The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01072175




Registration number
NCT01072175
Ethics application status
Date submitted
12/02/2010
Date registered
19/02/2010
Date last updated
5/07/2019

Titles & IDs
Public title
Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212
Scientific title
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
Secondary ID [1] 0 0
113220
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - GSK2118436
Treatment: Drugs - GSK1120212

Experimental: Arm Part A - Day 1: GSK2118436 75mg; Day 2 through Day 16: GSK1120212 2mg; Day 15: GSK2118436 75mg +GSK1120212 2mg Drug-drug interaction

Experimental: Arm Part B - GSK2118436 + GSK1120212 Dose escalation to a maximum tolerated combination dose

Experimental: Arm Part C - GSK2118436 + GSK1120212 cohort expansion for safety and efficacy


Treatment: Drugs: GSK2118436
GSK2118436 is a potent and selective inhibitor of BRAF kinase activity with a mode of action consistent with adenosine triphosphate-competitive inhibition.

Treatment: Drugs: GSK1120212
GSK1120212 is a potent and highly selective inhibitor of MEK1/2 activation and kinase activity.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Part A: Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib - 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.
Timepoint [1] 0 0
Day 15
Primary outcome [2] 0 0
Part A: AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites - 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.
Timepoint [2] 0 0
Day 15
Primary outcome [3] 0 0
Part B: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) - 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.
Timepoint [3] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
Primary outcome [4] 0 0
Part B: Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline - 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.
Timepoint [4] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
Primary outcome [5] 0 0
Part B: Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range - 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.
Timepoint [5] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
Primary outcome [6] 0 0
Part B: Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline - 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.
Timepoint [6] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
Primary outcome [7] 0 0
Part B: Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range - 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.
Timepoint [7] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
Primary outcome [8] 0 0
Part B: Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure - 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.
Timepoint [8] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
Primary outcome [9] 0 0
Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator - 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.
Timepoint [9] 0 0
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)
Primary outcome [10] 0 0
Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR) - 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.
Timepoint [10] 0 0
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)
Primary outcome [11] 0 0
Part C (Crossover): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator - 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.
Timepoint [11] 0 0
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)
Primary outcome [12] 0 0
Part C (Randomized): Progression-free Survival (PFS) as Assessed by the Investigator - 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.
Timepoint [12] 0 0
From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 7 years)
Primary outcome [13] 0 0
Part C (Crossover): Progression-free Survival (PFS) as Assessed by the Investigator - 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.
Timepoint [13] 0 0
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)
Primary outcome [14] 0 0
Part C (Randomized): Progression-free Survival (PFS) as Assessed by the Blinded Independent Central Review (BICR) - 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
Timepoint [14] 0 0
From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 19 months)
Primary outcome [15] 0 0
Part C (Randomized): Duration of Response as Assessed by the Investigator and Blinded Independent Central Review (BICR) - 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.
Timepoint [15] 0 0
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)
Primary outcome [16] 0 0
Part C (Randomized): Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) - 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.
Timepoint [16] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Primary outcome [17] 0 0
Part C (Randomized): Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline - 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.
Timepoint [17] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Primary outcome [18] 0 0
Part C (Randomized): Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range - 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.
Timepoint [18] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Primary outcome [19] 0 0
Part C (Randomized): Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline - 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.
Timepoint [19] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Primary outcome [20] 0 0
Part C (Randomized): Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range - 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.
Timepoint [20] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Primary outcome [21] 0 0
Part C (Randomized): Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure - 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.
Timepoint [21] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Primary outcome [22] 0 0
Part D (Analyte=GSK2118436): Maximum Plasma Concentration (Cmax) of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib - 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.
Timepoint [22] 0 0
Day 1 and Day 21
Primary outcome [23] 0 0
Part D (Analyte=GSK2118436): Tmax of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib - 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.
Timepoint [23] 0 0
Day 1 and Day 21
Primary outcome [24] 0 0
Part D (Analyte=GSK2118436): AUC (0-tau) and AUC (0-inf) of Single and Repeat Doses of Dabrafenib Alone and in Combination With Trametinib - 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.
Timepoint [24] 0 0
Day 1 and Day 21
Primary outcome [25] 0 0
Part D: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) - 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.
Timepoint [25] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Primary outcome [26] 0 0
Part D: Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline - 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.
