GSK1120212

Progression-free survival (PFS) is defined as the time from randomization to the first documented occurrence of disease progression (PD) or death. PFS for investigator-assessed and blinded, independent, central review committee (BRIC)-assessed responses was summarized per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, which is a set of published rules defining when cancer participants improve (respond), stay the same (stabilize), or worsen (progress) during treatment. Disease progression is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Primary Efficacy Population included all participants with BRAF V600E mutation-positive melanoma without a history of brain metastases.

PFS is defined as the time from RAN until the earliest date of documented radiological PD or DT due to any cause. PD was assessed by the INV according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. PD is defined as at least a 20% increase in the sum of the diameters (SD) of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation. For participants (PAR) who did not have a documented date of PD or DT, PFS was censored at the date of the last adequate assessment. For PAR who received subsequent anti-cancer therapy prior to the date of documented PD or DT, PFS was censored at the date of the last adequate assessment prior to the initiation of therapy.

An AE is any untoward medical occurrence in a participant (par.) or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the 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.

Hematology and clinical chemistry data were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 3.0. 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 Grade 3 or Grade 4 occurred. Hematology tests where the toxicity grade is defined by NCI-CTCAE includes hemoglobin, international normalized ratio (INR), lymphocytes, total neutrophils, platelet count, and partial thromboplastin time (PTT). Participants with missing baseline grades were assumed to have a baseline grade of 0. Only those participants (par.) with laboratory values for worst-case on-therapy (defined as the worst shift that occurred at any time during the treatment period) are presented.

Hematology and clinical chemistry data were summarized according to NCI-CTCAE grade, version 3.0. 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 Grade 3 or Grade 4 occurred. Clinical chemistry tests where the toxicity grade is defined by NCI-CTCAE includes albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase (AST), total bilirubin, calcium, creatinine, glucose, bicarbonate, potassium, magnesium, sodium, and phosphorus. Participants with missing Baseline grades were assumed to have a Baseline grade of 0. Only those participants (par.) with laboratory values for worst-case on-therapy are presented.

Change from Baseline in heart rate is categorized as decrease to \<60 beats per minute (bpm), change to normal or no change, and increase to \>100 bpm. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants are counted twice if the participant heart rate value decreased to \<60 bpm and increased to \>100 bpm post-baseline. Only those participants (par.) with heart rate values for worst-case on-therapy are presented.

Change from Baseline in systolic blood pressure (SBP) is categorized as: Grade 0 (\<120 millimeters of mercury \[mmHg\]), Grade 1 (120-139 mmHg), Grade 2 (140-159 mmHg), and Grade 3/4 (\>=160 mmHg). Change from Baseline in diastolic blood pressure (DBP) is categorized as: Grade 0 (\<80 mmHg), Grade 1 (80-89 mmHg), Grade 2 (90-99 mmHg), and Grade 3/4 (\>=100 mmHg). An increase is defined as an increase in the CTCAE grade relative to the Baseline grade. Participants with missing Baseline values are assumed to have a Baseline value of grade 0. Only those participants (par.) with blood pressure values for worst-case on-therapy are presented.

Change from Baseline in temperature is categorized as a decrease to \<=35 degrees celsius (C), change to normal or no change, and increase to \>=38 degrees C. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants (par.) are counted twice if the participant temperature value decreased to \<=35 degrees C and increased to \>=38 degrees C post-Baseline. Only those participants with temperature values for worst-case on-therapy are presented.

Overall response rate (ORR=CR+CRp+Marrow CR+MLFS+PR) was calculated from the investigator's assessment of response recorded within the first eight weeks of treatment. CR includes complete remission. Complete remission is a state in which the participant must be free of all symptoms related to leukemia and have an absolute neutrophil count \>=1 x 10\^9/L, platelet count \>=100 x 10\^9/L, and normal marrow differential (\<=5% blasts). PR includes partial remission. Partial remission is a state in which the participant has a CR with 6 to 25% abnormal cells in the marrow or 50% decrease in bone marrow blasts. CRp is as per CR but platelet count \<100 x 10\^9/L. MLFS is a state in which the participant has a normal marrow differential (\<5% blasts), neutrophil, and platelet counts are not considered.

Overall survival is defined as the time from randomization until death due to any cause. For the analysis of overall survival, the last date of known contact was used for those participants who were not dead at the time of analysis; such participants were considered censored.

Best confirmed response was assessed by the Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Best response was measured either as a complete response (CR), defined as the disappearance of all target lesions and pathological lymph nodes \<10 millimeters (mm), or a partial response (PR), defined as at least a 30% decrease in the sum of the diameters of target lesions. To be assigned a status of confirmed CR or PR, a confirmatory disease assessment was required no less than 28 days after the criteria for response were first met.

The number of participants with best confirmed response was analyzed for the following subgroups of participants previously treated with standard therapy but not BRAF inhibitors: (1) participants with prior (before the start of this study) brain metastases (mets); (2) participants without prior brain mets; (3) participants with BRAF mutation V600E; (4) participants with BRAF mutation V600E and no prior brain mets; and (5) participants with BRAF mutation V600K. Objective response was assessed per RECIST version 1.1. Objective response was measured either as CR, defined as the disappearance of all target lesions and pathological lymph nodes \<10 mm, or PR, defined as at least a 30% decrease in the sum of the diameters of target lesions. To be assigned a status of confirmed CR or PR, a confirmatory disease assessment was required no less than 28 days after the criteria for response were first met. Brain metastasis is a cancer that has spread to the brain from another location of the body.

An interim analysis was performed using data collected approximately 12 and 13 weeks after the 30th participant was enrolled in the prior BRAF inhibitor and prior standard therapy groups, respectively. The best unconfirmed response by the investigator per RECIST version 1.1 was assessed. The study design permitted stopping the study for futility if \<3 best confirmed responses were observed in the first 30 participants of each treatment arm after completing the first post-dose assessment at Week 8. Best response was measured as either a CR, defined as the disappearance of all target lesions and pathological lymph nodes \<10 millimeters, or a PR, defined as at least a 30% decrease in the sum of the diameters of target lesions.

Adverse events, serious adverse events, dose reductions or delays, withdrawals due to toxicities and changes in laboratory values and vital signs

Defined as stringent complete response, complete response, very good partial response, or partial response, using the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma

Defined as confirmed complete response or confirmed partial response rate, using Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1

Adverse events, serious adverse events, dose reductions or delays, withdrawals due to toxicities and changes in laboratory values and vital signs

Absolute bioavailability (F) of GSK1120212 calculated as the ratio of dose-normalized area under the concentration-time curve from time 0 (pre-dose) extrapolated to infinity (AUC(0-inf)) of oral to IV dosing

• Area under the plasma concentration-time curve from time zero (pre-dose) to time t (AUC(0-t)), AUC(0-inf), Cmax, and tmax.

• Total and relative excretion of radioactivity in urine and feces following a single, 2 mg oral solution dose of \[14C\]GSK1120212