Trial Outcomes & Findings for First-time-in-human (FTIH) Study of GSK3145095 Alone and in Combination With Other Anticancer Agents in Adults With Advanced Solid Tumors (NCT NCT03681951)

Results Overview

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose which results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or other situations.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

8 participants

Primary outcome timeframe

Up to Day 95

Results posted on

2020-07-31

Participant Flow

This was an open-label study to investigate the safety, clinical activity, pharmacokinetics, and pharmacodynamics of GSK3145095 administered alone and in combination with anticancer agents including Pembrolizumab in adult participants with selected advanced solid tumors.

Total 8 participants were included in part 1 of the study across United States. This study was terminated during Part 1 (Monotherapy dose escalation \[DE\]) and hence Part 2,3,4 were not conducted following an internal review of the company's current research and development portfolio.

Participant milestones

Participant milestones
Measure	Part 1-GSK3145095 50 mg BID Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.	Part 2- GSK3145095+ Pembrolizumab 200 mg Part 2 was to be initiated after evaluation of safety and toxicity data of Part 1. Participants in this combination therapy arm were planned to receive GSK3145095 at one dose level below the highest dose shown to have an acceptable toxicity profile in at least 3 participants in Part 1 in combination with 200 mg pembrolizumab as Intravenous (IV) infusion over 30 minutes (min) for every 3 weeks.	Part 3- GSK3145095+ Pembrolizumab 200 mg Part 3 was to be initiated after evaluation of safety and toxicity data of part 2. Participants in this combination therapy arm were planned to receive GSK3145095 at recommended dose level determined during Part 2, with 200 mg pembrolizumab as IV infusion for every 3 weeks	Part 4- GSK3145095+ Anticancer Agent In Part 4, participants were planned to receive GSK3145095 at recommended dose level determined during Part 2, in combination with anticancer agent.
Part1: Monotherapy DE (Up to Day 95) STARTED	8	0	0	0	0	0	0	0
Part1: Monotherapy DE (Up to Day 95) COMPLETED	0	0	0	0	0	0	0	0
Part1: Monotherapy DE (Up to Day 95) NOT COMPLETED	8	0	0	0	0	0	0	0
Part2:Combination Therapy(Upto 2yr90day) STARTED	0	0	0	0	0	0	0	0
Part2:Combination Therapy(Upto 2yr90day) COMPLETED	0	0	0	0	0	0	0	0
Part2:Combination Therapy(Upto 2yr90day) NOT COMPLETED	0	0	0	0	0	0	0	0
Part 3:Dose Expansion (Up to 2yr90day) STARTED	0	0	0	0	0	0	0	0
Part 3:Dose Expansion (Up to 2yr90day) COMPLETED	0	0	0	0	0	0	0	0
Part 3:Dose Expansion (Up to 2yr90day) NOT COMPLETED	0	0	0	0	0	0	0	0
Part 4: Dose Expansion(Up to 2 yr90day) STARTED	0	0	0	0	0	0	0	0
Part 4: Dose Expansion(Up to 2 yr90day) COMPLETED	0	0	0	0	0	0	0	0
Part 4: Dose Expansion(Up to 2 yr90day) NOT COMPLETED	0	0	0	0	0	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Part 1-GSK3145095 50 mg BID Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.	Part 2- GSK3145095+ Pembrolizumab 200 mg Part 2 was to be initiated after evaluation of safety and toxicity data of Part 1. Participants in this combination therapy arm were planned to receive GSK3145095 at one dose level below the highest dose shown to have an acceptable toxicity profile in at least 3 participants in Part 1 in combination with 200 mg pembrolizumab as Intravenous (IV) infusion over 30 minutes (min) for every 3 weeks.	Part 3- GSK3145095+ Pembrolizumab 200 mg Part 3 was to be initiated after evaluation of safety and toxicity data of part 2. Participants in this combination therapy arm were planned to receive GSK3145095 at recommended dose level determined during Part 2, with 200 mg pembrolizumab as IV infusion for every 3 weeks	Part 4- GSK3145095+ Anticancer Agent In Part 4, participants were planned to receive GSK3145095 at recommended dose level determined during Part 2, in combination with anticancer agent.
Part1: Monotherapy DE (Up to Day 95) Lost to Follow-up	1	0	0	0	0	0	0	0
Part1: Monotherapy DE (Up to Day 95) Physician Decision	4	0	0	0	0	0	0	0
Part1: Monotherapy DE (Up to Day 95) Withdrawal by Subject	3	0	0	0	0	0	0	0