Timepoint [26] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Primary outcome [27] 0 0
Part D: Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range - 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.
Timepoint [27] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Primary outcome [28] 0 0
Part D: Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline - 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.
Timepoint [28] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Primary outcome [29] 0 0
Part D: Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range - 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.
Timepoint [29] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Primary outcome [30] 0 0
Part D: Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure - 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
Timepoint [30] 0 0
From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Secondary outcome [1] 0 0
Part A: Steady State Concentration of Trametinib With Concomitant Administration of Dabrafenib - The steady state plasma concentration (Css) of trametinib with concomitant dabrafenib administration was assessed at Day 15 and Day 16. At steady state the amount of drug administered (in a given time period) is equal to the amount of drug eliminated.
Timepoint [1] 0 0
Day 15 and Day 16
Secondary outcome [2] 0 0
Part B: AUC [0-tau] of Dabrafenib (DAB) and Its Metabolite in Combination With Trametinib - Area under the concentration-time curve from time zero (predose) until the last time of quantifiable concentration (AUC [0-tau]) was assessed. Blood samples for PK analysis of dabrafenib and its the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
Timepoint [2] 0 0
Day 15 and Day 21
Secondary outcome [3] 0 0
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 - Pre-dose (trough) concentration at the end of the dosing interval (Ctau) and maximum plasma concentration (Cmax) were assessed for plasma dabrafenib (DAB) following repeat dosing of DAB administered in combination with trametinib (T). The trough concentration is defined as the plasma level of a pharmaceutical product measured just before the next dose. Blood samples for PK analysis of the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) of dabrafenib were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
Timepoint [3] 0 0
Day 15 and Day 21
Secondary outcome [4] 0 0
Part B: Tmax of Dabrafenib and Its Metabolite in Combination With Trametinib - The tmax is defined as the time of occurenceof Cmax. Tha tmax was assessed for plasma dabrafenib (DAB) following repeat dosing of dabrafenib 75 and 150 mg BID administered in combination with trametinib. Blood samples for PK analysis of the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) of dabrafenib were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
Timepoint [4] 0 0
Day 15 and Day 21
Secondary outcome [5] 0 0
Part B (Analyte=GSK1120212): AUC (0-tau) Assessment of Trametinib in Combination With Dabrafenib - AUC (0-tau) is defined as area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration. AUC (0-tau) was assessed for plasma trametinib following repeat dosing of trametinib in combination with dabrafenib. Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 15 pre-dose and Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
Timepoint [5] 0 0
Day 15 and Day 21
Secondary outcome [6] 0 0
Part B (Analyte=GSK1120212): Ctau and Cmax Assessments of Trametinib in Combination With Dabrafenib - Pre-dose (trough) concentration at the end of the dosing interval (Ctau) and maximum plasma concentration (Cmax) were assessed for plasma trametinib following repeat dosing of trametinib in combination with dabrafenib. Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 15 pre-dose or Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
Timepoint [6] 0 0
Day 15 and Day 21
Secondary outcome [7] 0 0
Part B (Analyte=GSK1120212): Tmax Assessment of Trametinib in Combination With Dabrafenib - The tmax is defined as the time of occurrence of Cmax. The PK parameter for tmax was assessed for plasma trametinib following repeat dosing of trametinib in combination with dabrafenib. Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 15 pre-dose or Day 21 pre-dose and at 1, 2, 4, 6, and 8 hours post-dose administration.
Timepoint [7] 0 0
Day 15 and Day 21
Secondary outcome [8] 0 0
Part B: Number of Participants With BRAFi-naïve Mutant Metastatic Melanoma With the Best Overall Response as Assessed by Investigator - Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be <10 milimeter [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 response 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. BRAFi-naïve participants were those with BRAF-mutation-positive melanoma who had not received prior therapy with a BRAF inhibitor.
Timepoint [8] 0 0
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)
Secondary outcome [9] 0 0
Part B: Duration of Response as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma - 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. BRAFi-naïve participants were those with BRAF-mutation-positive melanoma who had not received prior therapy with a BRAF inhibitor.
Timepoint [9] 0 0
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)
Secondary outcome [10] 0 0
Part B: Progression-free Survival (PFS) as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma - 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. BRAFi-naïve were the participants with BRAF-mutation positive melanoma who had not received prior therapy with a BRAF-inhibitor..
Timepoint [10] 0 0
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)
Secondary outcome [11] 0 0
Part B: Overall Survival (OS) in BRAFi Naïve Melanoma Participants - OS is defined as the interval of time between the first dose of study medication until the date of death due to any cause. For the participants who did not die, overall survival was censored at the date of last contact.
Timepoint [11] 0 0
From the date of first dose until date of death due to any cause (up to approximately 8 years)
Secondary outcome [12] 0 0
Part B: Pre- and Post-dose H-scores for Individual Participants - p-ERK and p-AKT, biomarkers in tumor biopsies, were assessed for participants with BRAF mutant colorectal cancer. The H-score, which is a composite score that comprises intensity and percentage of staining, is a method of assessing the amount of protein or phospho-protein present in a biopsy sample. The score is obtained by the formula: (3 * percentage of strongly staining nuclei) + (2 * percentage of moderately staining nuclei) + (percentage of weakly staining nuclei). The H-score ranges from 0 to 300, with a score of 0 representing the absence of any of the target protein and an H-score of 300 representing maximum staining and intensity of the target protein.
