An Open-Label, Dose-Escalation, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the BRAF Inhibitor GSK2118436 in Combination With the MEK Inhibitor GSK1120212 in Subjects With BRAF Mutant Metastatic Melanoma
Overview
- Phase
- Phase 2
- Intervention
- GSK2118436
- Conditions
- Cancer
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 430
- Locations
- 1
- Primary Endpoint
- Part B: Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
This was an open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2118436 and GSK1120212 in combination. This study was designed in four parts. In Part A, the effect of repeat doses of GSK1120212 on the pharmacokinetics of single dose GSK2118436 was investigated prior to evaluating combination regimens. In Part B, the range of tolerated dose combinations was identified using a dose-escalation procedure. In Part C, different dose combinations of GSK2118436 and GSK1120212 were evaluated, based on results from the dose escalation cohorts. In Part D, the pharmacokinetics and safety of GSK2118436 administered as HPMC capsules alone and in combination with GSK1120212 was evaluated.
Detailed Description
During Part A, a cohort of subjects received a single dose of GSK2118436 alone (Day 1) and then repeat doses of GSK1120212 for (Day 2 through Day 15). The dose regimen of GSK1120212 were continuous dosing. A second single dose of GSK2118436 was administered on Day 15 concomitantly with GSK1120212. Day 16 through Day 28 was a washout period, during which no study medication was administered. Starting on Day 29, subjects who elected to continue participation in the study were doses with GSK2118436. The dose of GSK2118436 after Day 29 might be altered based on emerging data from the first-time-in human study BRF112680. The dose might be increased to a dose level that has been completed and determined to be less than or equal to the maximum tolerated dose in that study. Part B of the study enrolled cohorts in escalating doses to identify a set of allowable doses to be expanded in Part C. Subjects were enrolled in a 3+3 cohort design, with provisional dose levels of both drugs. The decision regarding escalation to the next dose levels of GSK1120212 and GSK2118436 was further guided by a Bayesian logistic regression model. The first cohort started at low doses for both drugs. Doses up to 300 mg/day for GSK2118436 and up to 3 mg QD for GSK1120212 were studied. The starting dose might be lowered based on emerging data from other studies and from Part A. Expansion cohorts enrolled in Part C at dose levels of GSK2118436 and GSK1120212 as defined in Part B. One of the selected doses might include GSK2118436 administered as monotherapy at a tolerable dose (less than or equal to the maximum tolerated dose) determined in BRF112680. Part C was a randomized open-label Phase II portion of the study, and consisted of expansion cohorts investigating 2 to 3 dose levels of GSK2118436 and GSK1120212 dosing in combination, and GSK2118436 administered as monotherapy. Subjects were assigned to treatment arms in a randomized fashion to compare tolerability and safety. Population PK parameters, clinical activity, durability of response and safety of GSK2118436 and GSK1120212 dosed orally in combination and GSK2118436 as monotherapy were evaluated. Part D consisted of evaluation of the pharmacokinetics of GSK2118436 HPMC capsules administered as monotherapy and in combination with GSK1120212. Pharmacokinetics of GSK2118436 was assessed following a single dose on Day 1 and after repeat dosing (Day 21) and compared between combination and monotherapy. The pharmacokinetics of GSK1120212 was also be assessed. Safety, tolerability and clinical activity were evaluated in 4 dosing cohorts. These cohorts might be expanded for additional safety data. Subjects were randomized to different cohorts.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Capable of given written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
- •Male or female age 18 years or greater; able to swallow and retain oral medication.
- •BRAF mutation positive melanoma or colorectal cancer; other BRAF mutation positive tumor types may be considered.
- •Measurable disease according to RECIST version 1.
- •Eastern Cooperative Oncology Group Performance Status of 0 or 1 for Parts A and B. Subjects with Eastern Cooperative Oncology Group Performance Status of 2 or less may be entered into Part C with approval of medical monitor.
- •Agree to contraception requirements.
- •Calcium phosphorus product less than 4.0mmol2/L
- •Adequate organ system function.
Exclusion Criteria
- •Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy).
- •Part A and Part B: Prior exposure to BRAF or MEK inhibitors unless approved by the GSK Medical Monitor.
- •Part C: Prior exposure to BRAF or MEK inhibitors. Prior anti-cancer therapy in the metastatic setting, with the exception of up to one regimen of chemotherapy and/or interleukin-2 (IL-2).
- •Part D: Prior exposure to BRAF inhibitors. A washout period of 6 weeks is required for ipilimumab.
- •Received an investigational anti-cancer drug within 4 weeks or 5 half-lives (whichever is shorter) of study drug administration--- at least 14 days must have passed between the last dose of prior investigational anti-cancer drug and the first dose of study drug.
- •Current use of a prohibited medication or requires any of these medications during treatment with study drug.
