CompletedNCT01943851Updated Oct 1, 2024Results posted

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

A Phase 2 interventional study of GSK525762 in Neoplasms, sponsored by GlaxoSmithKline. Completed at 15 sites in 5 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-10-01.

Sponsored by GlaxoSmithKline · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 111
Allocation: Non-randomized
Ages: 18 Years and older
Sex: All

Study 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.

Conditions studied

Neoplasms

Browse trials for

Keywords

leukemia
Acute myeloid leukemia
BET inhibitor
lymphoma
Myelodysplastic syndromes
Oncology
multiple myeloma
GSK525762

In context

Neoplasms

9,610 studies on the registry are indexed under Neoplasms; 2,508 are open to participants now.

This study's enrollment of 111 is above the median of 50 across 7,429 interventional studies indexed under Neoplasms.

Browse Neoplasms studies →

Lead sponsor

GlaxoSmithKline is the lead sponsor of 3,647 studies on the registry; 118 are open to participants now.

Of its 264 completed or terminated interventional studies of FDA-regulated products, 239 (91%) have results posted.

Browse GlaxoSmithKline studies →

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

Written informed consent provided.
Males and females 18 years old or older.
In Part 1 and, Part 2, subjects must have AML, MM, or NHL. Subjects with AML, are eligible if they • have relapsed and/or refractory disease, OR are>=65 years of age and not candidates for or have refused standard chemotherapy. Subjects with multiple myeloma are eligible if they have progressed despite therapy with an alkylating agent, proteasome inhibitor, and immunomodulatory agent, either as individual regimens or in combination. Subjects with NHL are eligible if they have received at least two prior lines of systemic therapy, including at least one line of immunochemotherapy with an anti-CD20 antibody (if their tumor expresses CD20).

In Part 2, the NHL cohort will separately enrol subjects with double- and triple hit lymphoma, so that a minimum of 10 subjects with this subset of disease will be enrolled. To be eligible for this sub-cohort, tumor sample from the subject must demonstrate rearrangement and/or overexpression of MYC and either BCL2 and/or BCL6 genes. Evaluation of double- or triple-hit status may be performed via appropriate local testing, and the determination of double- or triple-hit diagnosis will be at the discretion of the investigator and GSK Medical Monitor.

Subjects with a prior history of stem cell transplant (autologous and/or allogeneic) are allowed if
- At least 3 months has elapsed from the time of transplant and
- the subject has recovered from transplant-associated toxicities prior to the first dose of GSK525762, and For subjects with a prior history of allogeneic transplant,
- the subject has been off systemic immunosuppressive medications (including but not limited to: cyclosporine, tacrolimus, mycophenolate mofetil, or corticosteroids) for at least 1 month prior to the first dose of GSK525762. Topical steroids are permitted
- there are no signs or symptoms of graft versus host disease, other than Grade 1 skin involvement.
Eastern Cooperative Oncology Group (ECOG) performance status of \<=1.
Subject must be stable enough to be expected to complete dosing through the DLT observation period as assessed by the investigator.
Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases, a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 milli-International units per milliliter and estradiol \< 40 picograms per milliliter (\< 140 picomole per liter) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods defined in protocol if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least two to four weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method; Child-bearing potential and agrees to use one of the contraception methods for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until at least 7 months after the last dose of study medication; Negative serum pregnancy test \<= 7 days prior to first study drug dose; Female subjects who are lactating must discontinue nursing prior to the first dose of study treatment and must refrain from nursing throughout the treatment period and for 5 half-lives of GSK525762 or at least 28 days (whichever is longer) following the last dose of study treatment.
Male subjects must agree to use one of the methods of contraception specified. This method must be used from the time of the first dose of study medication until 16 weeks after the last dose of study medication. In addition, male subjects whose partners are or become pregnant must continue to use condoms for 7 days after stopping study medications.
Adequate organ system function.
Ability to comply with dietary and tobacco/alcohol abstinence requirements.

