A Dose Escalation Study to Investigate the Safety, Pharmacokinetics (PK), Pharmacodynamics (PD) and Clinical Activity of GSK525762 in Subjects With Relapsed, Refractory Hematologic Malignancies

Phase 2

Completed

Conditions: Neoplasms

Interventions: Drug: GSK525762

Registration Number: NCT01943851

Lead Sponsor: GlaxoSmithKline

Brief Summary: This is an open-label repeat dose, multicenter, 2-part study to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) for GSK525762 given once-daily (QD) orally. Part 1 of the study is a dose escalation phase to select the recommended Part 2 dose (RP2D) based on the safety, PK, and PD profiles observed after oral administration of GSK525762. Eligible subjects with select relapsed refractory hematological malignancies (acute myeloid leukemia \[AML\], non-Hodgkin's Lymphoma \[NHL\]and multiple myeloma \[MM\]), will be enrolled in the QD and/or BID dosing cohorts until a MTD is established. Subjects may continue treatment in the study until disease progression, unacceptable toxicity, or withdrawal of consent. . Upon determination of the MTD, twice daily (BID) dosing cohorts may be opened to collect additional safety data and evaluate the preliminary efficacy of GSK525762 administered BID. Part 2 will explore clinical activity at the MTD or RP2D; separate expansion cohorts will be planned for acute myeloid leukemia (AML), non-Hodgkin's Lymphoma (NHL, including an exploratory sub-cohort of subjects with myc and B-Cell Leukemia (BCL)2 and/or BCL6 rearrangements/overexpression \[double- and triple-hit lymphoma\]), and multiple myeloma (MM). This is the first study of this agent to be conducted in subjects with these relapsed and/or refractory hematological malignancies for which no standard therapies are anticipated to result in a durable remission.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 111

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Part 1: GSK525762 QD Cohort	GSK525762	Subject will be administered a 5 milligram (mg) starting dose of GSK525762, oral tablets, QD. Dose escalations will be performed in Part 1 and dose adjustments are allowed to address tolerability and safety issues. Thereafter, subjects will be enrolled in a standard 3+3 design. Separate dose escalation cohorts will be opened for subjects with AML, NHL, and MM for QD dosing. Dose escalation will continue until an MTD is determined or until a dose of 200 mg per day is reached.
Part 2: GSK525762 dose expansion cohort	GSK525762	After the MTD has been determined in Part1, Part 2 dose expansion cohorts will be opened for AML, NHL and MM.
Part 1: GSK525762 BID Cohort	GSK525762	Subject will be administered a starting dose of GSK525762, oral tablets, 20 mg BID (12 hours apart, total daily dose of 40 mg). Dose escalations will be performed in Part 1 and dose adjustments are allowed to address tolerability and safety issues. Thereafter, subjects will be enrolled in a standard 3+3 design. Separate dose escalation cohorts will be opened for subjects with AML, NHL, and MM, for BID dosing. Dose escalation will continue until an MTD is determined or until a dose of 200 mg per day is reached.

Primary Outcome Measures

Name	Time	Method
Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)	Up to 3 weeks	An event was considered DLT if it occurred within first 3weeks of treatment \& met one of following criteria:unless it was clearly established that event is unrelated to treatment:Grade4 neutropenia persisting for \>=7 days/febrile neutropenia not responding to treatment within 24hours, Grade4 thrombocytopenia lasting more than 7day \& not responding to transfusions/Grade3 thrombocytopenia associated with bleeding (\>10milliliter \[mL\]), Drug-related Grade 3/4 non-hematologic toxicity as described in National Cancer Institute-Common Terminology Criteria for Adverse Events(NCI-CTCAE)version 4.0, Drug-related Grade2 non-hematological toxicity, Grade2 Troponin T elevation(central laboratory\>Upper Limit of Normal\[ULN\]),measured on two separate occasions within 48 hours, Treatment delay of 14 days/greater due to unresolved drug-related toxicity,ALT\>=3xULN+bilirubin\>=2xULN(\>35% direct)/Alanine aminotransferase(ALT) between 3-5xULN with bilirubin\<2xULN but with hepatitis symptom/rash/ALT\>=5xULN.
Part 1: Number of Participants With Worst-case Post-Baseline Abnormal Electrocardiogram (ECG) Findings (Investigator Reading)	Up to 86.9 weeks	12-lead ECGs were recorded with the participants in a supine position using an ECG machine. Number of participants with worst-case clinically significant and not clinically significant abnormal ECG findings have been presented. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.
Part 1: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) and AE Leading to Discontinuation (AELD)	Up to 86.9 weeks	An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and SAE is defined as any untoward medical occurrence that, at any dose which results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or, is a congenital anomaly/birth defect. AELD is adverse events leading to permanent discontinuation of study treatment.
Part 1: Number of Participants With Dose Reductions	Up to 86.9 weeks	Number of participants with dose reductions due to any reason is presented.
Part 1: Number of Participants With Any Dose Interruptions or Delays	Up to 86.9 weeks	Number of participants with any dose interruptions/ delays is presented.
Part 1: Number of Participants With Grade Change From Baseline in Clinical Chemistry Parameters	Up to 86.9 weeks	Blood samples were collected for the analysis of following clinical chemistry parameters: glucose, prothrombin international normalized ratio (Pro. INR), albumin, amylase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, calcium, calcium ionized, cholesterol, creatinine, creatine kinase, lipase, potassium, magnesium, sodium, triglycerides, alkaline phosphatase (ALP). Laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death related to AE. Higher grade indicates greater severity. An increase was defined as an increase relative to Baseline. Baseline was the most recent, non-missing value prior to or on the first study treatment dose date. Data for worst-case post Baseline with any grade increase is presented.
Part 1: Number of Participants With Worst-case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method	Up to 86.9 weeks	Urine samples were collected to assess glucose, ketones, occult blood, urine protein, and monoclonal protein (monoclonal pro). The dipstick test gave results in a semi-quantitative manner, and results for urinalysis parameters were recorded as negative, trace, 1+, 2+, 3+ indicating proportional concentrations in the urine sample. Any increase was defined as any increase in proportional concentrations relative to Baseline. Baseline was the most recent, non-missing value prior to or on the first study treatment dose date. Data for worst-case post Baseline with any increase is presented.
Part 1: Number of Participants With Grade Change From Baseline in Hematology Parameters	Up to 86.9 weeks	Blood samples were collected for the analysis of following hematology parameters: hemoglobin, lymphocytes, neutrophils, platelets and leukocytes. The laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death related to AE. Higher grade indicates greater severity. An increase is defined as an increase in CTCAE grade relative to Baseline grade. Baseline was the most recent, non-missing value prior to or on the first study treatment dose date. Data for worst-case post Baseline with any grade increase is presented.
Part 1: Number of Participants With Worst Case Vital Signs Results Relative to Baseline: Pulse Rate and Body Temperature	Up to 86.9 weeks	Vital signs (pulse rate and temperature) were measured after resting for at least 5 minutes in a supine or semi-recumbent position. The clinical concern ranges were: For pulse rate (low \<60 beats per minute \[bpm\] and high \>100 bpm); For body temperature (\<=35 degrees Celsius or \>=38 degrees Celsius). Participants were counted in the worst case category that their value changed to (low, normal or high), unless there was no change in their category. Participants whose value category was unchanged, or whose value became normal, were recorded in the "To Normal or No Change" category. Participants were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%. Baseline was the most recent, non-missing value prior to or on the first study treatment dose date.
Part 1: Number of Participants With Increase to Grade 3 From Baseline in Vital Signs: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)	Up to 86.9 weeks	DBP and SBP were measured after resting for at least 5 minutes in a supine or semi-recumbent position. They were graded according to NCI-CTCAE version 4.0. For SBP: Grade 0 (\<=120 millimeter of mercury \[mmHg\]), Grade 1 (121-139 mmHg), Grade 2 (140-159 mmHg), Grade 3 (\>=160 mmHg). For DBP: Grade 0 (\<=80 mmHg), Grade 1 (81-89 mmHg), Grade 2 (90-99 mmHg), Grade 3 (\>=100 mmHg). Higher grade indicates greater severity. Baseline was the most recent, non-missing value prior to or on the first study treatment dose date. An increase is defined as an increase in grade relative to Baseline grade. Number of participants with increase to Grade 3 from Baseline is presented.
Part 2: Objective Response Rate Lasting at Least 4 Months (ORR4) (CTCL Cohorts)	Up to 36.4 weeks	ORR4 for CTCL cohorts is defined as the percentage of participants that have achieved a CR or PR lasting at least 4 months per global response criteria and the modified severity weighted assessment tool (mSWAT). ORR4 and 95% exact confidence interval is presented.
Part 2: Objective Response Rate (ORR) (MDS Cohort)	Up to 36.4 weeks	ORR for MDS cohort is defined as the percentage of participants achieving Complete Response (CR), Marrow CR, CRp (as per CR but platelet count \<100 x 10\^9 cells/Liter\[L\]), CRi (as per CR but platelet count \<100 x 10\^9cells/L or neutrophil count \<1 x 10\^9 cells/L), or Partial Response (PR) per response criteria. Complete response is defined as bone marrow \<=5% myeloblasts with normal maturation of all cell lines, with hemoglobin concentration of \>=11 grams per deciliter (g/dL), absolute neutrophil count \>=1 x 10\^9 cells/L, platelet count \>=100x10\^9 cells/L and 0% blasts in the peripheral blood. Marrow CR is defined as Bone marrow \<=5% myeloblasts and decrease by \>=50% over pre-treatment. Objective response rate was determined by the investigator according to international myeloma working group (IMWG) response criteria.

