Investigation of GSK2879552 in Subjects With Relapsed/Refractory Small Cell Lung Carcinoma

Blood samples were collected from participants for pharmacokinetic analysis including AUC (0-t) following single (Day 1) and repeat dose (Day 15) administration of GSK2879552. Pharmacokinetic analysis of GSK2879552 in Part 1 was conducted by non-compartmental methods. The analysis was performed on Pharmacokinetic Population which included all participants in the All Treated Population for whom a pharmacokinetic sample was obtained and analyzed. NA represents data was not available. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected from participants for pharmacokinetic analysis including AUC (0-infinity) following single (Day 1) dose administration of GSK2879552. Pharmacokinetic analysis of GSK2879552 in Part 1 was conducted by non-compartmental methods. NA represents data was not available.

Blood samples were collected from participants for pharmacokinetic analysis including AUC (0-tau) following repeat (Day 15) dose administration of GSK2879552. Pharmacokinetic analysis of GSK2879552 in Part 1 was conducted by non-compartmental methods. NA represents data was not available.

Blood samples were collected from participants for pharmacokinetic analysis including Cmax following single (Day 1) and repeat dose (Day 15) administration of GSK2879552. Pharmacokinetic analysis of GSK2879552 in Part 1 was conducted by non-compartmental methods. NA represents data was not available. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected from participants for pharmacokinetic analysis including Tmax following single (Day 1) and repeat dose (Day 15) administration of GSK2879552. Tmax is the time to reach Cmax, determined directly from the concentration-time data. Pharmacokinetic analysis of GSK2879552 in Part 1 was conducted by non-compartmental methods. NA represents data was not available. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected from participants for pharmacokinetic analysis including lambda z following single (Day 1) and repeat dose (Day 15) administration of GSK2879552. Pharmacokinetic analysis of GSK2879552 in Part 1 was conducted by non-compartmental methods. NA represents data was not available. The data for Day 15 was not computed due to the long half-life of GSK2879552 . Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Blood samples were collected from participants for pharmacokinetic analysis including T1/2 following single (Day 1) and repeat dose (Day 15) administration of GSK2879552. Pharmacokinetic analysis of GSK2879552 in Part 1 was conducted by non-compartmental methods. NA represents data was not available. The data for Day 15 was not computed due to the long half-life of GSK2879552. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

The accumulation ratio was analyzed using analysis of variance (ANOVA) for AUC (0-tau) on Day 15 versus AUC (0-tau) on Day 1 by dose cohort. Only dose cohorts with repeat daily dosing were analyzed. The observed accumulation ratio (Ro) was determined based on AUC data to estimate the extent of accumulation after repeat dosing. The Ro of GSK2879552 was estimated by calculating the ratio of the geometric least squares (GLS) means of the pharmacokinetic parameter between Day 15 and Day 1 for all dose levels and the corresponding 90 percent confidence interval (CI) for each ratio.

Time invariance was assessed to evaluate whether the pharmacokinetics remains unaltered after repeat dosing. The mixed effect model was fitted with day as a fixed effect and participant as a random effect for each treatment (dose) separately. AUC (0-tau) on Day 15 was compared to AUC (0-infinity) on Day 1 in order to assess time invariance for each dose. The ratio and 90 percent CI were calculated by back-transforming the difference between the LS means for the two days and associated 90 percent CI, for each dose. Only dose cohorts with repeat daily dosing were analyzed.

The clinical activity of GSK2879552 given orally in participants with SCLC was evaluated by assessing disease control rate. Clinical response was assessed by the investigator using computer tomography or magnetic resonance imaging scans. Clinical response was defined as disease control rate (CR+PR+SD) based on RECIST version 1.1 at Week 16. Disease control rate was defined as number of participants achieving CR, PR and SD per RECIST version 1.1. The number of participants achieving disease control rate have been presented.

The pharmacokinetic/pharmacodynamic relationship of GSK2879552 administered orally was characterized by linear and/or non-linear mixed effect models. Only dose cohorts with repeat daily dosing were included in the analysis of platelet as a pharmacodynamic effect. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Percentage change from Baseline was defined as post-dose visit value minus Baseline value, divided by Baseline value and multiplied by 100. Estimates and standard error have been presented.