Exclusion criteria

Exclusion Criteria

Haematological malignancy associated with human immunodeficiency virus (HIV) infection or solid organ transplant or history of known Hepatitis B Antigen or positive Hepatitis C antibody (confirmed by Recombinant ImmunoBlot Assay [RIBA], if available or alternately confirmed by Hepatitis C Virus [HCV] Ribonucleic acid [RNA]).
History or concurrent malignancy of solid tumours, except for below. Exception: Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Subjects with second malignancies that are indolent or definitively treated may be enrolled even if less than 5 years have elapsed since treatment. Consult the GSK Medical Monitor if unsure whether second malignancies meet requirements specified above.
Currently receiving cancer therapy (chemotherapy, radiation therapy, immuno- therapy, biologic therapy, hormonal therapy, surgery, and/or tumour embolization).The following are allowed: Hydroxyurea for proliferative disease, Corticosteroids, Use of hematopoetic growth factors is permitted at the discretion of the investigator according to published guidelines (e.g., National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH), etc.). The following are NOT allowed: Investigational anti cancer drug within 2 weeks prior to the first dose of GSK525762; Major surgery, radiotherapy, or immunotherapy within 4 weeks of GSK525762 Chemotherapy regimens with delayed toxicity within the last 4 weeks. Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last 2 weeks.

Nitrosourea or mitomycin C within the last 6 weeks

Evidence of severe of uncontrolled infection.
Use of anticoagulants (e.g., warfarin, heparin) at therapeutic levels within 7 days prior to the first dose of GSK525762. Low dose (prophylactic) low molecular weight heparin (LMWH) is permitted. In addition, INR must be monitored in accordance with local institutional practices, as appropriate.
Current use of a prohibited medication or requires any of these medications during treatment with the investigational drugs. This includes excluding current medications known or suspected to be associated QT prolongation. In addition, any subject who is expected to require a QT prolonging medication while on trial should not be enrolled.
Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding episodes). Any serious and/or unstable pre-existing medical (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the investigator.
Symptomatic or untreated Central nervous system (CNS) disease, Subjects with a history of CNS disease (leukemia, lymphoma or myeloma) are permitted to enrol if they have previously received appropriate therapy and CNS remission has been documented. Subject with primary CNS lymphoma (defined as isolated CNS lymphoma without systemic involvement) are excluded from study.
Cardiac abnormalities as evidenced by any of the following: History or current clinically significant uncontrolled arrhythmias or hypertension; Clinically significant conduction abnormalities or arrhythmias, subjects with Bundle Branch Block; Presence of cardiac pacemaker; History or evidence of current >=Class II congestive heart failure as defined by New York Heart Association (NYHA); History of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting within the past 3 months.
Any of the following ECG findings or assessments including: Baseline QTcF interval >=450 milliseconds; Clinically significant ECG assessments should be reviewed by the site cardiologist prior to study entry.
GSK525762 is a benzodiazepine class molecule. Any serious known immediate or delayed hypersensitivity reaction(s) to GSK525762 or idiosyncrasy to drugs chemically related to the investigational drug.
Evidence of hemoptysis within the last 7 days.
History of major gastrointestinal bleeding within the last 3 months or any evidence of active gastrointestinal bleeding excludes the subject.
Presence of gastrointestinal disease that would significantly affect compound absorption.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Non-randomized
Intervention model: Single group
Masking: None (open label)
Enrollment: 111 participants (actual)

Study arms

Experimental
Part 1: GSK525762 QD Cohort
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.
Drug: GSK525762
Experimental
Part 1: GSK525762 BID Cohort
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.
Drug: GSK525762
Experimental
Part 2: GSK525762 dose expansion cohort
After the MTD has been determined in Part1, Part 2 dose expansion cohorts will be opened for AML, NHL and MM.
Drug: GSK525762

Interventions

DrugGSK525762
GSK525762 1 mg, 10 mg and 30 mg will be supplied as white to off-white, amorphous free base and white to slightly colored crystalline besylate tablets, round, biconvex tablets with no markings. GSK525762 will be administered with 240 milliliter (mL) water.