- •Current use of therapeutic warfarin.
- •Any major surgery, radiotherapy, or immunotherapy within the last 4 weeks. Limited radiotherapy within the last 2 weeks.
- •Chemotherapy regimens with delayed toxicity within the last 4 weeks. Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last 2 weeks.
- •Unresolved toxicity greater than National Cancer Institute-Common Terminology Criteria for Adverse Events version 4 Grade 1 from previous anti-cancer therapy except alopecia.
Arms & Interventions
Arm Part A
Day 1: GSK2118436 75mg; Day 2 through Day 16: GSK1120212 2mg; Day 15: GSK2118436 75mg +GSK1120212 2mg Drug-drug interaction
Intervention: GSK2118436
Arm Part A
Day 1: GSK2118436 75mg; Day 2 through Day 16: GSK1120212 2mg; Day 15: GSK2118436 75mg +GSK1120212 2mg Drug-drug interaction
Intervention: GSK1120212
Arm Part B
GSK2118436 + GSK1120212 Dose escalation to a maximum tolerated combination dose
Intervention: GSK2118436
Arm Part C
GSK2118436 + GSK1120212 cohort expansion for safety and efficacy
Intervention: GSK2118436
Arm Part C
GSK2118436 + GSK1120212 cohort expansion for safety and efficacy
Intervention: GSK1120212
Outcomes
Primary Outcomes
Part B: Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
Clinical Chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.
Part A: Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib
Time Frame: Day 15
Blood samples for PK analysis of dabrafenib and its the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at pre-dose and at 1, 2, 3, 4, 6, 8, 10, and 24 hours after dabrafenib administration. From the plasma concentration-time curve, the PK parameter Cmax was determined by standard non-compartmental analysis using WinNonlin. Cmax data are reported as geometric least squares means.
Part B: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An 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/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.
Part A: AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites
Time Frame: Day 15
Blood samples for PK analysis of dabrafenib and its metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at pre-dose and at 1, 2, 3, 4, 6, 8, 10, and 24 hours after dabrafenib administration. AUC is defined as the area under the dabrafenib concentration-time curve as a measure of drug exposure. AUC (0-inf) is defined as the area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time. AUC (0-t) is defined as area under the concentration-time curve from time zero (pre-dose) to the last time of quantifiable concentration. Date are reported as geometric least square means.
Part B: Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.
Part B: Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
Hematology parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.
Part B: Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
For Hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.
Part B: Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
Blood pressure and heart rate were summarized according to NCI CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred. Blood pressure measurement included systolic blood pressure (SBP, millimeters of mercury \[mmHg\]) and diastolic BP (DBP). Heart rate is the measure of heart beats per minute (bpm). Changes in heart rate, either decrease to \<60 bpm, change to normal or no change, or increase to \>100 bpm are presented.
Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator
Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 7 years)
Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be \<10 millimeters \[mm\] in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by an investigator as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR)
Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 19 months)
Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by BICR as per RECIST, version 1.1.
Part C (Crossover): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator
Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 7 years)
Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by an investigator as per RECIST, version 1.1.
Part C (Randomized): Progression-free Survival (PFS) as Assessed by the Investigator
Time Frame: From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 7 years)
PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not had a documented date of events, PFS and survival were censored at the date of the last adequate assessment.
Part C (Randomized): Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Hematology parameters were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.
Part C (Crossover): Progression-free Survival (PFS) as Assessed by the Investigator
Time Frame: From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 7 years)
PFS is defined as the interval between the first dose of study medication and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants received anti-cancer therapy prior to the date of documented events, and censored at the last adequate assessment, prior to the initiation of therapy. If the participant did not have a documented date of events, PFS and survival were censored at the date of the last adequate assessment.
Part C (Randomized): Progression-free Survival (PFS) as Assessed by the Blinded Independent Central Review (BICR)
Time Frame: From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 19 months)
PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the BICR according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not had a documented date of events, PFS and survival were censored at the date of the last adequate assessment
Part C (Randomized): Duration of Response as Assessed by the Investigator and Blinded Independent Central Review (BICR)
Time Frame: First documented evidence of PR or CR until the date of the first documented sign of disease progression or the date of death due to any cause (up to approximately 19 months)
Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]) is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.
Part C (Randomized): Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.
Part C (Randomized): Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Clinical Chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.
Part C (Randomized): Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.
Part C (Randomized): Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
For Hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.
Part C (Randomized): Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Blood pressure were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred.lood pressure measurement included systolic blood pressure (BP, milimeter of mercury \[mmHg\]) and diastolic BP (DBP). Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value. Heart Rate is the measure of heart beats per minute (bpm). Changes in heart rate, either decrease to \<60 bpm, change to normal or no change, or increase to \>100 bpm are presented.
