Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01072175
First received: February 12, 2010
Last updated: September 19, 2013
Last verified: September 2013
  Purpose

This is an open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2118436 and GSK1120212 in combination. This study is designed in four parts. In Part A, the effect of repeat doses of GSK1120212 on the pharmacokinetics of single dose GSK2118436, will be investigated prior to evaluating combination regimens. In Part B, the range of tolerated dose combinations will be identified using a dose-escalation procedure. In Part C, different dose combinations of GSK2118436 and GSK1120212 will be 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 will be evaluated.


Condition Intervention Phase
Cancer
Drug: GSK2118436
Drug: GSK1120212
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, Dose-Escalation, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and ClinicalActivity of the BRAF Inhibitor GSK2118436 in Combination With the MEK Inhibitor GSK1120212 in Subjects With BRAF Mutant Metastatic Melanoma

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib in Part A [ Time Frame: Day 15 ] [ Designated as safety issue: No ]
    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.

  • AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites in Part A [ Time Frame: Day 15 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part B [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks ) ] [ Designated as safety issue: No ]
    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. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.

  • Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part B [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks) ] [ Designated as safety issue: No ]
    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. For clinical chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Clinical chemistry parameters included: hyponatremia, gamma glutamyltransferase (GGT), phosphorous inorganic, alkaline phosphatase, hyperglycemia, aspartate aminotransferase (AST), hypokalemia, albumin, alanine aminotransferase (ALT), total bilirubin, hyperkalemia, hypoglycemia, creatinine, lactate dehydrogenase, urea/blood urea nitrogen (BUN), bicarbonate, chloride, creatine clearance, total protein, uric acid, and troponin T.

  • Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part B [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks) ] [ Designated as safety issue: No ]
    Hematology parameters 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 Grade 3 or Grade 4 occurred. For hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Hematology parameters included: lymphocytes decreased, total neutrophils, hemoglobin decreased, white blood cell counts, platelet counts, monocytes, mean corpuscular hemoglobin concentration (MCHC), eosinophils, basophils, mean corpuscular hemoglobin, mean corpuscular volume, red blood cell count, hemotocrit, and reticulocytes.

  • Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part B [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks) ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator in Part C (Randomized) [ 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 47 weeks) ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR) in Part C (Randomized) [ 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 36 weeks) ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator in Part C (Crossover) [ 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 15 weeks) ] [ Designated as safety issue: No ]
    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.

  • Duration of Response as Assessed by the Investigator and Blinded Independent Central Review (BICR) in Part C (Randomized) [ 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 17 months) ] [ Designated as safety issue: No ]
    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.

  • Progression-free Survival (PFS) as Assessed by the Investigator in Part C (Randomized) [ 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 17 months) ] [ Designated as safety issue: No ]
    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 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.

  • Progression-free Survival (PFS) as Assessed by the Blinded Independent Central Review (BICR) in Part C (Randomized) [ 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 17 months) ] [ Designated as safety issue: No ]
    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 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

  • Progression-free Survival (PFS) as Assessed by the Investigator in Part C (Crossover) [ 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 9 months) ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part C (Randomized) [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximatley 75 weeks) ] [ Designated as safety issue: No ]
    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. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.

  • Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part C (Randomized) [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 75 weeks) ] [ Designated as safety issue: No ]
    Clinical chemistry 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 to any grade, Grade 3 or Grade 4 occurred. For clinical chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Clinical chemistry parameters included: albumin, alkaline phosphate (ALKP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total Bilirubin, calcium, creatine kinase, creatinine, gamma glutamyltransferase (GGT), glucose, potassium, magnesium, sodium, inorganic phosphorus. Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  • Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part C (Randomized) [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 75 weeks) ] [ Designated as safety issue: No ]
    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 to any grade, Grade 3 or Grade 4 occurred. For hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Hematology parameters included: hemoglobin, lymphocytes, Total absolute neutrophil count (ANC), platelet count, white blood cells (WBC) count. Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  • Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part C (Randomized) [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximlately 75 weeks) ] [ Designated as safety issue: No ]
    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.