What researchers measure

Primary outcomes

Part 1: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) and AE Leading to Discontinuation (AELD)
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.
Time frame: Up to 86.9 weeks
Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
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.
Time frame: Up to 3 weeks
Part 1: Number of Participants With Dose Reductions
Number of participants with dose reductions due to any reason is presented.
Time frame: Up to 86.9 weeks
Part 1: Number of Participants With Any Dose Interruptions or Delays
Number of participants with any dose interruptions/ delays is presented.
Time frame: Up to 86.9 weeks
Part 1: Number of Participants With Grade Change From Baseline in Clinical Chemistry Parameters
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.
Time frame: Up to 86.9 weeks
Part 1: Number of Participants With Grade Change From Baseline in Hematology Parameters
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.
Time frame: Up to 86.9 weeks
Part 1: Number of Participants With Worst-case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method
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.
Time frame: Up to 86.9 weeks
Part 1: Number of Participants With Worst Case Vital Signs Results Relative to Baseline: Pulse Rate and Body Temperature
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.
Time frame: Up to 86.9 weeks
Part 1: Number of Participants With Increase to Grade 3 From Baseline in Vital Signs: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
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.
Time frame: Up to 86.9 weeks
Part 1: Number of Participants With Worst-case Post-Baseline Abnormal Electrocardiogram (ECG) Findings (Investigator Reading)
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.
Time frame: Up to 86.9 weeks
Part 2: Objective Response Rate (ORR) (MDS Cohort)
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.
Time frame: Up to 36.4 weeks
Part 2: Objective Response Rate Lasting at Least 4 Months (ORR4) (CTCL Cohorts)
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.
Time frame: Up to 36.4 weeks

Secondary outcomes

Part 1: Overall Response Rate (ORR)- Investigator Assessment
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.
Time frame: Up to 86.9 weeks
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
Plasma samples for pharmacokinetic (PK) analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Time frame: Week 1 Day 1: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
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
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.
Time frame: Week 2 Day 7: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Part 1: Maximum Observed Concentration (Cmax) and Minimum Plasma Concentration (Cmin) of GSK525762 Following Single Dose Administration
Plasma samples for PK analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Time frame: Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Part 1: Cmax and Cmin of GSK525762 Following Repeat Dose Administration
Plasma samples for PK analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Time frame: Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Part 1: Trough Concentration (Ctau) of GSK525762 Following Repeat Dose Administration
Plasma samples for PK analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Time frame: Week 2 Day 7: Pre-dose on Days 4, 6 and 7
Part 1: Time of Maximum Concentration (Tmax) of GSK525762 Following Single Dose Administration
Plasma samples for PK analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Time frame: Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Part 1: Tmax of GSK525762 Following Repeat Dose Administration
Plasma samples for PK analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Time frame: Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Part 1: Terminal Half Life (T1/2) of GSK525762 Following Single Dose Administration
Plasma samples for PK analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Time frame: Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Part 1: T1/2 of GSK525762 Following Repeat Dose Administration
Plasma samples for PK analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.
Time frame: Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Part 1: Time Invariance (RS) of GSK525762
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.
Time frame: 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
Part 1: Accumulation Ratio (RO) of GSK525762
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.
Time frame: 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
Part 2: Apparent Clearance (CL/F) of GSK525762 After Single Dose Administration
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.
Time frame: Week 1 Day 1: pre-dose and at 0.5 - 2 hour, 4 - 8 hours post-dose
Part 2: Apparent Clearance (CL/F) of GSK525762 After Repeat Dose Administration
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.
Time frame: Week 3 Day 1: pre-dose and at 0.5 - 2 hour, 4 - 8 hours post-dose
Part 2: Apparent Central Volume of Distribution (V1/F) of GSK525762 Following Single Dose Administration
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.
Time frame: Week 1 Day 1: pre-dose and at 0.5 - 2 hour, 4 - 8 hours post-dose
Part 2: Apparent Central Volume of Distribution (V1/F) of GSK525762 Following Repeat Dose Administration
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.
Time frame: Week 3 Day 1: pre-dose and at 0.5 - 2 hour, 4 - 8 hours post-dose
Part 1: AUC(0-24) and AUC[0-inf] of GSK3529246 (Active Metabolite) Following Single Dose Administration
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.
Time frame: Week 1 Day 1: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Part 1: AUC(0-24) and AUC(0-tau) of GSK3529246 (Active Metabolite) Following Repeat Dose Administration
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.
Time frame: Week 2 Day 7: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Part 1: Cmax and Cmin of GSK3529246 (Active Metabolite) Following Single Dose Administration
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.
Time frame: Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Part 1: Cmax and Cmin of GSK3529246 (Active Metabolite) Following Repeat Dose Administration
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.
Time frame: Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Part 1: Trough Concentration (Ctau) of GSK3529246 (Active Metabolite) Following Repeat Dose Administration
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.
Time frame: Week 2 Day 7: Pre-dose on Days 4, 6 and 7
Part 1: Tmax of GSK3529246 (Active Metabolite) Following Single Dose Administration
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.
Time frame: Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Part 1: Tmax of GSK3529246 (Active Metabolite) Following Repeat Dose Administration
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.
Time frame: Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Part 1: T1/2 of GSK3529246 (Active Metabolite) Following Single Dose Administration
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.
Time frame: Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Part 1: T1/2 of GSK3529246 (Active Metabolite) Following Repeat Dose Administration
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.
Time frame: Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Part 1: Time Invariance (RS) of GSK3529246 (Active Metabolite)
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.
Time frame: 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
Part 1: Accumulation Ratio (RO) of GSK3529246 (Active Metabolite)
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.
Time frame: 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
Part 2: Apparent Clearance (CL/F) of GSK3529246 (Active Metabolite) Following Single Dose Administration
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.
Time frame: Week 1 Day 1: pre-dose and at 0.5 - 2 hours, 4 - 8 hours post-dose
Part 2: Apparent Clearance (CL/F) of GSK3529246 (Active Metabolite) Following Repeat Dose Administration
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.
Time frame: Week 3 Day 1: pre-dose and at 0.5 - 2 hours, 4 - 8 hours post-dose
Part 2: Apparent Central Volume of Distribution (V1/F) of GSK3529246 (Active Metabolite) Following Single Dose Administration
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.
Time frame: Week 1 Day 1: pre-dose and at 0.5 - 2 hours, 4 - 8 hours post-dose
Part 2: Apparent Central Volume of Distribution (V1/F) of GSK3529246 (Active Metabolite) Following Repeat Dose Administration
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.
Time frame: Week 3 Day 1: pre-dose and at 0.5 - 2 hours, 4 - 8 hours post-dose
Part 2: Change From Baseline in Skindex-29 Domain Scores (Emotional, Functioning and Symptoms Score) for CTCL Cohort
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.
Time frame: Baseline (pre-dose Week1 Day1) and Week 3, Week 7, Week 10, Week 16 and Week 24
Part 2: Number of Participants With Non-serious AEs and SAEs and AELDs
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.
Time frame: Up to 36.4 weeks
Part 2: Number of Participants With Dose Reductions
Number of participants with dose reductions due to any reason is presented.
Time frame: Up to 36.4 weeks
Part 2: Number of Participants With Dose Interruptions/Delays
Number of participants with any dose interruptions or delays is presented.
Time frame: Up to 36.4 weeks
Part 2: Number of Participants With Grade Change From Baseline in Clinical Chemistry Parameters
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.
Time frame: Up to 36.4 weeks
Part 2: Number of Participants With Grade Change From Baseline in Hematology Parameters
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.
Time frame: Up to 36.4 weeks
Part 2: Number of Participants With Worst-case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method
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.
Time frame: Up to 36.4 weeks
Part 2: Number of Participants With Worst Case Vital Signs Results Relative to Baseline: Pulse Rate and Body Temperature
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.
Time frame: Up to 36.4 weeks
Part 2: Number of Participants With Increase to Grade 3 From Baseline in Vital Signs: DBP and SBP
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.
Time frame: Up to 36.4 weeks
Part 2: Number of Participants With Worst-case Post-Baseline Abnormal Electrocardiogram (ECG) Findings (Investigator Reading)
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.
Time frame: Up to 36.4 weeks
Part 2: Progression Free Survival (PFS)
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.
Time frame: Up to 36.4 weeks
Part 2: Duration of Response (DOR)
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.
Time frame: Up to 36.4 weeks
Part 2: Overall Survival (OS)
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.
Time frame: Up to 36.4 weeks