Timepoint [12] 0 0
Screening and at disease progression (up to approximately 8 years)
Secondary outcome [13] 0 0
Part C (Randomized): Overall Survival (OS) - OS is defined as the interval of time between the date of randomization until the date of death due to any cause. For the participants who did not die, overall survival was censored at the date of last contact. When calculating overall survival, deaths following crossover were included.
Timepoint [13] 0 0
From the date of randomization until date of death due to any cause (up to approximately 7 years)
Secondary outcome [14] 0 0
Part C: Plasma Concentrations of Dabrafenib and Its Metabolites - Plasma concentrations of dabrafenib and its metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were assesed following daily dose of dabrafenib and trametinib.
Timepoint [14] 0 0
Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56
Secondary outcome [15] 0 0
Part C: Plasma Concentrations of Trametinib - Plasma concentrations of trametinib was assessed following daily dose of dabrafenib and trametinib.
Timepoint [15] 0 0
Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56
Secondary outcome [16] 0 0
Part C: Oral Clearance (CL/F) of Dabrafenib and Trametinib - Oral clearance (CL/F) of dabrafenib and trametinib were assessed using a population approach. Oral clearance (CL/F) is defined as the apparent volume of plasma in the vascular compartment cleared of drug per unit time by the processes of metabolism and excretion. For dabrafenib, population CL/F is defined as inducible and non-inducible CL/F. As dabrafenib induces its own metabolism, total oral clearance at steady state includes a non-induced (Day 1) component and an induced component, as estimated by a population PK model.
Timepoint [16] 0 0
Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48
Secondary outcome [17] 0 0
Part C: Oral Volume of Distribution (V/F) of Dabrafenib and Trametinib - Oral volume of distribution (V/F) of dabrafenib and trametinib were assessed using a population approach. Oral volume of distribution (V/F) is defined as the apparent volume of distribution in the central compartment.
Timepoint [17] 0 0
Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48
Secondary outcome [18] 0 0
Part D: Cmax of Dabrafenib Metabolites - The maximum concentration (Cmax) of dabrafenib metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) after single and repeat doses of DAB alone and in combination with trametinib was measured at Day 1 and Day 21.
Timepoint [18] 0 0
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
Secondary outcome [19] 0 0
Part D: Tmax of Dabrafenib Metabolites - The time to Cmax (tmax) of DAB metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) after single and repeat doses of DAB alone and in combination with trametinib was measuered at Day 1 and Day 21.
Timepoint [19] 0 0
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
Secondary outcome [20] 0 0
Part D: Area Under the Concentration-time Curve (AUC) of Dabrafenib Metabolites - Area under the concentration-time curve (AUC) from pre-dose to dosing interval (AUC[0-tau]), from pre-dose to the last time of quantifable concentration (AUC[0-tau]), and from pre-dose extrapolated to infinity (AUC[0-inf]) of DAB metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) after single and repeat doses of DAB alone and in combination with trametinib was measured at Day 1 and Day 21.
Timepoint [20] 0 0
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
Secondary outcome [21] 0 0
Part D: Cmax Assessment of Trametinib - Cmax of trametinib after single and repeat dose in combination with DAB was observed at Day 1 and Day 21. 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 (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.Participants receiving DAB 75 mg to DAB 75 mg + Trametinib 2 mg and those receiving DAB 150 mg to DAB 150 mg + Trametinib 2 mg did not receive Trametinib until Day 29; therefore, Cmax was not analyzed in these participants at Days 1 and 21.
Timepoint [21] 0 0
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
Secondary outcome [22] 0 0
Part D: Tmax Assessment of Trametinib - The tmax of trametinib after single and repeat dose in combination with dabrafenib (DAB) was observed at Day 1 and Day 21. 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 (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.Participants receiving DAB 75 mg to DAB 75 mg + Trametinib 2 mg and those receiving DAB 150 mg to DAB 150 mg + Trametinib 2 mg did not receive Trametinib until Day 29; therefore, tmax was not analyzed in these participants at Days 1 and 21.
Timepoint [22] 0 0
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
Secondary outcome [23] 0 0
Part D: Area Under the Concentration-time Curve Assessment of Trametinib - AUC(0-tau) after single and repeat dose of teametinib alone and in combination with dabrafenib was observed at Day 1 and Day 21. 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 (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.Participants receiving DAB 75 mg to DAB 75 mg + Trametinib 2 mg and those receiving DAB 150 mg to DAB 150 mg + Trametinib 2 mg did not receive Trametinib until Day 29; therefore, AUC(0-tau) was not analyzed in these participants at Days 1 and 21.
Timepoint [23] 0 0
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
Secondary outcome [24] 0 0
Part D: Number of Participants With the Best Overall Response as Assessed by the Investigator in Participants - Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be <10 milimeter [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]). To be assigned a status of PR or CR, a confirmatory disease assessment should be performed no less than 28 days after the criteria for response are first met. Response was evaluated by an investigator as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
Timepoint [24] 0 0
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)
Secondary outcome [25] 0 0
Part D: Duration of Response as Assessed by the Investigator - 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.
Timepoint [25] 0 0
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)
Secondary outcome [26] 0 0
Part D: Progression-free Survival (PFS) as Assessed by the Investigator - 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.
Timepoint [26] 0 0
From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 7 years)
Secondary outcome [27] 0 0
Part D: Overall Survival (OS) - OS is defined as the interval of time between the date of randomization until the date of death due to any cause. For the participants who did not die, overall survival was censored at the date of last contact.
Timepoint [27] 0 0
From the date of first dose until date of death due to any cause (up to approximately 7 years)