  • Maximum Plasma Concentration (Cmax) of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436) [ Time Frame: Day 1 and Day 21 ] [ Designated as safety issue: No ]
    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.

  • The Tmax of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436) [ Time Frame: Day 1 and Day 21 ] [ Designated as safety issue: No ]
    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.

  • AUC (0-tau) and AUC (0-inf) of Single and Repeat Doses of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436) [ Time Frame: Day 1 and Day 21 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part D [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks) ] [ Designated as safety issue: No ]
    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. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.

  • Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part D [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks) ] [ Designated as safety issue: No ]
    Clinical chemistry parameters were summarized according to NCI CTCAE grade, version 4.0. G1, Mild; G2, Moderate; G3, Severe; G4, Life-threatening or disabling; G5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred. Changes above (High) and below (Low) the normal range were evaluated for parameters not graded. Included:hyponatremia,gamma glutamyltransferase (GGT),aspartate aminotransferase (AST),hyperglycemia,alkaline phosphatase,hypokalemia,alanine aminotransferase (ALT),phosphorus inorganic,creatine kinase,total bilirubin,albumin,hyperkalemia, hypomagnesemia,lipase,hypokalemia,hyponatremia,urea/blood urea nitogen (BUN),bicarbonate,creatine clearance,chloride,C-reactive protein,total protein,uric acid,troponin I,direct bilirubin,creatine kinase MB mass, chloride,total protein,bicarbonate,uric acid,creatine clearance,lactate dehydrogenase. Worst case change from BL was calculated as the post-BL value minus the BL value.

  • Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part D [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks) ] [ Designated as safety issue: No ]
    Hematology parameters 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 Grade 3 or Grade 4 occurred. For hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Hematology parameters included lymphocytes, total neutrophils, hemoglobin, white blood cell count, platelet count, monocytes, mean corpuscle hemoglobin concentration, eosinophils, basophils, mean corpuscle hemoglobin, mean corpuscle volume, red blood cell count, hematocrit, erythrocyte sedimentation, reticulocytes. Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  • Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part D [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks) ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Steady State Concentration of Trametinib With Concomitant Administration of Dabrafenib in Part A [ Time Frame: Day 15 and Day 16 ] [ Designated as safety issue: No ]
    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.

  • The AUC [0-tau] of Dabrafenib (DAB) and Its Metabolite in Combination With Trametinib (T) in Part B [ Time Frame: Day 15 and Day 21 ] [ Designated as safety issue: No ]
    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.

  • 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 in Part B [ Time Frame: Day 15 and Day 21 ] [ Designated as safety issue: No ]
    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.

  • The Tmax of Dabrafenib and Its Metabolite in Combination With Trametinib in Part B [ Time Frame: Day 15 and Day 21 ] [ Designated as safety issue: No ]
    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.

  • The AUC (0-tau) Assessment of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212) [ Time Frame: Day 15 and Day 21 ] [ Designated as safety issue: No ]
    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.

  • The Ctau and Cmax Assessments of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212) [ Time Frame: Day 15 and Day 21 ] [ Designated as safety issue: No ]
    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.

  • The Tmax Assessment of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212) [ Time Frame: Day 15 and Day 21 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With BRAFi-naïve Mutant Metastatic Melanoma With the Best Overall Response as Assessed by Investigator in Part B [ Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to 103 weeks) ] [ Designated as safety issue: No ]
    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.

  • Duration of Response as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma in Part B [ Time Frame: 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 22 months) ] [ Designated as safety issue: No ]
    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.

  • Progression-free Survival (PFS) as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma in Part B [ Time Frame: From the date of first dose to the earliest date of disease progression (PD) or death due to any cause (up to approximately 22 months) ] [ Designated as safety issue: No ]
    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..

  • Overall Survival (OS) in Part B BRAFi Naïve Melanoma Participants [ Time Frame: From the date of first dose until date of death due to any cause (up to approximately 22 months) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in p-ERK and Other Biomarkers in Tumor Biopsies in Participants With BRAF Mutant Colorectal Cancer in Part B [ Time Frame: Screening and at disease progression (up to approximately 8 months) ] [ Designated as safety issue: No ]
    Change in p-ERK and other biomarkers in tumor biopsies were assessed for participants with BRAF mutant colorectal cancer. Validation of p-ERK is currently ongoing; thus, data are not available at this time.

  • Overall Survival (OS) in Part C [ Time Frame: From the date of randomization until date of death due to any cause (up to approximately 17 months) ] [ Designated as safety issue: No ]
    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.

  • Plasma Concentrations of Dabrafenib and Its Metabolites in Part C [ Time Frame: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56 ] [ Designated as safety issue: No ]
    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.

  • Plasma Concentrations of Trametinib in Part C [ Time Frame: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56 ] [ Designated as safety issue: No ]
    Plasma concentrations of trametinib was assessed following daily dose of dabrafenib and trametinib.

  • Oral Clearance (CL/F) of Dabrafenib and Trametinib [ Time Frame: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48 ] [ Designated as safety issue: No ]
    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.

  • Oral Volume of Distribution (V/F) of Dabrafenib and Trametinib [ Time Frame: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48 ] [ Designated as safety issue: No ]
    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.

  • Cmax of Dabrafenib Metabolites in Part D [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • The Tmax of Dabrafenib Metabolites in Part D [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Area Under the Concentration-time Curve (AUC) of Dabrafenib Metabolites in Part D [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • The Cmax Assessment of Trametinib in Part D [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • The Tmax Assessment of Trametinib in Part D [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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 75 mg plus Trametinib 2 mg did not receive Trametinib until Day 29; therefore, tmax was not analyzed in these participants at Days 1 and 21.

  • Area Under the Concentration-time Curve Assessment of Trametinib in Part D [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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 75 mg plus Trametinib 2 mg did not receive Trametinib until Day 29; therefore, tmax was not analyzed in these participants at Days 1 and 21.

  • Number of Participants With the Best Overall Response as Assessed by the Investigator in Participants in Part D [ Time Frame: 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 280 days ) ] [ Designated as safety issue: No ]
    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.

  • Duration of Response as Assessed by the Investigator in Part D [ Time Frame: 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 13 months) ] [ Designated as safety issue: No ]
    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.

  • Progression-free Survival (PFS) as Assessed by the Investigator in Part D [ Time Frame: From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 13 months) ] [ Designated as safety issue: No ]
    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.

  • Overall Survival in Part D [ Time Frame: From the date of first dose until date of death due to any cause (up to approximately 14 months) ] [ Designated as safety issue: No ]
    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. Validation of OS is currenlty ongoing; thus, data are not available at this time.


Enrollment: 430
Study Start Date: March 2010
Estimated Study Completion Date: May 2016
Primary Completion Date: May 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm Part A
Day 1: GSK2118436 75mg; Day 2 through Day 16: GSK1120212 2mg; Day 15: GSK2118436 75mg +GSK1120212 2mg Drug-drug interaction
Drug: GSK2118436
GSK2118436 is a potent and selective inhibitor of BRAF kinase activity with a mode of action consistent with adenosine triphosphate-competitive inhibition.
Drug: GSK1120212
GSK1120212 is a potent and highly selective inhibitor of MEK1/2 activation and kinase activity.
Experimental: Arm Part B
GSK2118436 + GSK1120212 Dose escalation to a maximum tolerated combination dose
Drug: GSK2118436
GSK2118436 is a potent and selective inhibitor of BRAF kinase activity with a mode of action consistent with adenosine triphosphate-competitive inhibition.
Experimental: Arm Part C
GSK2118436 + GSK1120212 cohort expansion for safety and efficacy
Drug: GSK2118436
GSK2118436 is a potent and selective inhibitor of BRAF kinase activity with a mode of action consistent with adenosine triphosphate-competitive inhibition.
Drug: GSK1120212
GSK1120212 is a potent and highly selective inhibitor of MEK1/2 activation and kinase activity.