Baseline Characteristics

First-time-in-human (FTIH) Study of GSK3145095 Alone and in Combination With Other Anticancer Agents in Adults With Advanced Solid Tumors

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1-GSK3145095 50 mg BID n=8 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.	Part 2- GSK3145095+ Pembrolizumab 200 mg Part 2 was to be initiated after evaluation of safety and toxicity data of Part 1. Participants in this combination therapy arm were planned to receive GSK3145095 at one dose level below the highest dose shown to have an acceptable toxicity profile in at least 3 participants in Part 1 in combination with 200 mg pembrolizumab as Intravenous (IV) infusion over 30 minutes (min) for every 3 weeks.	Part 3- GSK3145095+ Pembrolizumab 200mg Part 3 was to be initiated after evaluation of safety and toxicity data of part 2. Participants in this combination therapy arm were planned to receive GSK3145095 at recommended dose level determined during Part 2, with 200 mg pembrolizumab as IV infusion for every 3 weeks.	Part 4- GSK3145095+ Anticancer Agent In Part 4, participants were planned to receive GSK3145095 at recommended dose level determined during Part 2, in combination with anticancer agent	Total n=8 Participants Total of all reporting groups
Age, Continuous	66.5 Years STANDARD_DEVIATION 5.68 • n=93 Participants	—	—	—	—	—	—	—	66.5 Years STANDARD_DEVIATION 5.68 • n=8 Participants
Sex: Female, Male Female	4 Participants n=93 Participants	—	—	—	—	—	—	—	4 Participants n=8 Participants
Sex: Female, Male Male	4 Participants n=93 Participants	—	—	—	—	—	—	—	4 Participants n=8 Participants
Race/Ethnicity, Customized Race · BLACK OR AFRICAN AMERICAN	1 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=40 Participants	1 Participants n=8 Participants
Race/Ethnicity, Customized Race · WHITE/CAUCASIAN/EUROPEAN HERITAGE	6 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=40 Participants	6 Participants n=8 Participants
Race/Ethnicity, Customized Race · MISSING	1 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=40 Participants	1 Participants n=8 Participants

PRIMARY outcome

Timeframe: Up to Day 95

Population: All treated Population consisted of all participants who received at least one dose of GSK3145095. Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose which results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or other situations.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=8 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 Non-serious AEs	8 Participants	—	—	—	—
Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 SAEs	4 Participants	—	—	—	—

PRIMARY outcome

Timeframe: Up to 2 years and 90 days

Population: All treated Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose which results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or other situations.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Up to Day 95

Population: All treated Population: Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

All adverse events were analyzed using National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. Graded from Grade 1: mild asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated, Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL), Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL, Grade 4: Life-threatening consequences; urgent intervention indicated, Grade 5: death related AE. Higher grade indicates more severe condition. Number of participants with maximum severity grades were presented.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=8 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Number of Participants With AEs by Severity Grades-Part 1 Grade 1	0 Participants	—	—	—	—
Number of Participants With AEs by Severity Grades-Part 1 Grade 2	3 Participants	—	—	—	—
Number of Participants With AEs by Severity Grades-Part 1 Grade 3	4 Participants	—	—	—	—
Number of Participants With AEs by Severity Grades-Part 1 Grade 4	1 Participants	—	—	—	—
Number of Participants With AEs by Severity Grades-Part 1 Grade 5	0 Participants	—	—	—	—