Eligibility
Key inclusion criteria
Key

- 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 1.1.

- 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/L2.

- Adequate organ system function.

Key
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

- History of retinal vein occlusion, central serous retinopathy or glaucoma.

- Predisposing factors to retinal vein occlusion including uncontrolled hypertension,
uncontrolled diabetes, uncontrolled hyperlipidemia, and coagulopathy.

- Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk
factor for retinal vein occlusion or central serous retinopathy.

- Intraocular pressure greater than 21mm Hg as measured by tonography.

- Glaucoma diagnosed within one month prior to study Day 1.

- Presence of active gastrointestinal disease or other condition that will interfere
significantly with the absorption, distribution, metabolism or excretion of drugs.

- Known human immunodeficiency virus, Hepatitis B or Hepatitis C infection.

- Primary malignancy of the central nervous system.

- Untreated or symptomatic brain metastasis, leptomeningeal disease or spinal cord
compression. Subjects who are on a stable dose of corticosteroids for more than 1
month or off corticosteroids for 2 weeks can be enrolled with approval of medical
monitor. Subjects are not permitted to receive enzyme-inducing anti-epileptic drugs.

- Subjects with brain metastases are excluded, unless

a. All known lesions must be previously treated with surgery or stereotactic
radiosurgery, and- b. Brain lesion(s), if still present, must be confirmed stable
(i.e. no increase in lesion size) for =90 days prior to first dose on study (must be
documented with two consecutive MRI or CT scans using contrast), and c. Asymptomatic
with no corticosteroids requirement for = 30 days prior to first dose on study, and d.
No enzyme-inducing anticonvulsants for = 30 days prior to first dose on study.

- History of alcohol or drug abuse within 6 months prior to screening.

- Psychological, familial, sociological or geographical conditions that do not permit
compliance with the protocol.

- QTc interval greater than or equal to 480msecs.

- History of acute coronary syndromes (including unstable angina), coronary angioplasty,
or stenting within the past 24 weeks.

- Class II, III, or IV heart failure as defined by the New York Heart Association
functional classification system.

- Abnormal cardiac valve morphology (subjects with minimal abnormalities can be entered
on study with approval from the medical monitor.

- Treatment refractory hypertension defined as a blood pressure of systolic> 140 mmHg
and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy

- Patients with intra-cardiac defibrillators or permanent pacemakers.

- Cardiac metastases

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the study drugs or excipients.

- Pregnant or lactating female.

- Unwillingness or inability to follow the procedures required in the protocol.

- Uncontrolled diabetes, hypertension or other medical conditions that may interfere
with assessment of toxicity.

- Subjects with known glucose 6 phosphate dehydrogenase deficiency.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Novartis Investigative Site - Westmead
Recruitment hospital [2] 0 0
Novartis Investigative Site - Heidelberg
Recruitment postcode(s) [1] 0 0
2145 - Westmead
Recruitment postcode(s) [2] 0 0
3084 - Heidelberg
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
Connecticut
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Maryland
Country [6] 0 0
United States of America
State/province [6] 0 0
Massachusetts
Country [7] 0 0
United States of America
State/province [7] 0 0
Minnesota
Country [8] 0 0
United States of America
State/province [8] 0 0
Pennsylvania
Country [9] 0 0
United States of America
State/province [9] 0 0
Tennessee
Country [10] 0 0
United States of America
State/province [10] 0 0
Texas

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT01072175
Trial related presentations / publications
Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov 1;367(18):1694-703. doi: 10.1056/NEJMoa1210093. Epub 2012 Sep 29.
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications