A Phase 2 interventional study of Dabrafenib and Trametinib in Melanoma, sponsored by GlaxoSmithKline. Terminated at 7 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-02-18.
Sponsored by GlaxoSmithKline · Phase 2, Interventional, and Diagnostic
This is a three-arm, open-label, randomised Phase II study to evaluate whether the different sequencing of dabrafenib and trametinib monotherapies and the upfront combination has an impact on translational or clinical activity in subjects with BRAF mutant metastatic unresectable stage IIIc or IV melanoma. Both dabrafenib and trametinib have demonstrated clinical activity as monotherapies and in combination in BRAF-mutant melanoma. However, duration of responses seem to be limited due to acquired drug resistance. The goal of this protocol is to study the sequential effects of BRAF and MEK inhibition on skin, blood and tumour biomarkers and to study the correlation between biomarkers and response to treatment and intrapatient toxicity. Approximately 54 eligible subjects will be randomised in the ratio of 1:1:1 to one of the three treatment arms.
3,006 studies on the registry are indexed under Melanoma; 520 are open to participants now.
This study's enrollment of 48 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:
Eligible subjects will receive dabrafenib 150 milligrams (mg) twice a day (BID) continuously during 8 weeks of monotherapy treatment followed by the combination of trametinib 2 mg once daily with dabrafenib 150 mg BID until disease progression, death or unacceptable toxicity.
Drug: Dabrafenib · Drug: Trametinib
Eligible subjects will receive trametinib 2 mg per day continuously during 8 weeks of monotherapy treatment followed by the combination of trametinib 2 mg once daily with dabrafenib 150 mg BID until disease progression, death or unacceptable toxicity.
Drug: Dabrafenib · Drug: Trametinib
Eligible subjects will receive trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
Drug: Dabrafenib · Drug: Trametinib
Dabrafenib will be provided as 50 mg and 75 mg capsules.
Trametinib study medication will be provided as 0.5 mg and 2.0 mg tablets.
Number of Participants With Percentage Change From Baseline in Extracellular Signal-regulated Kinase (ERK) Phosphorylation (p-ERK) H Score From Week 0 to Week 2
Intra-tumoral expression levels of ERK measured using immunohistochemistry methods. The H score value ranged from 0 to a maximum score of 300 (strongest expression) was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0 \[no staining\], 1+ \[weak staining\], 2+ \[medium staining\] and 3+ \[strongest staining\]). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. The data has been presented for combination therapy calculated from Week 0 to Week 2. The analysis was based on the biomarker Population which included all participants with biopsy performed at screening and at least once during treatment.
Time frame: Baseline (Week 0) and up to 2 weeks
Number of Participants With Percentage Change in p-ERK H Score From Week 8 to Week 10
Intra-tumoral expression levels of ERK were measured using immunohistochemistry methods. The H score value ranged from 0 to a maximum score of 300 (strongest expression) was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0 \[no staining\], 1+ \[weak staining\], 2+ \[medium staining\] and 3+ \[strongest staining\]). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. The data has been presented for dabrafenib followed by combination therapy and trametinib followed by combination therapy, calculated from Week 8 to Week 10.
Time frame: Week 8 and up to 10 weeks
Number of Participants With Overall Response Rate (ORR)
Clinical response was evaluated by ORR, which was defined as the number of participants with a confirmed or an unconfirmed complete response (CR) or partial response (PR) at any time per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. CR was defined as disappearance of all target lesions. PR was defined as at least a 30 percent decrease in the sum of the diameters of target lesions. Number of participants with ORR (CR+PR) has been presented. The analysis was based on the Intent-to-Treat Population (ITT) which included all the randomized participants whether or not randomized treatment was administered.
Time frame: Up to 3.2 years
Number of Participants With Change in Vital Signs From Baseline
Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and heat rate (HR) were measured. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus the Baseline value. The number of participants with heart rate "decrease to \< 60" and "increase to \>100" have been presented. For SBP and DBP, "any grade increase" have been presented. Any grade increase in SBP, including grade 0 (\<120), grade 1 (120-139), grade 2 (140-159), grade 3 (\>=160) and DBP including grade 0 (\<80), grade 1 (80-89), grade 2 (90-99), grade 3 (\>=100) have been presented. The analysis was based on the Safety Population which included all participants who received at least one dose of randomized treatment and was based on the actual treatment received. Only those participants available at specified time point were analyzed (represented by n=x in category titles).