PRIMARY outcome

Timeframe: Up to 2 years and 90 days

Population: All treated Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

All adverse events were to be analyzed using NCI-CTCAE Version 5.0. Graded from Grade 1: mild asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated, Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL, Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL, Grade 4: Life-threatening consequences; urgent intervention indicated, Grade 5: death related AE. Higher grade indicates more severe condition.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Up to Day 28

Population: All treated Population: Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

All toxicities were graded using NCI-CTCAE version 5.0. An AE was considered a DLT if it occurred during the first 28 days of treatment, was considered by the investigator to be clinically relevant, and met one of the following DLT criteria: hematologic toxicity: Grade 4 neutropenia, febrile neutropenia, Grade 4 anemia, Grade 3 thrombocytopenia, Grade 3 thrombocytopenia with bleeding; Grade 3 or greater non-hematologic toxicity, any Grade 2 ocular toxicity requiring systemic steroids.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=8 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Number of Participants With Dose-limiting Toxicities (DLTs)-Part 1	0 Participants	—	—	—	—

PRIMARY outcome

Timeframe: Up to 28 days

Population: All treated Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

All toxicities were graded using NCI-CTCAE version 5.0. An AE was considered a DLT if it occurred during the first 28 days of treatment, was considered by the investigator to be clinically relevant, and met one of the following DLT criteria: hematologic toxicity: Grade 4 neutropenia, febrile neutropenia, Grade 4 anemia, Grade 3 thrombocytopenia, Grade 3 thrombocytopenia with bleeding; Grade 3 or greater non-hematologic toxicity, any Grade 2 ocular toxicity requiring systemic steroids.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Until response, disease progression, initiation of another anticancer therapy or death whichever is earlier (maximum follow-up up to 2 years 90 days)

Population: All treated Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 3 was not initiated.

A participant's disease status and determination of disease progression at post Baseline visits was to be evaluated by the local investigator's assessments by RECIST version 1.1. The overall response rate (ORR)-CR and PR was to be determined by the investigator assessment of the participants computed tomography (CT) or magnetic resonance imaging (MRI) using RECIST version 1.1 criteria for target lesions. ORR is defined as the percentage of participants with a best overall confirmed CR or PR at any time as per disease-specific criteria. PR is when there is at least 30 percent decrease in sum of the longest diameter of the target lesions. Complete Response is when there is disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 millimeters (mm).

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Until response, disease progression, initiation of another anticancer therapy or death whichever is earlier (maximum follow-up up to 2 years and 90 days)

Population: All treated Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 4 was not initiated.

A participant's disease status and determination of disease progression at post Baseline visits was to be evaluated by the local investigator's assessments by RECIST version 1.1. The overall response rate (complete response and partial response) was to be determined by the investigator assessment of the participants CT or MRI using RECIST version 1.1 criteria for target lesions. ORR is defined as the percentage of participants with a best overall confirmed CR or PR at any time as per disease-specific criteria. Partial Response is when there is at least 30 percent decrease in sum of the longest diameter of the target lesions. Complete Response is when there is disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 mm.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Until response, disease progression, initiation of another anticancer therapy or death whichever is earlier (maximum follow-up up to 95 days)

Population: All treated Population: Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Best overall response is defined as the best unconfirmed response (Complete Response \[CR\] \> Partial Response \[PR\] \> Stable Disease \[SD\] \[or non-CR/non-PD\] \> Progressive Disease \[PD\] \> Not Evaluable \[NE\]) from treatment start date until disease progression or initiation of new anti-cancer therapy, whichever is earlier, as assessed by the investigator per RECIST version 1.1 Criteria. The BOR rate is defined as the percentage of participants with each best unconfirmed response category. Participants with unknown or missing responses were treated as non-responders, i.e., these participants were included in the denominator when calculating percentages of response.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=8 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Best Overall Response (BOR) Rate-Part 1 Complete response	0 Percentage of participants	—	—	—	—
Best Overall Response (BOR) Rate-Part 1 Partial response	0 Percentage of participants	—	—	—	—
Best Overall Response (BOR) Rate-Part 1 Stable disease	0 Percentage of participants	—	—	—	—
Best Overall Response (BOR) Rate-Part 1 Progressive disease	62.5 Percentage of participants	—	—	—	—
Best Overall Response (BOR) Rate-Part 1 Not evaluable	37.5 Percentage of participants	—	—	—	—

SECONDARY outcome

Timeframe: Until response, disease progression, initiation of another anticancer therapy or death whichever is earlier (maximum follow-up up to 2 years and 90 days)

Population: All treated Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Best overall response is defined as the best unconfirmed response (CR \> PR \> SD \[or non-CR/non-PD\] \> PD\] \> NE) from treatment start date until disease progression or initiation of new anti-cancer therapy, whichever is earlier, as assessed by the investigator per RECIST 1.1 Criteria. The BOR rate is defined as the percentage of participants with each best unconfirmed response category. Participants with unknown or missing responses were treated as non-responders, i.e., these participants were included in the denominator when calculating percentages of response.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Until disease progression or death whichever is earlier (maximum follow-up up to 2 years and 90 days)

Population: All treated Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 3 was not initiated.

PFS is defined as time from the date of first dose to the date of disease progression according to clinical or radiological assessment or death due to any causes, whichever occurs earliest. If the participant received subsequent anti-cancer therapy prior to the date of documented events, PFS was to be censored at the last adequate assessment (e.g., assessment where visit level response is confirmed response, partial response or stable disease) prior to the initiation of therapy. Otherwise, if the participant did not have a documented date of event, PFS was to be censored at the date of the last adequate assessment.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Until disease progression or death whichever is earlier (maximum follow-up up to 2 years and 90 days)

Population: All treated Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 4 was not initiated.

PFS is defined as time from the date of first dose to the date of disease progression according to clinical or radiological assessment or death due to any causes, whichever occurs earliest. If the participant received subsequent anti-cancer therapy prior to the date of documented events, PFS was to be censored at the last adequate assessment (e.g., assessment where visit level response is confirmed response, partial response or stable disease) prior to the initiation of therapy. Otherwise, if the participant did not have a documented date of event, PFS was to be censored at the date of the last adequate assessment.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Until death (maximum follow-up up to 2 years and 90 days)

Population: All treated Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 3 was not initiated.

Overall survival is defined as time from the date of first dose to the date of death due to any cause. If a participant does not have a documented date of death, time of death is censored at the date of last contact.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Until death (maximum follow-up up to 2 years and 90 days)

Population: All treated Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 4 was not initiated.

Overall survival is defined as time from the date of first dose to the date of death due to any cause. If a participant does not have a documented date of death, time of death is censored at the date of last contact.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 2 years and 90 days

Population: All treated Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 3 was not initiated.

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose which results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or other situations.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 2 years and 90 days

Population: All treated Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 4 was not initiated.

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose which results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or other situations.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 2 years and 90 days

Population: All treated Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 3 was not initiated.

All adverse events were planned to be analyzed using NCI-CTCAE Version 5.0. Graded from Grade 1: mild asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated, Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL, Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL, Grade 4: Life-threatening consequences; urgent intervention indicated, Grade 5: death related AE. Higher grade indicates more severe condition.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 2 years and 90 days

Population: All treated Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 4 was not initiated.

All adverse events were planned to be analyzed using NCI-CTCAE Version 5.0. Graded from Grade 1: mild asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated, Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL, Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL, Grade 4: Life-threatening consequences; urgent intervention indicated, Grade 5: death related AE. Higher grade indicates more severe condition.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: Pharmacokinetic (PK) Population. The PK Population consisted of all participants from the All-Treated Population for whom a PK sample was obtained and analyzed. Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of AUC(0-t) following single dose of GSK3145095 on Day 1 and was calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=8 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Area Under the Plasma Drug Concentration Versus Time Curve (AUC[0-t]) Following Single Dose of GSK3145095 on Day 1-Part 1	17411.6 Hour*nanograms per milliliter Geometric Coefficient of Variation 13.0	—	—	—	—

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of AUC (0-t) following single dose of GSK3145095 on Day 1 and was to be calculated by standard non-compartmental analysis.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of AUC (0-tau) following single dose of GSK3145095 on Day 1 and was calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=8 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Area Under the Concentration-time Curve Over the Dosing Interval (AUC [0-tau]) Following Single Dose of GSK3145095 on Day 1-Part 1	11263.4 Hour*nanograms per milliliter Geometric Coefficient of Variation 19.2	—	—	—	—

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of AUC (0-tau) following single dose of GSK3145095.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of Cmax following single dose of GSK3145095 on Day 1 and was calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=8 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Maximum Observed Plasma Drug Concentration (Cmax) Following Single Dose of GSK3145095 on Day 1-Part 1	1435.0 Nanograms per milliliter Geometric Coefficient of Variation 25.7	—	—	—	—

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of Cmax following single dose of GSK3145095 on Day 1.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of Cmin following single dose of GSK3145095 on Day 1 and was calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=8 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Minimum Observed Plasma Drug Concentration (Cmin) Following Single Dose of GSK3145095 on Day 1-Part 1	344.8 Nanograms per milliliter Geometric Coefficient of Variation 20.0	—	—	—	—

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of Cmin following single dose of GSK3145095 on Day 1.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of tmax following single dose of GSK3145095 on Day 1 and was calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=8 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Time to Maximum Observed Plasma Drug Concentration (Tmax) Following Single Dose of GSK3145095 on Day 1-Part 1	2.100 Hours Interval 1.57 to 5.83	—	—	—	—

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of tmax following single dose of GSK3145095 on Day 1.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Only those participants with data available at the specified data points were analyzed. Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of CL/F following single dose of GSK3145095 on Day 1 and was calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=6 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Clearance (CL/F) Following Single Dose of GSK3145095 on Day 1-Part 1	2.149 Liters per hour Geometric Coefficient of Variation 10.9	—	—	—	—

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of CL/F following single dose of GSK3145095 on Day 1.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Only those participants with data available at the specified data points were analyzed. Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of Vz/F following single dose of GSK3145095 on Day 1 and was calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=6 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Volume of Distribution (Vz/F) Following Single Dose of GSK3145095 on Day 1-Part 1	32.89 Liters Geometric Coefficient of Variation 17.3	—	—	—	—

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of V/F following single dose of GSK3145095 on Day 1.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Only those participants with data available at the specified data points were analyzed. Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of t1/2 following single dose of GSK3145095 on Day 1 and was calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=6 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Terminal Half-life (t1/2) Following Single Dose of GSK3145095 on Day 1-Part 1	10.608 Hour Geometric Coefficient of Variation 14.1	—	—	—	—

SECONDARY outcome

Timeframe: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of t1/2 following single dose of GSK3145095 on Day 1.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose

Population: PK Population: Only those participants with data available at the specified data points were analyzed. Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of AUC (0-t) following repeat dose of GSK3145095 on Day 15 and was calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=4 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
AUC (0-t) Following Repeat Dose of GSK3145095 on Day 15-Part 1	19110.5 Hour*nanograms per milliliter Geometric Coefficient of Variation 56.3	—	—	—	—

SECONDARY outcome

Timeframe: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of AUC (0-t) following repeat dose of GSK3145095 on Day 15.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose

Population: PK Population: Only those participants with data available at the specified data points were analyzed. Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of AUC (0-tau) following repeat dose of GSK3145095 on Day 15 and was calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=4 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
AUC (0-tau) Following Repeat Dose of GSK3145095 on Day 15-Part 1	19110.5 Hour*nanograms per milliliter Geometric Coefficient of Variation 56.3	—	—	—	—

SECONDARY outcome

Timeframe: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of AUC (0-tau) following repeat dose of GSK3145095 on Day 15.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose

Population: PK Population: Only those participants with data available at the specified data points were analyzed. Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of Cmax following repeat dose of GSK3145095 on Day 15 and was calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=4 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Cmax Following Repeat Dose of GSK3145095 on Day 15-Part 1	2104.4 Nanograms per milliliter Geometric Coefficient of Variation 42.0	—	—	—	—

SECONDARY outcome

Timeframe: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of Cmax following repeat dose of GSK3145095 on Day 15.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose

Population: PK Population: Only those participants with data available at the specified data points were analyzed. Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of Cmin following repeat dose of GSK3145095 on day 15 and was calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=4 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Cmin Following Repeat Dose of GSK3145095 on Day 15-Part 1	953.6 Nanograms per milliliter Geometric Coefficient of Variation 114.5	—	—	—	—

SECONDARY outcome

Timeframe: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of Cmin following repeat dose of GSK3145095 on Day 15.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose

Population: PK Population: Only those participants with data available at the specified data points were analyzed. Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of tmax following repeat dose of GSK3145095 and was calculated by standard non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=4 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Tmax Following Repeat Dose of GSK3145095 on Day 15-Part 1	2.575 Hour Interval 2.12 to 7.97	—	—	—	—

SECONDARY outcome

Timeframe: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of tmax following repeat dose of GSK3145095 on Day 15.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose

Population: PK Population: Only those participants with data available at the specified data points were analyzed. Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of CL/F following repeat dose of GSK3145095 on Day 15. For accurate estimation of CL/F following repeated administration, it is imperative that steady state has been achieved. As the attainment of steady state could not be confirmed with certainty, CL/F was not computed following repeated dose.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=4 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
CL/F Following Repeat Dose of GSK3145095 on Day 15-Part 1	NA Liters per hour Geometric Coefficient of Variation NA For accurate estimation of CL/F following repeated administration, it is imperative that steady state has been achieved. As the attainment of steady state could not be confirmed with certainty, CL/F was not computed following repeated dose.	—	—	—	—

SECONDARY outcome

Timeframe: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of CL/F following repeat dose of GSK3145095 on Day 15.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose

Population: PK Population: Only those participants with data available at the specified data points were analyzed. Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of Vz/F following repeat dose of GSK3145095 on Day 15. As t1/2 following repeated administration could not be computed, Vz/F whose estimation is dependent upon the t1/2 could not be estimated as well.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=4 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Vz/F Following Repeat Dose of GSK3145095 on Day 15-Part 1	NA Liters Geometric Coefficient of Variation NA As t1/2 following repeated administration could not be computed, Vz/F whose estimation is dependent upon the t1/2 could not be estimated as well.	—	—	—	—

SECONDARY outcome

Timeframe: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of V/F following repeat dose of GSK3145095 on Day 15.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose

Population: PK Population: Only those participants with data available at the specified data points were analyzed. Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at the indicated time points for the determination of t1/2 following repeat dose of GSK3145095 on Day 15. t1/2 following repeated administration was not computed because duration of observation (12 hours from the morning dose) was too short (less than 2 times the average half-life observed after the first dose) for its accurate estimation.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=4 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
T1/2 Following Repeat Dose of GSK3145095 on Day 15-Part 1	NA Hour Geometric Coefficient of Variation NA t1/2 following repeated administration was not computed because duration of observation (12 hours from the morning dose) was too short (less than 2 times the average half-life observed after the first dose) for its accurate estimation.	—	—	—	—