Other outcomes

Part 2: Time to Progression (TTP) for Participants With MM
Time to Progression was planned to be analyzed.
Time frame: Up to 36.4 weeks
Part 1: Changes in Cardiac QT Duration Corrected for Heart Rate by Fridericia's Formula (QTcF) and Other Safety Parameters in Relation to GSK525762 PK Concentrations
Changes in QTcF and other safety parameters in relation to GSK525762 PK concentrations was planned to be analyzed.
Time frame: Up to 86.9 weeks
Part 1: Number of Participants With Dose /Exposure Markers Related Change in Molecular Markers in Tumor Tissue and/or Peripheral Blood Samples
Number of participants with dose /exposure markers related change in molecular markers (e.g. gene transcription and/or expression of proteins regulated by Bromodomain \[BRD\] proteins) in tumor tissue and/or peripheral blood samples were planned to be analyzed.
Time frame: Up to 86.9 weeks
Part 2: Plasma Concentrations of GSK525762 in Relationship With Safety and Efficacy Parameters Derived From Pharmacokinetic/Pharmacodynamic (PK/PD) Model
Plasma concentrations of GSK525762 in relationship with safety and efficacy parameters derived from PK/PD model was planned to be analyzed.
Time frame: Up to 36.4 weeks
Part 2: Number of Participants With Dose /Exposure Markers Related Change in Molecular Markers in Tumor Tissue and/or Peripheral Blood Samples
Number of participants with dose /exposure markers related change in molecular markers (e.g. gene transcription and/or expression of proteins regulated by Bromodomain proteins) in tumor tissue and/or peripheral blood samples were planned to be analyzed.
Time frame: Up to 36.4 weeks
Part 1: Overall Survival (OS)
Overall survival (defined as the interval of time in months between the date of first dose and the date of death due to any cause) was planned to be analyzed.
Time frame: Up to 86.9 weeks

Results

Posted May 19, 2021

Participant flow

This was an open-label repeat dose, multicenter study to investigate the safety, pharmacokinetics (PK), pharmacodynamics and clinical activity of GSK525762 in participants with relapsed, refractory hematologic malignancies. The study was conducted in 2 parts: Part 1 (dose escalation) and Part 2 (dose expansion)

Part 1 (Up to 86.9 Weeks)

Participant flow — Part 1 (Up to 86.9 Weeks)
Milestone	Part 1: GSK525762 5 mg QD	Part 1: GSK525762 10 mg QD	Part 1: GSK525762 20 mg QD	Part 1: GSK525762 30 mg QD MM	Part 1: GSK525762 40 mg QD	Part 1: GSK525762 40 mg QD MM	Part 1: GSK525762 60 mg QD AML	Part 1: GSK525762 60 mg QD NHL	Part 1: GSK525762 60 mg QD MM	Part 1: GSK525762 75 mg QD AML	Part 1: GSK525762 80 mg QD	Part 1: GSK525762 80 mg QD AML	Part 1: GSK525762 80 mg QD NHL	Part 1: GSK525762 100 mg QD AML	Part 1: GSK525762 120 mg QD AML
Started	1	1	1	5	1	4	8	18	3	8	1	7	7	16	6
Completed	1	1	1	4	0	4	7	16	2	8	1	7	7	15	6
Not completed	0	0	0	1	1	0	1	2	1	0	0	0	0	1	0
Withdrew: Withdrawal by subject	0	0	0	1	0	0	1	1	1	0	0	0	0	0	0
Withdrew: Lost to follow-up	0	0	0	0	1	0	0	1	0	0	0	0	0	0	0
Withdrew: Investigator discretion	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0

Part 2 (Up to 36.4 Weeks)

Participant flow — Part 2 (Up to 36.4 Weeks)
Milestone	Part 2: GSK525762 60 mg QD CTCL	Part 2: GSK525762 75 mg QD MDS	Part 2: GSK525762 80 mg QD CTCL
Started	7	16	1
Completed	1	13	0
Not completed	6	3	1
Withdrew: Withdrawal by subject	2	0	0
Withdrew: Study closed/terminated	4	3	1

Outcome measures

PrimaryPart 1: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) and AE Leading to Discontinuation (AELD)

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.