Time frame: Baseline and up to 3.2 years
Number of Participants With Clinically Significant Abnormal Findings Undergoing Physical Examinations
Complete physical examination included assessments of eyes, neurological and cardiovascular systems, lungs, abdomen, and any other areas with signs and symptoms of disease, and of the head, neck, ears, nose, mouth, throat, thyroid, lymph nodes, extremities, and a full skin exam to assess cutaneous malignancies and proliferative skin diseases. This analysis was planned but data was not captured in the database. Abnormal changes were captured as adverse events if they were clinically significant.
Time frame: Up to 3.2 years
Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline
The ECOG scale of performance status describes the level of functioning of participants in terms of their ability to care for themselves, daily activity, and physical ability. The ECOG performance was recorded as per ECOG performance status grades ranging from 0 (fully active, able to carry on all pre-disease performance without restriction) to 5 (dead). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The Baseline performance status of participants with respect to worst-case on-therapy performance status has been presented.
Time frame: Baseline and up to 3.2 years
Number of Participants With Abnormal Electrocardiograms (ECG) Findings
Single measurements of 12-lead ECGs were obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, corrected QT interval (QTc), Bazett's Corrected QT interval (QTcB), Friderica's Corrected QT interval (QTcF). Number of participants with abnormal ECG findings (Abnormal - Not Clinically Significant and Abnormal - Clinically Significant ) at any time post-Baseline visit have been presented.
Time frame: Up to 3.2 years
Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline
Echocardiograms (ECHO) was performed to assess cardiac ejection fraction and cardiac valve morphology. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on-therapy value has been presented.
Time frame: Baseline and up to 3.2 years
Number of Participants With Change in Clinical Chemistry Parameters From Baseline
Blood samples were collected for evaluation of clinical chemistry parameters including sodium, potassium, calcium, albumin, total protein, blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GCT), phosphate, C-reactive protein (CRP), hypercalcemia, hyperkalemia, hypernatremia, hypocalcemia, hypokalemia, hyponatremia, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, direct bilirubin and estimated creatinine clearance (CRTCE). Baseline was defined as the most recent non-missing value from a central laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on therapy value for number of participants with any grade increase in clinical chemistry parameters for has been presented. Only those participants available at specified time point were analyzed (represented by n=x in category titles).
Time frame: Baseline and up to 3.2 years
Number of Participants With Change in Hematology Parameters From Baseline
Blood samples were collected for evaluation of hematology parameters including hemoglobin, white blood cell (WBC), platelet count, basophils, eosinophils, lymphocytes, monocytes, total neutrophils, lymphocytopenia and lymphocytosis. Baseline was defined as the most recent non-missing value from a central laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on therapy value for number of participants with any grade increase in hematology parameters for has been presented.
Time frame: Baseline and up to 3.2 years
Number of Participants With Incidence of Squamous Cell Carcinoma and Keratoacanthoma
The safety profile of dabrafenib and trametinib in monotherapy as well as in combination therapy was characterized by determining the number of participants with incidence of squamous cell carcinoma and keratoacanthoma.
Time frame: Up to 3.2 years
Number of Participants With On-treatment Serious Adverse Events (SAEs) and Non-SAEs
An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function.
Time frame: Up to 3.2 years
Plasma Pharmacokinetic Concentration of Trametinib
Blood samples were collected for pharmacokinetic analysis of trametinib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method.
Time frame: 4 to 8 hours post-dose at Weeks 2, 8 and 10
Plasma Pharmacokinetic Concentration of Dabrafenib
Blood samples were collected for pharmacokinetic analysis of Dabrafenib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method.
Time frame: 4 to 8 hours post-dose at Weeks 2, 8 and 10
This is an open label, randomized, phase II study to compare the combination of dabrafenib with trametinib versus the combination after eight weeks of monotherapy with dabrafenib or trametinib in metastatic and unresectable stage III or IV melanoma. The study was terminated early due to slow enrollment and limited numbers of viable tissue samples.