Detailed Description:

During Part A, a cohort of subjects will receive 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 will be continuous dosing. A second single dose of GSK2118436 will be administered on Day 15 concomitantly with GSK1120212. Day 16 through Day 28 will be a washout period, during which no study medication is administered. Starting on Day 29, subjects who elect to continue participation in the study will dose with GSK2118436. The dose of GSK2118436 after Day 29 may be altered based on emerging data from the first-time-in human study BRF112680. The dose may 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 will enroll cohorts in escalating doses to identify a set of allowable doses to be expanded in Part C. Subjects will 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 will be further guided by a Bayesian logistic regression model. The first cohort will start at low doses for both drugs. Doses up to 300 mg/day for GSK2118436 and up to 3 mg QD for GSK1120212 have been studied to date. The starting dose may be lowered based on emerging data from other studies and from Part A.

Expansion cohorts will be enrolled in Part C at dose levels of GSK2118436 and GSK1120212 as defined in Part B. One of the selected doses may include GSK2118436 administered as monotherapy at a tolerable dose (less than or equal to the maximum tolerated dose) determined in BRF112680. Part C is a randomized open-label Phase II portion of the study, and will consist of expansion cohorts investigating 2 to 3 dose levels of GSK2118436 and GSK1120212 dosing in combination, and GSK2118436 administered as monotherapy. Subjects will be 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 will be evaluated.

Part D will consist of evaluation of the pharmacokinetics of GSK2118436 HPMC capsules administered as monotherapy and in combination with GSK1120212. Pharmacokinetics of GSK2118436 will be assessed following a single dose on Day 1 and after repeat dosing (Day 21) and compared between combination and monotherapy. The pharmacokinetics of GSK1120212 will also be assessed. Safety, tolerability and clinical activity will also be evaluated in 4 dosing cohorts. These cohorts may be expanded for additional safety data. Subjects will be randomized to different cohorts.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 1.1.
  • 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.

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01072175

Locations
United States, California
GSK Investigational Site
Los Angeles, California, United States, 90025
GSK Investigational Site
San Francisco, California, United States, 94115
United States, Colorado
GSK Investigational Site
Aurora, Colorado, United States, 80045
United States, Connecticut
GSK Investigational Site
New Haven, Connecticut, United States, 06520
United States, Florida
GSK Investigational Site
Tampa, Florida, United States, 33612
United States, Maryland
GSK Investigational Site
Lutherville Timonium, Maryland, United States, 21093
United States, Massachusetts
GSK Investigational Site
Boston, Massachusetts, United States, 02114
GSK Investigational Site
Boston, Massachusetts, United States, 02215
United States, Minnesota
GSK Investigational Site
Rochester, Minnesota, United States, 55905
United States, Pennsylvania
GSK Investigational Site
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
GSK Investigational Site
Nashville, Tennessee, United States, 37232
GSK Investigational Site
Nashville, Tennessee, United States, 37203
United States, Texas
GSK Investigational Site
Houston, Texas, United States, 77030-4009
Australia, New South Wales
GSK Investigational Site
Westmead, New South Wales, Australia, 2145
Australia, Victoria
GSK Investigational Site
Heidelberg, Victoria, Australia, 3084
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided by GlaxoSmithKline

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01072175     History of Changes
Other Study ID Numbers: 113220
Study First Received: February 12, 2010
Results First Received: June 27, 2013
Last Updated: September 19, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
drug-drug interaction
BRAF inhibitor
expansion cohorts
melanoma
dose escalation
MEK inhibitor

Additional relevant MeSH terms:
Dabrafenib
Trametinib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014