SECONDARY outcome

Timeframe: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at the indicated time points for the determination of t1/2 following repeat dose of GSK3145095 on Day 15.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose

Population: PK Population: Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Dose proportionality was to be evaluated for GSK3145095 using a fixed effects power model. Estimated slope was to be presented to express dose proportionality. As only one dose level (100 mg) was tested prior to termination of the study and multiple dose levels are required to investigate dose proportionality, hence dose proportionality could not be analyzed.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=8 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Dose Proportionality of GSK3145095 for Dose Levels 100 mg (50 mg BID) to 1600 mg (800 mg BID) Using AUC (0-t) Following Single Dose-Part 1	NA Slope of log dose As only one dose level (100 mg) was tested prior to termination of the study and multiple dose levels are required to investigate dose proportionality, hence dose proportionality could not be analyzed.	—	—	—	—

SECONDARY outcome

Timeframe: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose

Population: PK Population: Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Dose proportionality was to be evaluated for GSK3145095 using a fixed effects power model. Estimated slope was to be presented to express dose proportionality. As only one dose level (100 mg) was tested prior to termination of the study and multiple dose levels are required to investigate dose proportionality, hence dose proportionality could not be analyzed.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=8 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Dose Proportionality of GSK3145095 for Dose Levels 100 mg (50 mg BID) to 1600 mg (800 mg) BID Using Cmax Following Single Dose-Part 1	NA Slope of log dose As only one dose level (100 mg) was tested prior to termination of the study and multiple dose levels are required to investigate dose proportionality, hence dose proportionality could not be analyzed.	—	—	—	—

SECONDARY outcome

Timeframe: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose

Population: PK Population: Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Dose proportionality was to be evaluated for GSK3145095 using a fixed effects power model. Estimated slope was to be presented to express dose proportionality. As only one dose level (100 mg) was tested prior to termination of the study and multiple dose levels are required to investigate dose proportionality, hence dose proportionality could not be analyzed.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=8 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Dose Proportionality of GSK3145095 for Dose Levels 100 mg (50 mg BID) to 1600 mg (800 mg BID) Using AUC (0-tau) Following Repeat Dose-Part 1	NA Slope of log dose As only one dose level (100 mg) was tested prior to termination of the study and multiple dose levels are required to investigate dose proportionality, hence dose proportionality could not be analyzed.	—	—	—	—

SECONDARY outcome

Timeframe: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose

Population: PK Population: Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Dose proportionality was to be evaluated for GSK3145095 using a fixed effects power model. Estimated slope was to be presented to express dose proportionality. As only one dose level (100 mg) was tested prior to termination of the study and multiple dose levels are required to investigate dose proportionality, hence dose proportionality could not be analyzed.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=8 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Dose Proportionality of GSK3145095 for Dose Levels 100 mg (50 mg BID) to 1600 mg (800 mg BID) Using Cmax Following Repeat Dose-Part 1	NA Slope of log dose As only one dose level (100 mg) was tested prior to termination of the study and multiple dose levels are required to investigate dose proportionality, hence dose proportionality could not be analyzed.	—	—	—	—

SECONDARY outcome

Timeframe: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Dose proportionality was to be evaluated for GSK3145095 using a fixed effects power model. Estimated slope was to be presented to express dose proportionality.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Dose proportionality was to be evaluated for GSK3145095 using a fixed effects power model. Estimated slope was to be presented to express dose proportionality.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8,10, and 24 hours post dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Dose proportionality was to be evaluated for GSK3145095 using a fixed effects power model. Estimated slope was to be presented to express dose proportionality.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Dose proportionality was to be evaluated for GSK3145095 using a fixed effects power model. Estimated slope was to be presented to express dose proportionality.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1: Pre-dose,0.5,1,1.5,2,3,4,6,8, 10, and 24 hour post-dose, Days 15: Pre-dose,0.5,1,1.5,2,3,4,6,8,10,24 hour post dose