| Milestone | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy |
|---|---|---|---|
| Started | 16 | 16 | 16 |
| Completed | 8 | 6 | 7 |
| Not completed | 8 | 10 | 9 |
| Withdrew: Adverse event | 0 | 6 | 4 |
| Withdrew: Other (study closed/terminated) | 5 | 3 | 4 |
| Withdrew: Physician decision | 2 | 1 | 0 |
| Withdrew: Withdrawal by subject | 1 | 0 | 1 |
Intra-tumoral expression levels of ERK measured using immunohistochemistry methods. The H score value ranged from 0 to a maximum score of 300 (strongest expression) was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0 \[no staining\], 1+ \[weak staining\], 2+ \[medium staining\] and 3+ \[strongest staining\]). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. The data has been presented for combination therapy calculated from Week 0 to Week 2. The analysis was based on the biomarker Population which included all participants with biopsy performed at screening and at least once during treatment.
| Participants | Combination Therapy |
|---|---|
| Any Increase or No Changes | 2 |
| Any Decrease up to 80 percent | 1 |
| Any Decrease > 80 percent | 2 |
Intra-tumoral expression levels of ERK were measured using immunohistochemistry methods. The H score value ranged from 0 to a maximum score of 300 (strongest expression) was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0 \[no staining\], 1+ \[weak staining\], 2+ \[medium staining\] and 3+ \[strongest staining\]). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. The data has been presented for dabrafenib followed by combination therapy and trametinib followed by combination therapy, calculated from Week 8 to Week 10.
| Participants | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy |
|---|---|---|
| Any Increase or No Changes | 1 | 1 |
| Any Decrease up to 80 percent | 0 | 1 |
| Any Decrease > 80 percent | 0 | 1 |
Clinical response was evaluated by ORR, which was defined as the number of participants with a confirmed or an unconfirmed complete response (CR) or partial response (PR) at any time per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. CR was defined as disappearance of all target lesions. PR was defined as at least a 30 percent decrease in the sum of the diameters of target lesions. Number of participants with ORR (CR+PR) has been presented. The analysis was based on the Intent-to-Treat Population (ITT) which included all the randomized participants whether or not randomized treatment was administered.
| Participants | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy |
|---|---|---|---|
| Number of Participants With Overall Response Rate (ORR) | 11 | 13 | 11 |
Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and heat rate (HR) were measured. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus the Baseline value. The number of participants with heart rate "decrease to \< 60" and "increase to \>100" have been presented. For SBP and DBP, "any grade increase" have been presented. Any grade increase in SBP, including grade 0 (\<120), grade 1 (120-139), grade 2 (140-159), grade 3 (\>=160) and DBP including grade 0 (\<80), grade 1 (80-89), grade 2 (90-99), grade 3 (\>=100) have been presented. The analysis was based on the Safety Population which included all participants who received at least one dose of randomized treatment and was based on the actual treatment received. Only those participants available at specified time point were analyzed (represented by n=x in category titles).