Part D (Analyte=GSK2118436): Maximum Plasma Concentration (Cmax) of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib
Time Frame: Day 1 and Day 21
The PK parameter Cmax was assessed. Blood samples for PK analysis of dabrafenib were obtained at pre-dose Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours (24 hour on Day 1 only) post-dose administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin. Cmax data are reported as geometric least squares means.
Part D (Analyte=GSK2118436): Tmax of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib
Time Frame: Day 1 and Day 21
tmax is defined as the time of occurenceof Cmax. Blood samples for PK analysis of dabrafenib were obtained at Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours (24 hour on Day 1 only) post-dose administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin.
Part D (Analyte=GSK2118436): AUC (0-tau) and AUC (0-inf) of Single and Repeat Doses of Dabrafenib Alone and in Combination With Trametinib
Time Frame: Day 1 and Day 21
The PK parameters were determined for area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration AUC (0-tau) and from time zero (pre-dose) extrapolated to infinite time AUC (0-inf). Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours (24 hour only on Day 1) post-dose administration.
Part D: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event for possible drug-induced liver injury.
Part D: Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Clinical Chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.
Part D: Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.
Part D: Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Hematology parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.
Part D: Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
For Hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.
Part D: Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure
Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Blood pressure were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred.lood pressure measurement included systolic blood pressure (BP, milimeter of mercury \[mmHg\]) and diastolic BP (DBP). Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value. Heart Rate is the measure of heartbeats per minute (bpm). Changes in heart rate, either decrease to \<60 bpm, change to normal or no change, or increase to \>100 bpm are presented
Secondary Outcomes
- Part A: Steady State Concentration of Trametinib With Concomitant Administration of Dabrafenib(Day 15 and Day 16)
- Part B: AUC [0-tau] of Dabrafenib (DAB) and Its Metabolite in Combination With Trametinib(Day 15 and Day 21)
- Part B: Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) and Maximum Plasma Concentration (Cmax) of Dabrafenib and Its Metabolite in Combination With Trametinib(Day 15 and Day 21)
- Part B: Tmax of Dabrafenib and Its Metabolite in Combination With Trametinib(Day 15 and Day 21)
- Part B (Analyte=GSK1120212): AUC (0-tau) Assessment of Trametinib in Combination With Dabrafenib(Day 15 and Day 21)
- Part B (Analyte=GSK1120212): Ctau and Cmax Assessments of Trametinib in Combination With Dabrafenib(Day 15 and Day 21)
- Part B (Analyte=GSK1120212): Tmax Assessment of Trametinib in Combination With Dabrafenib(Day 15 and Day 21)
- Part B: Number of Participants With BRAFi-naïve Mutant Metastatic Melanoma With the Best Overall Response as Assessed by Investigator(From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 8 years))
- Part B: Duration of Response as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma(First documented evidence of PR or CR until the earlier of date of disease progression or date of death due to any cause (up to approximately 8 years))
- Part B: Progression-free Survival (PFS) as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma(From the date of first dose to the earliest date of disease progression (PD) or death due to any cause (up to approximately 8 years))
- Part B: Overall Survival (OS) in BRAFi Naïve Melanoma Participants(From the date of first dose until date of death due to any cause (up to approximately 8 years))
- Part B: Pre- and Post-dose H-scores for Individual Participants(Screening and at disease progression (up to approximately 8 years))
- Part C (Randomized): Overall Survival (OS)(From the date of randomization until date of death due to any cause (up to approximately 7 years))
- Part C: Plasma Concentrations of Dabrafenib and Its Metabolites(Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56)
- Part C: Plasma Concentrations of Trametinib(Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56)
- Part C: Oral Clearance (CL/F) of Dabrafenib and Trametinib(Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48)
- Part C: Oral Volume of Distribution (V/F) of Dabrafenib and Trametinib(Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48)
- Part D: Cmax of Dabrafenib Metabolites(Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose)
- Part D: Tmax of Dabrafenib Metabolites(Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose)
- Part D: Area Under the Concentration-time Curve (AUC) of Dabrafenib Metabolites(Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose)
- Part D: Cmax Assessment of Trametinib(Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose)
- Part D: Tmax Assessment of Trametinib(Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose)
- Part D: Area Under the Concentration-time Curve Assessment of Trametinib(Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose)
- Part D: Number of Participants With the Best Overall Response as Assessed by the Investigator in Participants(From the date of first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 7 years))
- Part D: Duration of Response as Assessed by the Investigator(First documented evidence of PR or CR until the earlier of date of disease progression or date of death due to any cause (up to approximately 7 years))
- Part D: Progression-free Survival (PFS) as Assessed by the Investigator(From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 7 years))
- Part D: Overall Survival (OS)(From the date of first dose until date of death due to any cause (up to approximately 7 years))