Secondary Outcome Measures

Name	Time	Method
Part 1: Trough Concentration (Ctau) of GSK525762 Following Repeat Dose Administration	Week 2 Day 7: Pre-dose on Days 4, 6 and 7	Plasma samples for PK analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Part 1: Terminal Half Life (T1/2) of GSK525762 Following Single Dose Administration	Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for PK analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Part 1: AUC(0-24) and Area Under the Concentration-time Curve Over the Dosing Interval (AUC[0-tau]) of GSK525762 Following Repeat Dose Administration	Week 2 Day 7: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for PK analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis. AUC(0-24) represents AUC(0-tau) for repeat dose.
Part 1: Tmax of GSK3529246 (Active Metabolite) Following Repeat Dose Administration	Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK3529246 (active metabolite) were collected at the indicated time points. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. GSK3529246 is a metabolite of GSK525762.
Part 1: Tmax of GSK525762 Following Repeat Dose Administration	Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for PK analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Part 1: Cmax and Cmin of GSK525762 Following Repeat Dose Administration	Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for PK analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Part 1: Time of Maximum Concentration (Tmax) of GSK525762 Following Single Dose Administration	Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for PK analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Part 2: Apparent Clearance (CL/F) of GSK525762 After Single Dose Administration	Week 1 Day 1: pre-dose and at 0.5 - 2 hour, 4 - 8 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by empirical Bayes estimates. GSK525762 plasma concentration-time data was analyzed by Population PK methods using a non-linear mixed-effects modelling approach.
Part 1: Overall Response Rate (ORR)- Investigator Assessment	Up to 86.9 weeks	ORR is defined as the percentage of participants achieving stringent complete response (sCR), very good partial response (VGPR), partial response (PR) or minimal response (MR) for multiple myeloma (MM); CR or PR for Non-Hodgkin's Lymphoma (NHL); CR, CRp, CRi or PR for Acute Myeloid Leukemia (AML); CR, MR or PR for Myelodysplastic Syndrome (MDS) using the International Working Group (IWG) response criteria and IWG response criteria in myelodysplasia.
Part 1: Maximum Observed Concentration (Cmax) and Minimum Plasma Concentration (Cmin) of GSK525762 Following Single Dose Administration	Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for PK analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Part 1: Area Under the Concentration-time Curve (AUC) From Time Zero to 24 Hours(AUC[0-24]) and AUC Extrapolated to Infinity (AUC[0-inf]) of GSK525762 Following Single Dose Administration	Week 1 Day 1: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Part 1: Cmax and Cmin of GSK3529246 (Active Metabolite) Following Single Dose Administration	Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK3529246 (active metabolite) were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis. GSK3529246 is a metabolite of GSK525762.
Part 1: Cmax and Cmin of GSK3529246 (Active Metabolite) Following Repeat Dose Administration	Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK3529246 (active metabolite) were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis. GSK3529246 is a metabolite of GSK525762.
Part 1: Trough Concentration (Ctau) of GSK3529246 (Active Metabolite) Following Repeat Dose Administration	Week 2 Day 7: Pre-dose on Days 4, 6 and 7	Plasma samples for pharmacokinetic (PK) analysis of GSK3529246 (active metabolite) were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis. GSK3529246 is a metabolite of GSK525762.
Part 1: Tmax of GSK3529246 (Active Metabolite) Following Single Dose Administration	Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK3529246 (active metabolite) were collected at the indicated time points. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. GSK3529246 is a metabolite of GSK525762.
Part 1: Time Invariance (RS) of GSK3529246 (Active Metabolite)	Week 1 Day 1: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose; Week 2 Day 7: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK3529246 (active metabolite) were collected at the indicated time points. RS was calculated by taking ratio of AUC(0-24) on Week 2 Day 7 to AUC(0-inf) on Week 1 Day 1. PK parameters were calculated by standard non-compartmental analysis. GSK3529246 is a metabolite of GSK525762.
Part 1: Accumulation Ratio (RO) of GSK3529246 (Active Metabolite)	Week 1 Day 1: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose; Week 2 Day 7: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK3529246 (active metabolite) were collected at the indicated time points. Accumulation ratio was calculated by taking ratio of AUC(0-24) in Week 2 Day 7 to AUC (0-24) in Week 1 Day 1. PK parameters were calculated by standard non-compartmental analysis. GSK3529246 is a metabolite of GSK525762.
Part 1: T1/2 of GSK525762 Following Repeat Dose Administration	Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for PK analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Part 1: Time Invariance (RS) of GSK525762	Week 1 Day 1: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose; Week 2 Day 7: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK525762 were collected at the indicated time points. RS was calculated by taking ratio of AUC(0-24) on Week 2 Day 7 to AUC(0-inf) on Week 1 Day 1. PK parameters were calculated by standard non-compartmental analysis.
Part 2: Apparent Clearance (CL/F) of GSK525762 After Repeat Dose Administration	Week 3 Day 1: pre-dose and at 0.5 - 2 hour, 4 - 8 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by empirical Bayes estimates. GSK525762 plasma concentration-time data was analyzed by Population PK methods using a non-linear mixed-effects modelling approach.
Part 2: Change From Baseline in Skindex-29 Domain Scores (Emotional, Functioning and Symptoms Score) for CTCL Cohort	Baseline (pre-dose Week1 Day1) and Week 3, Week 7, Week 10, Week 16 and Week 24	The effects of treatment on disease-related symptoms/quality of life was assessed using the Skindex-29 Questionnaire, which inquires about how often (Never, Rarely, Sometimes, Often, All the time) during the previous 4 weeks the participant experienced the effect described in each of 29 items divided into 3 domains: Emotional (10 items), Symptoms (7 items) and Functioning (12 items). Responses to each item are transformed to a linear scale of 100, varying from 0 (no effect) to 100 (effect experienced all the time). Skindex-29 scores were reported as three individual domain scale scores; a scale score is the mean of a participant's responses to items in a given domain. Each domain score ranges from 0 (no effect) to 100 (effect experienced all the time), higher score implies higher impact of skin disease. Baseline was the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline is defined is post-dose visit value minus Baseline.
Part 2: Number of Participants With Non-serious AEs and SAEs and AELDs	Up to 36.4 weeks	An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and SAE is defined as any untoward medical occurrence that, at any dose which results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or, is a congenital anomaly/birth defect. AELD is adverse events leading to permanent discontinuation of study treatment.
Part 2: Number of Participants With Dose Interruptions/Delays	Up to 36.4 weeks	Number of participants with any dose interruptions or delays is presented.
Part 2: Overall Survival (OS)	Up to 36.4 weeks	OS is defined as the interval of time (in months) between the date of first dose and the date of death due to any cause. Median and inter-quartile range (first quartile and third quartile) of overall survival are presented.
Part 1: Accumulation Ratio (RO) of GSK525762	Week 1 Day 1: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose; Week 2 Day 7: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK525762 were collected at the indicated time points. Accumulation ratio was calculated by taking ratio of AUC(0-24) in Week 2 Day 7 to AUC (0-24) in Week 1 Day 1. PK parameters were calculated by standard non-compartmental analysis.
Part 2: Apparent Central Volume of Distribution (V1/F) of GSK525762 Following Single Dose Administration	Week 1 Day 1: pre-dose and at 0.5 - 2 hour, 4 - 8 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by empirical Bayes estimates. GSK525762 plasma concentration-time data was analyzed by Population PK methods using a non-linear mixed-effects modelling approach.
Part 1: AUC(0-24) and AUC[0-inf] of GSK3529246 (Active Metabolite) Following Single Dose Administration	Week 1 Day 1: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for PK analysis of GSK3529246 (active metabolite) were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis. GSK3529246 is a metabolite of GSK525762.