| Participants | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy |
|---|---|---|---|
| HR; Week 4; Decrease to <60; n=15,16,16 | 1 | 3 | 3 |
| HR; Week 4; Increase to >100; n=15,16,16 | 1 | 0 | 0 |
| HR; Week 8; Decrease to <60; n=16,16,14 | 1 | 2 | 2 |
| HR; Week 8; Increase to >100; n=16,16,14 | 2 | 0 | 0 |
| HR; Week 12; Decrease to <60; n=16,16,13 | 2 | 1 | 2 |
| HR; Week 12; Increase to >100; n=16,16,13 | 0 | 0 | 0 |
| HR; Week 16; Decrease to <60; n=14,16,13 | 0 | 0 | 2 |
| HR; Week 16; Increase to >100; n=14,16,13 | 0 | 0 | 0 |
| HR; Week 20; Decrease to <60; n=11,15,13 | 0 | 1 | 1 |
| HR; Week 20; Increase to >100; n=11,15,13 | 1 | 1 | 0 |
| HR; Week 24; Decrease to <60; n=12,14,13 | 1 | 2 | 2 |
| HR; Week 24; Increase to >100; n=12,14,13 | 1 | 2 | 0 |
| HR; Week 28; Decrease to <60; n=8,12,7 | 2 | 2 | 2 |
| HR; Week 28; Increase to >100; n=8,12,7 | 1 | 0 | 0 |
| HR; Week 32; Decrease to <60; n=7,11,8 | 1 | 0 | 0 |
| HR; Week 32; Increase to >100; n=7,11,8 | 1 | 0 | 0 |
| HR; Week 36; Decrease to <60; n=5,11,8 | 2 | 0 | 1 |
| HR; Week 36; Increase to >100; n=5,11,8 | 0 | 0 | 1 |
| HR; Week 40; Decrease to <60; n=6,11,7 | 1 | 1 | 0 |
| HR; Week 40; Increase to >100; n=6,11,7 | 0 | 0 | 0 |
| HR; Week 44; Decrease to <60; n=5,5,4 | 1 | 0 | 0 |
| HR; Week 44; Increase to >100; n=5,5,4 | 1 | 0 | 1 |
| HR; Week 48; Decrease to <60; n=5,4,4 | 1 | 0 | 1 |
| HR; Week 48; Increase to >100; n=5,4,4 | 0 | 0 | 1 |
| HR; Week 52; Decrease to <60; n=4,3,4 | 0 | 0 | 0 |
| HR; Week 52; Increase to >100; n=4,3,4 | 0 | 0 | 1 |
| HR; Week 56; Decrease to <60; n=4,3,4 | 1 | 0 | 3 |
| HR; Week 56; Increase to >100; n=4,3,4 | 0 | 0 | 0 |
| HR; Week 60; Decrease to <60; n=3,3,4 | 1 | 1 | 1 |
| HR; Week 60; Increase to >100; n=3,3,4 | 0 | 0 | 0 |
| HR; Week 64; Decrease to <60; n=3,3,3 | 1 | 0 | 0 |
| HR; Week 64; Increase to >100; n=3,3,3 | 0 | 0 | 0 |
| HR; Week 68; Decrease to <60; n=4,2,2 | 1 | 0 | 2 |
| HR; Week 68; Increase to >100; n=4,2,2 | 0 | 0 | 0 |
| HR; Week 72; Decrease to <60; n=3,2,2 | 0 | 0 | 0 |
| HR; Week 72; Increase to >100; n=3,2,2 | 0 | 0 | 0 |
| HR; Week 76; Decrease to <60; n=4,1,2 | 1 | 0 | 0 |
| HR; Week 76; Increase to >100; n=4,1,2 | 0 | 0 | 1 |
| HR; Week 80; Decrease to <60; n=3,1,2 | 1 | 0 | 0 |
| HR; Week 80; Increase to >100; n=3,1,2 | 0 | 0 | 0 |
| HR; Week 84; Decrease to <60; n=3,1,1 | 0 | 0 | 0 |
| HR; Week 84; Increase to >100; n=3,1,1 | 0 | 0 | 0 |
| HR; Week 88; Decrease to <60; n=3,1,1 | 1 | 0 | 0 |
| HR; Week 88; Increase to >100; n=3,1,1 | 0 | 0 | 0 |
| HR; Week 92; Decrease to <60; n=3,1,1 | 1 | 0 | 0 |
| HR; Week 92; Increase to >100; n=3,1,1 | 0 | 0 | 0 |
| HR; Week 96; Decrease to <60; n=3,1,1 | 1 | 0 | 0 |
| HR; Week 96; Increase to >100; n=3,1,1 | 0 | 0 | 0 |
| HR; Week 100; Decrease to <60; n=3,1,1 | 0 | 0 | 0 |
| HR; Week 100; Increase to >100; n=3,1,1 | 0 | 0 | 0 |
| HR; Week 104; Decrease to <60; n=3,1,1 | 0 | 0 | 0 |
| HR; Week 104; Increase to >100; n=3,1,1 | 0 | 0 | 0 |