Time frame:: Up to 86.9 weeks
Reported as:: Count of participants · Participants

Part 1: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) and AE Leading to Discontinuation (AELD)
Participants	Part 1: GSK525762 5 mg QD	Part 1: GSK525762 10 mg QD	Part 1: GSK525762 20 mg QD	Part 1: GSK525762 30 mg QD MM	Part 1: GSK525762 40 mg QD	Part 1: GSK525762 40 mg QD MM	Part 1: GSK525762 60 mg QD AML	Part 1: GSK525762 60 mg QD NHL	Part 1: GSK525762 60 mg QD MM	Part 1: GSK525762 75 mg QD AML	Part 1: GSK525762 80 mg QD	Part 1: GSK525762 80 mg QD AML	Part 1: GSK525762 80 mg QD NHL	Part 1: GSK525762 100 mg QD AML	Part 1: GSK525762 120 mg QD AML
Non-serious AEs	1	1	1	5	1	4	8	18	3	8	1	7	7	16	6
SAEs	1	0	0	4	0	3	6	12	2	8	1	6	7	14	6
AELD	0	0	0	1	0	1	3	3	0	2	0	3	1	8	2

PrimaryPart 1: Number of Participants With Dose Limiting Toxicities (DLTs)

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.

Time frame:: Up to 3 weeks
Reported as:: Count of participants · Participants

Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
Participants	Part 1: GSK525762 5 mg QD	Part 1: GSK525762 10 mg QD	Part 1: GSK525762 20 mg QD	Part 1: GSK525762 30 mg QD MM	Part 1: GSK525762 40 mg QD	Part 1: GSK525762 40 mg QD MM	Part 1: GSK525762 60 mg QD AML	Part 1: GSK525762 60 mg QD NHL	Part 1: GSK525762 60 mg QD MM	Part 1: GSK525762 75 mg QD AML	Part 1: GSK525762 80 mg QD	Part 1: GSK525762 80 mg QD AML	Part 1: GSK525762 80 mg QD NHL	Part 1: GSK525762 100 mg QD AML	Part 1: GSK525762 120 mg QD AML
Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)	0	0	0	0	0	0	0	2	0	0	0	0	0	0	1

PrimaryPart 1: Number of Participants With Dose Reductions

Number of participants with dose reductions due to any reason is presented.

Time frame:: Up to 86.9 weeks
Reported as:: Count of participants · Participants

Part 1: Number of Participants With Dose Reductions
Participants	Part 1: GSK525762 5 mg QD	Part 1: GSK525762 10 mg QD	Part 1: GSK525762 20 mg QD	Part 1: GSK525762 30 mg QD MM	Part 1: GSK525762 40 mg QD	Part 1: GSK525762 40 mg QD MM	Part 1: GSK525762 60 mg QD AML	Part 1: GSK525762 60 mg QD NHL	Part 1: GSK525762 60 mg QD MM	Part 1: GSK525762 75 mg QD AML	Part 1: GSK525762 80 mg QD	Part 1: GSK525762 80 mg QD AML	Part 1: GSK525762 80 mg QD NHL	Part 1: GSK525762 100 mg QD AML	Part 1: GSK525762 120 mg QD AML
Part 1: Number of Participants With Dose Reductions	0	0	0	0	0	1	0	8	0	1	0	0	5	3	1

PrimaryPart 1: Number of Participants With Any Dose Interruptions or Delays

Number of participants with any dose interruptions/ delays is presented.

Time frame:: Up to 86.9 weeks
Reported as:: Count of participants · Participants

Part 1: Number of Participants With Any Dose Interruptions or Delays
Participants	Part 1: GSK525762 5 mg QD	Part 1: GSK525762 10 mg QD	Part 1: GSK525762 20 mg QD	Part 1: GSK525762 30 mg QD MM	Part 1: GSK525762 40 mg QD	Part 1: GSK525762 40 mg QD MM	Part 1: GSK525762 60 mg QD AML	Part 1: GSK525762 60 mg QD NHL	Part 1: GSK525762 60 mg QD MM	Part 1: GSK525762 75 mg QD AML	Part 1: GSK525762 80 mg QD	Part 1: GSK525762 80 mg QD AML	Part 1: GSK525762 80 mg QD NHL	Part 1: GSK525762 100 mg QD AML	Part 1: GSK525762 120 mg QD AML
Part 1: Number of Participants With Any Dose Interruptions or Delays	1	0	1	3	0	3	5	15	2	7	1	6	7	13	6

PrimaryPart 1: Number of Participants With Grade Change From Baseline in Clinical Chemistry Parameters

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.