Part 1: AUC(0-24) and AUC(0-tau) of GSK3529246 (Active Metabolite) Following Repeat Dose Administration	Week 2 Day 7: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK3529246 (active metabolite) were collected at the indicated time points. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. GSK3529246 is a metabolite of GSK525762. AUC(0-tau) is AUC(0-24) for repeat dose.
Part 2: Number of Participants With Dose Reductions	Up to 36.4 weeks	Number of participants with dose reductions due to any reason is presented.
Part 2: Number of Participants With Grade Change From Baseline in Clinical Chemistry Parameters	Up to 36.4 weeks	Blood samples were collected for the analysis of following clinical chemistry parameters: glucose, Prothrombin international normalized ratio (Pro. INR), albumin, amylase, ALT, AST, bilirubin, calcium, calcium ionized, cholesterol, creatinine, creatine kinase, lipase, potassium, magnesium, sodium, Triglycerides, ALP. Laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death related to AE. Higher grade indicates greater severity. An increase was defined as an increase relative to Baseline. Baseline was the most recent, non-missing value prior to or on the first study treatment dose date. Data for worst-case post Baseline with any grade increase is presented.
Part 2: Number of Participants With Grade Change From Baseline in Hematology Parameters	Up to 36.4 weeks	Blood samples were collected for the analysis of following hematology parameters: hemoglobin, lymphocytes, neutrophils, platelets and leukocytes. The laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death related to AE. Higher grade indicates greater severity. An increase is defined as an increase in CTCAE grade relative to Baseline grade. Baseline was the most recent, non-missing value prior to or on the first study treatment dose date. Data for worst-case post Baseline with any grade increase is presented.
Part 2: Number of Participants With Worst-case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method	Up to 36.4 weeks	Urine samples were collected to assess glucose, ketones, occult blood, urine protein. The dipstick test gave results in a semi-quantitative manner, and results for urinalysis parameters were recorded as negative, trace, 1+, 2+, 3+ indicating proportional concentrations in the urine sample. Any increase was defined as any increase in proportional concentrations relative to Baseline. Baseline was the most recent, non-missing value prior to or on the first study treatment dose date. Data for worst-case post Baseline with any increase is presented.
Part 2: Apparent Central Volume of Distribution (V1/F) of GSK525762 Following Repeat Dose Administration	Week 3 Day 1: pre-dose and at 0.5 - 2 hour, 4 - 8 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by empirical Bayes estimates. GSK525762 plasma concentration-time data was analyzed by Population PK methods using a non-linear mixed-effects modelling approach.
Part 1: T1/2 of GSK3529246 (Active Metabolite) Following Single Dose Administration	Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK3529246 (active metabolite) were collected at the indicated time points. Pharmacokinetic parameters were calculated by standard non-compartmental analysis. GSK3529246 is a metabolite of GSK525762.
Part 1: T1/2 of GSK3529246 (Active Metabolite) Following Repeat Dose Administration	Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK3529246 (active metabolite) were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis. GSK3529246 is a metabolite of GSK525762.
Part 2: Apparent Clearance (CL/F) of GSK3529246 (Active Metabolite) Following Single Dose Administration	Week 1 Day 1: pre-dose and at 0.5 - 2 hours, 4 - 8 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK3529246 (active metabolite) were collected at the indicated time points. GSK3529246 is a metabolite of GSK525762. PK parameters were calculated by empirical Bayes estimates. GSK3529246 plasma concentration-time data was analyzed by Population PK methods using a non-linear mixed-effects modelling approach.
Part 2: Apparent Clearance (CL/F) of GSK3529246 (Active Metabolite) Following Repeat Dose Administration	Week 3 Day 1: pre-dose and at 0.5 - 2 hours, 4 - 8 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK3529246 (active metabolite) were collected at the indicated time points. GSK3529246 is a metabolite of GSK525762. Pharmacokinetic parameters were calculated by empirical Bayes estimates. GSK3529246 plasma concentration-time data was analyzed by Population PK methods using a non-linear mixed-effects modelling approach.