| HR; Week 108; Decrease to <60; n=2,0,1 | 1 | — | 0 |
| HR; Week 108; Increase to >100; n=2,0,1 | 0 | — | 0 |
| HR; Week 112; Decrease to <60; n=2,0,0 | 1 | — | — |
| HR; Week 112; Increase to >100; n=2, 0,0 | 0 | — | — |
| HR; Week 116; Decrease to <60; n=1, 0,0 | 0 | — | — |
| HR; Week 116; Increase to >100; n=1, 0,0 | 0 | — | — |
| HR; Week 120; Decrease to <60; n=1, 0,0 | 0 | — | — |
| HR; Week 120; Increase to >100; n=1, 0,0 | 0 | — | — |
| HR; Week 124; Decrease to <60; n=1, 0,0 | 0 | — | — |
| HR; Week 124; Increase to >100; n=1, 0,0 | 0 | — | — |
| SBP; Week 4; Any grade increase; n=15,16,16 | 1 | 8 | 4 |
| SBP; Week 8; Any grade increase; n=16,16,14 | 3 | 5 | 4 |
| SBP; Week 12; Any grade increase; n=16,16,13 | 3 | 5 | 2 |
| SBP; Week 16; Any grade increase; n=14,16,13 | 4 | 3 | 2 |
| SBP; Week 20; Any grade increase; n=11,15, 13 | 2 | 3 | 1 |
| SBP; Week 24; Any grade increase; n=12, 14,13 | 2 | 3 | 2 |
| SBP; Week 28; Any grade increase; n=8, 12,7 | 2 | 0 | 0 |
| SBP; Week 32; Any grade increase; n=7,11, 8 | 2 | 3 | 2 |
| SBP; Week 36; Any grade increase; n=5, 11, 8 | 3 | 3 | 1 |
| SBP; Week 40; Any grade increase; n=6,11, 7 | 1 | 4 | 2 |
| SBP; Week 44; Any grade increase; n=5, 5, 4 | 2 | 0 | 0 |
| SBP; Week 48; Any grade increase; n=5,4, 4 | 1 | 1 | 0 |
| SBP; Week 52; Any grade increase; n=4,3, 4 | 1 | 0 | 0 |
| SBP; Week 56; Any grade increase; n=4, 3, 4 | 0 | 0 | 0 |
| SBP; Week 60; Any grade increase; n=3, 2, 4 | 1 | 1 | 0 |
| SBP; Week 64; Any grade increase; n=3, 3, 3 | 1 | 0 | 0 |
| SBP; Week 68; Any grade increase; n=4,2, 2 | 2 | 0 | 0 |
| SBP; Week 72; Any grade increase; n=3,2, 2 | 1 | 0 | 0 |
| SBP; Week 76; Any grade increase; n=4, 1, 2 | 2 | 0 | 0 |
| SBP; Week 80; Any grade increase; n=3, 1, 2 | 2 | 0 | 0 |
| SBP; Week 84; Any grade increase; n=3, 1,1 | 2 | 0 | 0 |
| SBP; Week 88; Any grade increase; n=3, 1,1 | 0 | 0 | 0 |
| SBP; Week 92; Any grade increase; n=3, 1, 1 | 2 | 0 | 0 |
| SBP; Week 96; Any grade increase; n=3,1, 1 | 2 | 1 | 0 |
| SBP; Week 100; Any grade increase; n=3, 1, 1 | 0 | 0 | 0 |
| SBP; Week 104; Any grade increase; n=3, 1, 1 | 1 | 0 | 0 |
| SBP; Week 108; Any grade increase; n=2,0, 1 | 1 | — | 0 |
| SBP; Week 112; Any grade increase; n=2, 0, 0 | 0 | — | — |
| SBP; Week 116; Any grade increase; n=1, 0, 0 | 0 | — | — |
| SBP; Week 120; Any grade increase; n=1, 0, 0 | 0 | — | — |
| SBP; Week 124; Any grade increase; n=1, 0, 0 | 0 | — | — |
| DBP; Week 4; Any grade increase; n=15, 16, 16 | 2 | 10 | 5 |
| DBP; Week 8; Any grade increase; n=16, 16,14 | 4 | 8 | 3 |
| DBP; Week 12; Any grade increase; n=16, 16, 13 | 4 | 4 | 2 |
| DBP; Week 16; Any grade increase; n=14, 16,13 | 5 | 5 | 3 |
| DBP; Week 20; Any grade increase; n=11, 15,13 | 4 | 5 | 2 |
| DBP; Week 24; Any grade increase; n=12, 14,13 | 3 | 3 | 1 |
| DBP; Week 28; Any grade increase; n=8, 12,7 | 1 | 2 | 0 |
| DBP; Week 32; Any grade increase; n=7, 11,8 | 2 | 3 | 1 |
| DBP; Week 36; Any grade increase; n=5, 11,8 | 2 | 1 | 2 |
| DBP; Week 40; Any grade increase; n=6, 11,7 | 1 | 1 | 1 |
| DBP; Week 44; Any grade increase; n=5, 5,4 | 4 | 1 | 2 |
| DBP; Week 48; Any grade increase; n=5, 4,4 | 2 | 1 | 2 |
| DBP; Week 52; Any grade increase; n=4,3,4 | 2 | 0 | 0 |