Time frame:: Up to 86.9 weeks
Reported as:: Count of participants · Participants

Part 1: Number of Participants With Grade Change From Baseline in Clinical Chemistry Parameters
Participants	Part 1: GSK525762 5 mg QD	Part 1: GSK525762 10 mg QD	Part 1: GSK525762 20 mg QD	Part 1: GSK525762 30 mg QD MM	Part 1: GSK525762 40 mg QD	Part 1: GSK525762 40 mg QD MM	Part 1: GSK525762 60 mg QD AML	Part 1: GSK525762 60 mg QD NHL	Part 1: GSK525762 60 mg QD MM	Part 1: GSK525762 75 mg QD AML	Part 1: GSK525762 80 mg QD	Part 1: GSK525762 80 mg QD AML	Part 1: GSK525762 80 mg QD NHL	Part 1: GSK525762 100 mg QD AML	Part 1: GSK525762 120 mg QD AML
Glucose, n=1,1,1,5,1,4,7,18,3,8,1,7,7,16,6	1	0	1	3	1	3	6	16	2	8	1	6	6	15	3
Pro.INR, n=0,1,1,5,1,3,4,16,3,4,0,6,5,11,4	—	0	1	3	0	1	3	10	1	3	—	4	5	8	3
Albumin, n=1,1,1,5,1,4,7,18,3,8,1,7,7,16,6	1	0	1	1	1	0	4	7	1	3	1	3	3	6	1
ALT, n=1,1,1,5,1,4,8,18,3,8,1,7,7,15,6	0	0	0	1	0	1	1	4	1	1	0	1	3	4	0
Amylase, n=1,1,1,5,1,4,7,18,3,8,1,7,7,16,5	0	1	0	1	1	0	0	5	2	0	0	3	4	3	0
AST, n=1,1,1,5,1,4,8,18,3,8,1,7,7,16,6	0	0	1	1	0	0	1	5	1	0	0	3	3	4	1
Bilirubin, n=1,1,1,5,1,4,8,18,3,8,1,7,7,16,6	1	0	1	0	1	1	6	8	1	7	1	6	5	12	4
Calcium, n=1,1,1,5,1,4,7,18,3,8,1,7,7,16,6	0	0	0	2	0	1	5	6	0	5	0	4	1	6	5
Calcium Ionized, n=1,1,1,4,1,4,7,17,3,8,1,7,7,15,6	1	0	1	1	1	3	1	2	0	3	0	3	3	6	2
Cholesterol,n=1,1,1,4,1,4,3,17,3,6,1,7,6,10,3	0	0	1	1	0	1	0	1	1	1	1	2	2	3	0
Creatine Kinase, n=1,1,1,2,1,4,8,18,3,7,1,7,7,16,6	0	0	0	1	0	1	2	3	1	0	0	1	2	4	0
Creatinine, n=1,1,1,5,1,4,7,18,3,8,1,7,7,16,6	0	0	0	1	0	1	4	5	1	1	0	3	2	6	1
Lipase, n=1,1,1,5,1,4,6,18,3,8,1,7,6,15,6	0	0	0	0	1	1	0	5	0	2	0	2	3	0	1
Potassium, n=1,1,1,5,1,4,7,18,3,8,1,7,6,16,6	1	0	1	1	0	3	3	4	2	5	1	5	4	7	3
Magnesium,n=1,1,1,5,1,4,7,18,3,8,1,7,7,16,6	1	0	0	1	1	2	3	4	2	1	1	4	5	8	2
Sodium, n=1,1,1,5,1,4,7,18,3,8,1,7,7,16,6	1	0	0	3	1	3	3	6	1	4	1	4	2	9	3
Triglycerides, n=1,1,1,4,1,4,3,17,3,6,1,7,6,10,3	1	0	1	2	1	2	1	4	1	3	1	5	2	8	2
ALP, n=1,1,1,5,1,4,8,18,3,8,1,7,7,16,6	0	0	0	1	0	2	0	2	1	0	1	4	3	1	1

PrimaryPart 1: Number of Participants With Grade Change From Baseline in Hematology Parameters

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.