The pharmacokinetic/pharmacodynamic relationship of GSK2879552 administered orally was characterized by linear and/or non-linear mixed effect models. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Percentage change from Baseline was defined as post-dose visit value minus Baseline value, divided by Baseline value and multiplied by 100. Only dose cohorts with repeat daily dosing were included in the analysis of platelet as a pharmacodynamic effect. Estimates and standard error have been presented.

The pharmacokinetic/pharmacodynamic relationship of GSK2879552 administered orally was characterized by linear and/or non-linear mixed effect models. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Percentage change from Baseline was defined as post-dose visit value minus Baseline value, divided by Baseline value and multiplied by 100. Only dose cohorts with repeat daily dosing were included in the analysis of platelet as a pharmacodynamic effect. Estimates and standard error have been presented.

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. 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, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

An event was considered a DLT if it occured within the first 28 days of treatment, and meets one of the following criteria unless it can be clearly established that the event is unrelated to treatment: recurrent Grade 3 anemia after initial transfusion or Grade 3 anemia lasting > 7 days in participants who are not transfused, Grade 4 neutropenia, Grade 3 neutropenia > 7 days duration, febrile neutropenia as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, Grade 3 thrombocytopenia requiring dose reduction, Grade 4 thrombocytopenia lasting > 3 days or of any duration if associated with clinically significant bleeding, drug related Grade 3 or 4 non-hematologic toxicity, drug related Grade 2 toxicity (at any time during treatment) and treatment delay of 14 days or greater due to unresolved drug-related toxicity. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

The number of participants who had any dose reduction or delay were planned to be analyzed. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Participants were planned to be monitored from start of the study till the development of toxicity in Part 2. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Blood samples were planned to be collected for evaluation of clinical chemistry parameters including potassium, aspartate aminotransferase (AST), total bilirubin, creatinine, ALT, uric acid, glucose, GGT, albumin, sodium, calcium, alkaline phosphatase, and phosphorus inorganic. Baseline value was defined as the most recent, non-missing value from a central laboratory prior to or on the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Blood samples were planned to be collected for the analysis of hematology parameters including hemoglobin, lymphocytes, total neutrophils, platelet count and white blood cell (WBC) count. Baseline value was defined as the most recent, non-missing value from a central laboratory prior to or on the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Vital sign measurement includes SBP, DBP, temperature, respiration rate and heart rate. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Single measurements of 12-lead ECGs were planned to be obtained in a semi-recumbent or supine position after at least a 5 minutes rest using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

The complete physical examination includes assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. A brief physical examination includes assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Blood samples were planned to be collected for population pharmacokinetic analysis of GSK2879552 including clearance. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Blood samples were planned to be collected for population pharmacokinetic analysis of GSK2879552 including volume of distribution. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

The pharmacokinetic/pharmacodynamic relationship of GSK2879552 administered orally was planned to be characterized by linear and/or non-linear mixed effect models. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Percentage change from Baseline was defined as post-dose visit value minus Baseline value, divided by Baseline value and multiplied by 100. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

The pharmacokinetic/pharmacodynamic relationship of GSK2879552 administered orally was planned to be characterized by linear and/or non-linear mixed effect models. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Percentage change from Baseline was defined as post-dose visit value minus Baseline value, divided by Baseline value and multiplied by 100. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

The pharmacokinetic/pharmacodynamic relationship of GSK2879552 administered orally was planned to be characterized by linear and/or non-linear mixed effect models. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Percentage change from Baseline was defined as post-dose visit value minus Baseline value, divided by Baseline value and multiplied by 100. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Duration of response for participants is defined as the time from the first documented evidence of a PR or CR until the first documented sign of disease progression or death due to any cause. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

PFS is defined as the interval between the first dose of study medication and the earliest date of disease progression or death due to any cause. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

Overall response rate is defined as percentage of participants achieving CR and PR per RECIST version 1.1. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.