| DBP; Week 56; Any grade increase; n=4,3,4 | 1 | 1 | 0 |
| DBP; Week 60; Any grade increase; n=3,2,4 | 2 | 0 | 0 |
| DBP; Week 64; Any grade increase; n=3,3, 3 | 1 | 0 | 1 |
| DBP; Week 68; Any grade increase; n=4,2, 2 | 2 | 0 | 1 |
| DBP; Week 72; Any grade increase; n=3,2,2 | 1 | 0 | 1 |
| DBP; Week 76; Any grade increase; n=4,1,2 | 2 | 0 | 1 |
| DBP; Week 80; Any grade increase; n=3,1,2 | 1 | 0 | 1 |
| DBP; Week 84; Any grade increase; n=3,1,1 | 1 | 0 | 0 |
| DBP; Week 88; Any grade increase; n=3,1,1 | 1 | 0 | 0 |
| DBP; Week 92; Any grade increase; n=3, 1,1 | 1 | 0 | 1 |
| DBP; Week 96; Any grade increase; n=3, 1,1 | 2 | 0 | 1 |
| DBP; Week 100; Any grade increase; n=3,1,1 | 1 | 0 | 0 |
| DBP; Week 104; Any grade increase; n=3,1,1 | 1 | 0 | 1 |
| DBP; Week 108; Any grade increase; n=2,0,1 | 1 | — | 0 |
| DBP; Week 112; Any grade increase; n=2,0,0 | 0 | — | — |
| DBP; Week 116; Any grade increase; n=1,0,0 | 0 | — | — |
| DBP; Week 120; Any grade increase; n=1,0,0 | 0 | — | — |
| DBP; Week 124; Any grade increase; n=1,0,0 | 0 | — | — |
Complete physical examination included assessments of eyes, neurological and cardiovascular systems, lungs, abdomen, and any other areas with signs and symptoms of disease, and of the head, neck, ears, nose, mouth, throat, thyroid, lymph nodes, extremities, and a full skin exam to assess cutaneous malignancies and proliferative skin diseases. This analysis was planned but data was not captured in the database. Abnormal changes were captured as adverse events if they were clinically significant.
No measurements were reported for this outcome.
The ECOG scale of performance status describes the level of functioning of participants in terms of their ability to care for themselves, daily activity, and physical ability. The ECOG performance was recorded as per ECOG performance status grades ranging from 0 (fully active, able to carry on all pre-disease performance without restriction) to 5 (dead). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The Baseline performance status of participants with respect to worst-case on-therapy performance status has been presented.
| Participants | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy |
|---|---|---|---|
| 0 to 0 | 5 | 5 | 6 |
| 0 to 1 | 0 | 0 | 1 |
| 0 to 2 | 0 | 0 | 0 |
| 0 to 3 | 0 | 0 | 0 |
| 0 to 4-5 | 0 | 0 | 0 |
| 1 to 0 | 6 | 10 | 5 |
| 1 to 1 | 3 | 1 | 2 |
| 1 to 2 | 0 | 0 | 0 |
| 1 to 3 | 0 | 0 | 0 |
| 1 to 4-5 | 0 | 0 | 0 |
| 2 to 0 | 0 | 0 | 0 |
| 2 to 1 | 2 | 0 | 2 |
| 2 to 2 | 0 | 0 | 0 |
| 2 to 3 | 0 | 0 | 0 |
| 2 to 4-5 | 0 | 0 | 0 |
| 3 to 0 | 0 | 0 | 0 |
| 3 to 1 | 0 | 0 | 0 |
| 3 to 2 | 0 | 0 | 0 |
| 3 to 3 | 0 | 0 | 0 |
| 3 to 4-5 | 0 | 0 | 0 |
| 4-5 to 0 | 0 | 0 | 0 |
| 4-5 to 1 | 0 | 0 | 0 |
| 4-5 to 2 | 0 | 0 | 0 |
| 4-5 to 3 | 0 | 0 | 0 |
| 4-5 to 4-5 | 0 | 0 | 0 |
Single measurements of 12-lead ECGs were obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, corrected QT interval (QTc), Bazett's Corrected QT interval (QTcB), Friderica's Corrected QT interval (QTcF). Number of participants with abnormal ECG findings (Abnormal - Not Clinically Significant and Abnormal - Clinically Significant ) at any time post-Baseline visit have been presented.
