MedPath

Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212

Phase 2
Completed
Conditions
Cancer
Interventions
Drug: GSK2118436
Drug: GSK1120212
Registration Number
NCT01072175
Lead Sponsor
Novartis Pharmaceuticals
Brief Summary

This was an open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2118436 and GSK1120212 in combination. This study was designed in four parts. In Part A, the effect of repeat doses of GSK1120212 on the pharmacokinetics of single dose GSK2118436 was investigated prior to evaluating combination regimens. In Part B, the range of tolerated dose combinations was identified using a dose-escalation procedure. In Part C, different dose combinations of GSK2118436 and GSK1120212 were evaluated, based on results from the dose escalation cohorts. In Part D, the pharmacokinetics and safety of GSK2118436 administered as HPMC capsules alone and in combination with GSK1120212 was evaluated.

Detailed Description

During Part A, a cohort of subjects received a single dose of GSK2118436 alone (Day 1) and then repeat doses of GSK1120212 for (Day 2 through Day 15). The dose regimen of GSK1120212 were continuous dosing. A second single dose of GSK2118436 was administered on Day 15 concomitantly with GSK1120212. Day 16 through Day 28 was a washout period, during which no study medication was administered. Starting on Day 29, subjects who elected to continue participation in the study were doses with GSK2118436. The dose of GSK2118436 after Day 29 might be altered based on emerging data from the first-time-in human study BRF112680. The dose might be increased to a dose level that has been completed and determined to be less than or equal to the maximum tolerated dose in that study.

Part B of the study enrolled cohorts in escalating doses to identify a set of allowable doses to be expanded in Part C. Subjects were enrolled in a 3+3 cohort design, with provisional dose levels of both drugs. The decision regarding escalation to the next dose levels of GSK1120212 and GSK2118436 was further guided by a Bayesian logistic regression model. The first cohort started at low doses for both drugs. Doses up to 300 mg/day for GSK2118436 and up to 3 mg QD for GSK1120212 were studied. The starting dose might be lowered based on emerging data from other studies and from Part A.

Expansion cohorts enrolled in Part C at dose levels of GSK2118436 and GSK1120212 as defined in Part B. One of the selected doses might include GSK2118436 administered as monotherapy at a tolerable dose (less than or equal to the maximum tolerated dose) determined in BRF112680. Part C was a randomized open-label Phase II portion of the study, and consisted of expansion cohorts investigating 2 to 3 dose levels of GSK2118436 and GSK1120212 dosing in combination, and GSK2118436 administered as monotherapy. Subjects were assigned to treatment arms in a randomized fashion to compare tolerability and safety. Population PK parameters, clinical activity, durability of response and safety of GSK2118436 and GSK1120212 dosed orally in combination and GSK2118436 as monotherapy were evaluated.

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

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
430
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.

Key

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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.

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Study & Design

Study Type
INTERVENTIONAL
Study Design
Not specified
Arm && Interventions
GroupInterventionDescription
Arm Part AGSK2118436Day 1: GSK2118436 75mg; Day 2 through Day 16: GSK1120212 2mg; Day 15: GSK2118436 75mg +GSK1120212 2mg Drug-drug interaction
Arm Part AGSK1120212Day 1: GSK2118436 75mg; Day 2 through Day 16: GSK1120212 2mg; Day 15: GSK2118436 75mg +GSK1120212 2mg Drug-drug interaction
Arm Part BGSK2118436GSK2118436 + GSK1120212 Dose escalation to a maximum tolerated combination dose
Arm Part CGSK2118436GSK2118436 + GSK1120212 cohort expansion for safety and efficacy
Arm Part CGSK1120212GSK2118436 + GSK1120212 cohort expansion for safety and efficacy
Primary Outcome Measures
NameTimeMethod
Part B: Number of Participants With Worst-case Chemistry Toxicity Grade Change From BaselineFrom Baseline (Day 1) until Follow-up visit (up to approximately 8 years)

Clinical Chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

Part A: Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With TrametnibDay 15

Blood samples for PK analysis of dabrafenib and its the metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at pre-dose and at 1, 2, 3, 4, 6, 8, 10, and 24 hours after dabrafenib administration. From the plasma concentration-time curve, the PK parameter Cmax was determined by standard non-compartmental analysis using WinNonlin. Cmax data are reported as geometric least squares means.

Part B: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)

An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.

Part A: AUC (0-t) and AUC (0-inf) of Dabrafenib and Its MetabolitesDay 15

Blood samples for PK analysis of dabrafenib and its metabolites hydroxy-dabrafenib (GSK2285403), carboxy-dabrafenib (GSK2298683) and desmethyl-dabrafenib (GSK2167542) were obtained at pre-dose and at 1, 2, 3, 4, 6, 8, 10, and 24 hours after dabrafenib administration. AUC is defined as the area under the dabrafenib concentration-time curve as a measure of drug exposure. AUC (0-inf) is defined as the area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time. AUC (0-t) is defined as area under the concentration-time curve from time zero (pre-dose) to the last time of quantifiable concentration. Date are reported as geometric least square means.