Population: PK Population: Only those participants with data available at the specified data points were analyzed. Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Accumulation ratio was calculated as AUC(0-tau) at Day 15 divided by AUC(0-tau) at Day 1 for GSK3145095.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=4 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Accumulation Ratio Following Repeat Dose of GSK3145095 on Day 15-Part 1	1.792 Ratio of AUC Geometric Coefficient of Variation 57.5	—	—	—	—

SECONDARY outcome

Timeframe: Day 1: Pre-dose,0.5,1,1.5,2,3,4,6,8, 10, and 24 hour post-dose, Days 15: Pre-dose,0.5,1,1.5,2,3,4,6,8,10,24 hour post dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Accumulation ratio was to be calculated as AUC(0-tau) at Day 15 divided by AUC(0-tau) at Day 1 for GSK3145095.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1: Pre-dose,0.5,1,1.5,2,3,4,6,8,10, and 24 hour post-dose, Days 15: Pre-dose,0.5,1,1.5,2,3,4,6,8,10,24 hour post dose

Population: PK Population: Only those participants with data available at the specified data points were analyzed. Study was terminated in Part-1 during first escalation cohort "GSK3145095 50 mg BID", hence subsequent escalation cohorts were not initiated.

Blood samples were collected at indicated time points for analysis of time invariance. Time invariance was calculated as AUC(0-tau) at Day 15 divided by AUC(0-infinity) at Day 1 for GSK3145095.

Outcome measures

Outcome measures
Measure	Part 1-GSK3145095 50 mg BID n=2 Participants Participants received a single 50 milligram (mg) dose of GSK3145095 orally on Day 1. From study day 2, participants then received total daily dose of 100 mg GSK3145095 orally given as 50 mg twice a day (BID).	Part 1-GSK3145095 100 mg BID Participants were to receive a single 100 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 200 mg GSK3145095 given as 100 mg BID.	Part 1-GSK3145095 200 mg BID Participants were to receive a single 200 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 400 mg GSK3145095 given as 200 mg BID.	Part 1-GSK3145095 400 mg BID Participants were to receive a single 400 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 800 mg dose of GSK3145095 given as 400 mg BID	Part 1-GSK3145095 800 mg BID Participants were to receive a single 800 mg dose of GSK3145095 orally on Day 1. From study Day 2, participants were to receive 1600 mg dose of GSK3145095 given as 800 mg BID.
Time Invariance of GSK3145095-Part 1	0.78 Ratio Interval 0.71 to 0.85	—	—	—	—

SECONDARY outcome

Timeframe: Day 1: Pre-dose,0.5,1,1.5,2,3,4,6,8, 10, and 24 hour post-dose, Days 15: Pre-dose,0.5,1,1.5,2,3,4,6,8,10, and 24 hour post dose

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at indicated time points for analysis of time invariance. Time invariance were to be calculated as AUC(0-tau) at Day 15 divided by AUC(0-infinity) at Day 1 for GSK3145095.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Days 8,15 (anytime during visit); Days 22,43,64 and every 21 days thereafter (pre-dose), for up to 2 years

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at indicated time points for the determination of plasma concentration of pembrolizumab.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Days 8,15 (anytime during visit); Days 22,43,64 and every 21 days thereafter (pre-dose), for up to 2 years

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at indicated time points for the determination of Cmax of pembrolizumab.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Days 8,15 (anytime during visit); Days 22,43,64 and every 21 days thereafter (pre-dose), for up to 2 years

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at indicated time points for the determination of AUC (0-tau) of pembrolizumab.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Days 8,15 (anytime during visit); Days 22,43,64 and every 21 days thereafter (pre-dose), for up to 2 years

Population: PK Population: Data were not collected for this endpoint as study was terminated during Part 1. Subsequent Part 2 was not initiated.

Blood samples were to be collected at indicated time points for the determination of Cmin of pembrolizumab.