| Participants | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy |
|---|---|---|---|
| Abnormal - Not Clinically Significant | 9 | 10 | 9 |
| Abnormal - Clinically Significant | 0 | 1 | 0 |
Echocardiograms (ECHO) was performed to assess cardiac ejection fraction and cardiac valve morphology. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on-therapy value has been presented.
| Participants | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy |
|---|---|---|---|
| No Change Or Any Increase | 11 | 14 | 11 |
| >0-<10 Decrease | 4 | 2 | 3 |
| >=10 Decrease And >= Lower limit of Normal (Lln) | 1 | 0 | 2 |
Blood samples were collected for evaluation of clinical chemistry parameters including sodium, potassium, calcium, albumin, total protein, blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GCT), phosphate, C-reactive protein (CRP), hypercalcemia, hyperkalemia, hypernatremia, hypocalcemia, hypokalemia, hyponatremia, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, direct bilirubin and estimated creatinine clearance (CRTCE). Baseline was defined as the most recent non-missing value from a central laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on therapy value for number of participants with any grade increase in clinical chemistry parameters for has been presented. Only those participants available at specified time point were analyzed (represented by n=x in category titles).
| Participants | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy |
|---|---|---|---|
| ALT; n=16,16,16 | 3 | 13 | 9 |
| Albumin; n=16,16,16 | 2 | 5 | 2 |
| Alkaline phosphatase; n=16,16,16 | 5 | 10 | 4 |
| AST; n=16,16,16 | 8 | 15 | 12 |
| Bilirubin; n=16,16,16 | 0 | 2 | 0 |
| CRP;n=12,12,13 | 0 | 0 | 0 |
| Creatinine; n=16,16,16 | 0 | 0 | 0 |
| Direct bilirubin; n=4,6,3 | 0 | 0 | 0 |
| GCT; n=16,16,16 | 6 | 12 | 5 |
| Hypercalcemia; n=16,16,16 | 0 | 0 | 0 |
| Hyperkalemia; n=16,16,16 | 1 | 4 | 0 |
| Hypernatremia; n=16,16,16 | 3 | 4 | 1 |
| Hypocalcemia; n=16,16,16 | 7 | 7 | 4 |
| Hypokalemia; n=16,16,16 | 1 | 4 | 3 |
| Hyponatremia; n=16,16,16 | 7 | 7 | 5 |
| LDH; 16,16,15 | 0 | 0 | 0 |
| Phosphate; n=16,16,16 | 10 | 6 | 4 |
| Protein; n=16,16,16 | 0 | 0 | 0 |
| Urea; n=15,15,16 | 0 | 0 | 0 |
| CRTCE; n=5,2,5 | 0 | 0 | 0 |
Blood samples were collected for evaluation of hematology parameters including hemoglobin, white blood cell (WBC), platelet count, basophils, eosinophils, lymphocytes, monocytes, total neutrophils, lymphocytopenia and lymphocytosis. Baseline was defined as the most recent non-missing value from a central laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on therapy value for number of participants with any grade increase in hematology parameters for has been presented.
| Participants | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy |
|---|---|---|---|
| Basophils | 0 | 0 | 0 |
| Eosinophils | 0 | 0 | 0 |
| Hemoglobin | 4 | 6 | 4 |
| Leukocytes | 5 | 9 | 10 |
| Monocytes | 0 | 0 | 0 |
| Neutrophils | 6 | 9 | 9 |
| Platelets | 2 | 5 | 3 |
| Lymphocytopenia | 8 | 6 | 6 |
| Lymphocytosis | 2 | 0 | 0 |
The safety profile of dabrafenib and trametinib in monotherapy as well as in combination therapy was characterized by determining the number of participants with incidence of squamous cell carcinoma and keratoacanthoma.
| Participants | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy |
|---|---|---|---|
| Number of Participants With Incidence of Squamous Cell Carcinoma and Keratoacanthoma | 1 | 0 | 0 |
An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function.
| Participants | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy |
|---|---|---|---|
| Any Non-SAE | 16 | 16 | 15 |
| Any SAE | 8 | 7 | 4 |
Blood samples were collected for pharmacokinetic analysis of trametinib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method.