Part B: Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal RangeFrom Baseline (Day 1) until Follow-up visit (up to approximately 8 years)

For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

Part B: Number of Participants With Worst-case Hematology Toxicity Grade Change From BaselineFrom Baseline (Day 1) until Follow-up visit (up to approximately 8 years)

Hematology parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

Part B: Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal RangeFrom Baseline (Day 1) until Follow-up visit (up to approximately 8 years)

For Hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

Part B: Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood PressureFrom Baseline (Day 1) until Follow-up visit (up to approximately 8 years)

Blood pressure and heart rate were summarized according to NCI CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred. Blood pressure measurement included systolic blood pressure (SBP, millimeters of mercury \[mmHg\]) and diastolic BP (DBP). Heart rate is the measure of heart beats per minute (bpm). Changes in heart rate, either decrease to \<60 bpm, change to normal or no change, or increase to \>100 bpm are presented.

Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the InvestigatorFrom the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 7 years)

Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be \<10 millimeters \[mm\] in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by an investigator as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR)From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 19 months)

Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by BICR as per RECIST, version 1.1.

Part C (Crossover): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the InvestigatorFrom the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 7 years)

Best overall response is defined as complete response (CR: the disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis.) or partial reponse (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]). Participants with unknown or missing responses were considered as non-responders. To be assigned a status of PR or CR, a confirmatory disease assessment should have been performed no less than 28 days after the criteria for response were first met. Response was evaluated by an investigator as per RECIST, version 1.1.

Part C (Randomized): Progression-free Survival (PFS) as Assessed by the InvestigatorFrom the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 7 years)

PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not had a documented date of events, PFS and survival were censored at the date of the last adequate assessment.

Part C (Crossover): Progression-free Survival (PFS) as Assessed by the InvestigatorFrom the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 7 years)

PFS is defined as the interval between the first dose of study medication and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants received anti-cancer therapy prior to the date of documented events, and censored at the last adequate assessment, prior to the initiation of therapy. If the participant did not have a documented date of events, PFS and survival were censored at the date of the last adequate assessment.

Part C (Randomized): Progression-free Survival (PFS) as Assessed by the Blinded Independent Central Review (BICR)From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 19 months)

PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the BICR according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not had a documented date of events, PFS and survival were censored at the date of the last adequate assessment

Part C (Randomized): Duration of Response as Assessed by the Investigator and Blinded Independent Central Review (BICR)First documented evidence of PR or CR until the date of the first documented sign of disease progression or the date of death due to any cause (up to approximately 19 months)

Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]) is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.

Part C (Randomized): Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.

Part C (Randomized): Number of Participants With Worst-case Chemistry Toxicity Grade Change From BaselineFrom Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

Clinical Chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

Part C (Randomized): Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal RangeFrom Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

Part C (Randomized): Number of Participants With Worst-case Hematology Toxicity Grade Change From BaselineFrom Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

Hematology parameters were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

Part C (Randomized): Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal RangeFrom Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

For Hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

Part C (Randomized): Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood PressureFrom Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

Blood pressure were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred.lood pressure measurement included systolic blood pressure (BP, milimeter of mercury \[mmHg\]) and diastolic BP (DBP). Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value. Heart Rate is the measure of heart beats per minute (bpm). Changes in heart rate, either decrease to \<60 bpm, change to normal or no change, or increase to \>100 bpm are presented.

Part D (Analyte=GSK2118436): Maximum Plasma Concentration (Cmax) of a Single and Repeat Dose of Dabrafenib Alone and in Combination With TrametinibDay 1 and Day 21

The PK parameter Cmax was assessed. Blood samples for PK analysis of dabrafenib were obtained at pre-dose Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours (24 hour on Day 1 only) post-dose administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin. Cmax data are reported as geometric least squares means.

Part D (Analyte=GSK2118436): Tmax of a Single and Repeat Dose of Dabrafenib Alone and in Combination With TrametinibDay 1 and Day 21

tmax is defined as the time of occurenceof Cmax. Blood samples for PK analysis of dabrafenib were obtained at Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours (24 hour on Day 1 only) post-dose administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin.

Part D (Analyte=GSK2118436): AUC (0-tau) and AUC (0-inf) of Single and Repeat Doses of Dabrafenib Alone and in Combination With TrametinibDay 1 and Day 21

The PK parameters were determined for area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration AUC (0-tau) and from time zero (pre-dose) extrapolated to infinite time AUC (0-inf). Blood samples for PK analysis of the metabolites of dabrafenib were obtained at Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours (24 hour only on Day 1) post-dose administration.

Part D: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event for possible drug-induced liver injury.

