1/40 | 2/57 |
| Pulmonary embolismRespiratory, thoracic and mediastinal disorders | 1/40 | 1/57 |
| Decreased appetiteMetabolism and nutrition disorders | 1/40 | 0/57 |
| DehydrationMetabolism and nutrition disorders | 1/40 | 0/57 |
| DiarrheaGastrointestinal disorders | 1/40 | 0/57 |
| EndocarditisInfections and infestations | 1/40 | 0/57 |
| Gastrointestinal hemorrhageGastrointestinal disorders | 1/40 | 0/57 |
| HypoxiaRespiratory, thoracic and mediastinal disorders | 1/40 | 0/57 |
| Event | Trametinib 2 mg: Prior BRAF Inhibitors | Trametinib 2 mg: Prior Standard Therapy |
|---|---|---|
| DiarrheaGastrointestinal disorders | 19/40 | 33/57 |
| RashSkin and subcutaneous tissue disorders | 20/40 | 32/57 |
| NauseaGastrointestinal disorders | 19/40 | 23/57 |
| FatigueGeneral disorders | 14/40 | 24/57 |
| Edema peripheralGeneral disorders | 13/40 | 24/57 |
| Dermatitis acneiformSkin and subcutaneous tissue disorders | 8/40 | 21/57 |
| PruritusSkin and subcutaneous tissue disorders | 7/40 | 20/57 |
| ConstipationGastrointestinal disorders | 13/40 | 11/57 |
| Dry skinSkin and subcutaneous tissue disorders | 8/40 | 17/57 |
| VomitingGastrointestinal disorders | 11/40 | 16/57 |
| Age, Continuous(Years) | Trametinib 2 mg: Prior BRAF Inhibitors | Trametinib 2 mg: Prior Standard Therapy | Total |
|---|---|---|---|
| Mean | 55.6 ± 14.52 | 54.0 ± 12.60 | 54.7 ± 13.37 |
| Sex: Female, Male(Participants) | Trametinib 2 mg: Prior BRAF Inhibitors | Trametinib 2 mg: Prior Standard Therapy | Total |
|---|---|---|---|
| Female | 15 | 14 | 29 |
| Male | 25 | 43 | 68 |
| Race/Ethnicity, Customized(Participants) | Trametinib 2 mg: Prior BRAF Inhibitors | Trametinib 2 mg: Prior Standard Therapy | Total |
|---|---|---|---|
| White-Arabic/North African Heritage | 0 | 1 | 1 |
| White-White/Caucasian/European Heritage | 40 | 56 | 96 |
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