| Nanograms per milliliter | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy |
|---|---|---|---|
| WEEK 2 ; 4 to 8 HOURS POST-DOSE; n= 12, 14,13 | 1.4 ± 4.99 | 14.6 ± 5.15 | 16.3 ± 5.73 |
| WEEK 8 ; 4 to 8 HOURS POST-DOSE; n=12, 12, 10 | 0.6 ± 2.06 | 12.9 ± 8.82 | 13.8 ± 6.46 |
| WEEK 10 ; 4 to 8 HOURS POST-DOSE; n=13, 13, 11 | 10.5 ± 5.33 | 8.8 ± 7.50 | 14.7 ± 6.66 |
Blood samples were collected for pharmacokinetic analysis of Dabrafenib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method.
| Nanograms per milliliter | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy |
|---|---|---|---|
| WEEK 2 ; 4 to 8 HOURS POST-DOSE; n= 12, 14,13 | 219.7 ± 545.46 | 0.0 ± 0.00 | 438.1 ± 487.26 |
| WEEK 8 ; 4 to 8 HOURS POST-DOSE; n=12, 12, 10 | 259.1 ± 669.60 | 0.0 ± 0.00 | 226.5 ± 236.37 |
| WEEK 10 ; 4 to 8 HOURS POST-DOSE; n=13, 13, 11 | 92.6 ± 169.45 | 81.8 ± 168.16 | 429.2 ± 735.69 |
Collected over On-treatment serious adverse events (SAEs) and non-SAEs were collected from the start of the study treatment up to 3.2 years.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Dabrafenib Followed by Combination Therapy | 1/16 (6.3%) | 8/16 (50%) | 16/16 (100%) |
| Trametinib Followed by Combination Therapy | 0/16 (0%) | 7/16 (43.8%) | 16/16 (100%) |
| Combination Therapy | 2/16 (12.5%) | 4/16 (25%) | 15/16 (93.8%) |
| Event | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy |
|---|---|---|---|
| PyrexiaGeneral disorders | 2/16 | 3/16 | 0/16 |
| VomitingGastrointestinal disorders | 0/16 | 1/16 | 0/16 |
| Histiocytosis haematophagicBlood and lymphatic system disorders | 0/16 | 0/16 | 1/16 |
| NeutropeniaBlood and lymphatic system disorders | 0/16 | 1/16 | 0/16 |
| Left ventricular dysfunctionCardiac disorders | 0/16 | 1/16 | 0/16 |
| Adrenal insufficiencyEndocrine disorders | 0/16 | 1/16 | 0/16 |
| Abdominal painGastrointestinal disorders | 1/16 | 0/16 | 0/16 |
| DiarrhoeaGastrointestinal disorders | 0/16 | 1/16 | 0/16 |
| SubileusGastrointestinal disorders | 1/16 | 0/16 | 0/16 |
| Hepatocellular injuryHepatobiliary disorders | 0/16 | 0/16 | 1/16 |
| Event | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy |
|---|---|---|---|
| PyrexiaGeneral disorders | 5/16 | 13/16 | 6/16 |
| AstheniaGeneral disorders | 10/16 | 10/16 | 9/16 |
| ChillsGeneral disorders | 3/16 | 10/16 | 4/16 |
| HeadacheNervous system disorders | 9/16 | 9/16 | 6/16 |
| NauseaGastrointestinal disorders | 8/16 | 4/16 | 5/16 |
| RashSkin and subcutaneous tissue disorders | 4/16 | 8/16 | 3/16 |
| DiarrhoeaGastrointestinal disorders | 6/16 | 7/16 | 5/16 |
| FolliculitisInfections and infestations | 1/16 | 7/16 | 2/16 |
| Blood Creatine Phosphokinase IncreasedInvestigations | 5/16 | 7/16 | 5/16 |
| Back PainMusculoskeletal and connective tissue disorders | 7/16 | 4/16 | 2/16 |
| Age, Continuous(Years) | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy | Total |
|---|---|---|---|---|
| Mean | 56.6 ± 16.43 | 56.5 ± 11.77 | 58.9 ± 13.55 | 57.4 ± 13.79 |
| Sex: Female, Male(Participants) | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy | Total |
|---|---|---|---|---|
| Female | 7 | 8 | 6 | 21 |
| Male | 9 | 8 | 10 | 27 |
| Race/Ethnicity, Customized(Participants) | Dabrafenib Followed by Combination Therapy | Trametinib Followed by Combination Therapy | Combination Therapy | Total |
|---|---|---|---|---|
| Asian-South East Asian Heritage | 0 | 1 | 0 | 1 |
| White - White/Caucasian/European | 16 | 15 | 16 | 47 |
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GlaxoSmithKline