Part 2: Apparent Central Volume of Distribution (V1/F) of GSK3529246 (Active Metabolite) Following Single Dose Administration	Week 1 Day 1: pre-dose and at 0.5 - 2 hours, 4 - 8 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK3529246 (active metabolite) were collected at the indicated time points. GSK3529246 is a metabolite of GSK525762. Pharmacokinetic parameters were calculated by empirical Bayes estimates. GSK3529246 plasma concentration-time data was analyzed by Population PK methods using a non-linear mixed-effects modelling approach.
Part 2: Apparent Central Volume of Distribution (V1/F) of GSK3529246 (Active Metabolite) Following Repeat Dose Administration	Week 3 Day 1: pre-dose and at 0.5 - 2 hours, 4 - 8 hours post-dose	Plasma samples for pharmacokinetic (PK) analysis of GSK3529246 (active metabolite) were collected at the indicated time points. GSK3529246 is a metabolite of GSK525762. Pharmacokinetic parameters were calculated by empirical Bayes estimates. GSK3529246 plasma concentration-time data was analyzed by Population PK methods using a non-linear mixed-effects modelling approach.
Part 2: Number of Participants With Worst Case Vital Signs Results Relative to Baseline: Pulse Rate and Body Temperature	Up to 36.4 weeks	Vital signs (pulse rate and temperature) were measured after resting for at least 5 minutes in a supine or semi-recumbent position. The clinical concern ranges were: For pulse rate (low \<60 beats per minute \[bpm\] and high \>100 bpm); For body temperature (\<=35 degrees Celsius or \>=38 degrees Celsius). Participants were counted in the worst case category that their value changed to (low, normal or high), unless there was no change in their category. Participants whose value category was unchanged, or whose value became normal, were recorded in the "To Normal or No Change" category. Participants were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%. Baseline was the most recent, non-missing value prior to or on the first study treatment dose date.
Part 2: Number of Participants With Increase to Grade 3 From Baseline in Vital Signs: DBP and SBP	Up to 36.4 weeks	DBP and SBP were measured after resting for at least 5 minutes in a supine or semi-recumbent position. They were graded according to NCI-CTCAE version 4.0. For SBP: Grade 0 (\<=120 millimeter of mercury \[mmHg\]), Grade 1 (121-139 mmHg), Grade 2 (140-159 mmHg), Grade 3 (\>=160 mmHg). For DBP: Grade 0 (\<=80 mmHg), Grade 1 (81-89 mmHg), Grade 2 (90-99 mmHg), Grade 3 (\>=100 mmHg). Higher grade indicates greater severity. Baseline was the most recent, non-missing value prior to or on the first study treatment dose date. An increase is defined as an increase in grade relative to Baseline grade. Number of participants with increase to Grade 3 from Baseline is presented.
Part 2: Number of Participants With Worst-case Post-Baseline Abnormal Electrocardiogram (ECG) Findings (Investigator Reading)	Up to 36.4 weeks	12-lead ECGs were recorded with the participants in a supine position using an ECG machine. Number of participants with worst-case clinically significant and not clinically significant abnormal ECG findings have been presented. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.
Part 2: Progression Free Survival (PFS)	Up to 36.4 weeks	PFS defined as interval of time(in months) between date of first dose \& earlier of date of disease progression \& date of death due to any cause.Progression is participants(pt's)with MDS \& with \<5% blasts:\>=50% increase in blasts to\>5% blasts/pt's with 5-10% blasts:\>=50% increase to \>10% blasts, for pt's with 10-20% blasts:\>=50% increase to \>20% blasts,for pt's with 20%-30% blasts:\>=50% increase to \>30% blasts, for CTCL progression is \>=25% increase in skin disease from Baseline/new tumors (T3\[1 or more tumors(\>=1cm diameter\]) in pt's with T1(Limited patches,papules\&/or plaques covering \<10% of the skin surface;may further stratify into T1a \[patch only\] versus T1b \[plaque+-patch\]),T2(Patches,papules/plaques covering \>=10% of skin surface;may further stratify into T2a\[patch only\]versus T2b \[plaque+-patch\]) orT4(Confluence of erythema covering \>=80% body surface area) only skin disease/loss of response in those with CR/PR, increase of skin score of \> sum of nadir +50% Baseline score.
Part 2: Duration of Response (DOR)	Up to 36.4 weeks	Duration of response is defined as the time from the first documented evidence response (CR or PR lasting 4 months for CTCL; and CR, marrow CR, CRp, Cri or PR for MDS) until the first documented disease progression or death due to any cause. Median and inter-quartile range (first quartile and third quartile) of duration of response are presented.