Part D: Number of Participants With Worst-case Chemistry Toxicity Grade Change From BaselineFrom Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

Clinical Chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

Part D: Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal RangeFrom Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

For Clinical Chemistry parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

Part D: Number of Participants With Worst-case Hematology Toxicity Grade Change From BaselineFrom Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

Hematology parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. Participants with missing Baseline Grade were assumed to have Baseline Grade of 0. All increases were an increase in grade from Baseline. Only descriptive analysis.

Part D: Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal RangeFrom Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

For Hematology parameters that were not graded according to NCI CTCAE criteria, changes above (High) and below (Low) the normal range were evaluated. Participants with missing Baseline were assumed to be within normal range. Participants were counted twice if the subject "Decreased to Low" and Increase to High" during the post-baseline period. Only descriptive analysis.

Part D: Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood PressureFrom Baseline (Day 1) until Follow-up visit (up to approximately 7 years)

Blood pressure were summarized according to National Cancer Institutes (NCI) CTCAE grade, version 4.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to G3 or G4 occurred.lood pressure measurement included systolic blood pressure (BP, milimeter of mercury \[mmHg\]) and diastolic BP (DBP). Worst case change from Baseline was calculated as the post-Baseline value minus the Baseline value. Heart Rate is the measure of heartbeats per minute (bpm). Changes in heart rate, either decrease to \<60 bpm, change to normal or no change, or increase to \>100 bpm are presented

Secondary Outcome Measures
NameTimeMethod
Part A: Steady State Concentration of Trametinib With Concomitant Administration of DabrafenibDay 15 and Day 16

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.

Part B: AUC [0-tau] of Dabrafenib (DAB) and Its Metabolite in Combination With TrametinibDay 15 and Day 21

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.

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 TrametinibDay 15 and Day 21

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.

Part B: Tmax of Dabrafenib and Its Metabolite in Combination With TrametinibDay 15 and Day 21

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.

Part B (Analyte=GSK1120212): AUC (0-tau) Assessment of Trametinib in Combination With DabrafenibDay 15 and Day 21

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.

Part B (Analyte=GSK1120212): Ctau and Cmax Assessments of Trametinib in Combination With DabrafenibDay 15 and Day 21

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.

Part B (Analyte=GSK1120212): Tmax Assessment of Trametinib in Combination With DabrafenibDay 15 and Day 21

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.

Part B: Number of Participants With BRAFi-naïve Mutant Metastatic Melanoma With the Best Overall Response as Assessed by InvestigatorFrom the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 8 years)

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.

Part B: Duration of Response as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic MelanomaFirst 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)

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.

Part B: Progression-free Survival (PFS) as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic MelanomaFrom the date of first dose to the earliest date of disease progression (PD) or death due to any cause (up to approximately 8 years)

PFS is defined as the interval between the first dose of study medication and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. BRAFi-naïve were the participants with BRAF-mutation positive melanoma who had not received prior therapy with a BRAF-inhibitor..

Part B: Overall Survival (OS) in BRAFi Naïve Melanoma ParticipantsFrom the date of first dose until date of death due to any cause (up to approximately 8 years)

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.

Part B: Pre- and Post-dose H-scores for Individual ParticipantsScreening and at disease progression (up to approximately 8 years)

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.

Part C (Randomized): Overall Survival (OS)From the date of randomization until date of death due to any cause (up to approximately 7 years)

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.

Part C: Plasma Concentrations of Dabrafenib and Its MetabolitesDay 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56

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.

Part C: Plasma Concentrations of TrametinibDay 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56

Plasma concentrations of trametinib was assessed following daily dose of dabrafenib and trametinib.

Part C: Oral Clearance (CL/F) of Dabrafenib and TrametinibDay 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48

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.

Part C: Oral Volume of Distribution (V/F) of Dabrafenib and TrametinibDay 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48

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.

Part D: Cmax of Dabrafenib MetabolitesDay 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

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.

Part D: Tmax of Dabrafenib MetabolitesDay 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

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.

Part D: Area Under the Concentration-time Curve (AUC) of Dabrafenib MetabolitesDay 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

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.

Part D: Cmax Assessment of TrametinibDay 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

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.

Part D: Tmax Assessment of TrametinibDay 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

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.

Part D: Area Under the Concentration-time Curve Assessment of TrametinibDay 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

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.

Part D: Number of Participants With the Best Overall Response as Assessed by the Investigator in ParticipantsFrom 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)

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.

Part D: Duration of Response as Assessed by the InvestigatorFirst 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)

Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters \[e.g., percent change from Baseline\]) is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.

Part D: Progression-free Survival (PFS) as Assessed by the InvestigatorFrom the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 7 years)

PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.

Part D: Overall Survival (OS)From the date of first dose until date of death due to any cause (up to approximately 7 years)

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.

Trial Locations

Locations (1)

Novartis Investigative Site

🇦🇺

Heidelberg, Victoria, Australia

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