Time frame:: Up to 86.9 weeks
Reported as:: Count of participants · Participants

Part 1: Number of Participants With Grade Change From Baseline in Hematology Parameters
Participants	Part 1: GSK525762 5 mg QD	Part 1: GSK525762 20 mg QD	Part 1: GSK525762 30 mg QD MM	Part 1: GSK525762 40 mg QD	Part 1: GSK525762 40 mg QD MM	Part 1: GSK525762 60 mg QD AML	Part 1: GSK525762 60 mg QD NHL	Part 1: GSK525762 60 mg QD MM	Part 1: GSK525762 75 mg QD AML	Part 1: GSK525762 80 mg QD	Part 1: GSK525762 80 mg QD AML	Part 1: GSK525762 80 mg QD NHL	Part 1: GSK525762 100 mg QD AML	Part 1: GSK525762 120 mg QD AML
Hemoglobin, n=1,1,1,5,1,4,7,18,3,8,1,7,7,16,6	1	0	2	0	2	3	13	3	6	1	4	6	9	3
Lymphocytes, n=1,1,0,5,1,4,7,18,3,8,1,7,7,15,6	0	—	3	1	3	4	11	2	5	1	6	3	10	5
Neutrophils, n=1,1,0,5,1,4,7,18,3,8,1,7,7,15,5	0	—	4	0	3	1	6	2	5	0	2	5	3	1
Platelets, n=1,1,1,5,1,4,7,18,3,8,1,7,7,16,6	0	1	4	1	4	4	17	3	4	1	5	7	11	2
Leukocytes, n=1,1,1,5,1,4,7,18,3,8,1,7,7,16,6	0	1	4	1	3	2	9	3	4	1	3	4	9	3

PrimaryPart 1: Number of Participants With Worst-case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method

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.

Time frame:: Up to 86.9 weeks
Reported as:: Count of participants · Participants

Part 1: Number of Participants With Worst-case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method
Participants	Part 1: GSK525762 5 mg QD	Part 1: GSK525762 10 mg QD	Part 1: GSK525762 20 mg QD	Part 1: GSK525762 30 mg QD MM	Part 1: GSK525762 40 mg QD	Part 1: GSK525762 40 mg QD MM	Part 1: GSK525762 60 mg QD AML	Part 1: GSK525762 60 mg QD NHL	Part 1: GSK525762 60 mg QD MM	Part 1: GSK525762 75 mg QD AML	Part 1: GSK525762 80 mg QD	Part 1: GSK525762 80 mg QD AML	Part 1: GSK525762 80 mg QD NHL	Part 1: GSK525762 100 mg QD AML	Part 1: GSK525762 120 mg QD AML
Glucose, n=1,1,1,4,1,4,4,15, 3,5,0,3,5,8,1	0	0	0	1	0	1	1	0	0	2	—	0	2	2	1
Ketones, n=1,1,1,4,1,4,4,13,3,5,1,6,5,11,2	1	0	0	0	1	0	0	1	0	2	1	1	0	3	1
Occult blood, n=1,1,1,4,1,4,5,14,3,7,1,6,5,11,2	1	0	1	3	0	2	3	4	3	3	1	4	2	4	1
Protein, n=1,1,1,4,1,4,2,12,1,5,0,3,4,7,1	0	0	1	2	1	2	1	5	0	3	—	0	3	3	1
Monoclonal pro, n=0,0,0,0,0,1,0,0,2,0,0,0,0,0,0	—	—	—	—	—	0	—	—	0	—	—	—	—	—	—

PrimaryPart 1: Number of Participants With Worst Case Vital Signs Results Relative to Baseline: Pulse Rate and Body Temperature

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.

Time frame:: Up to 86.9 weeks
Reported as:: Count of participants · Participants

Part 1: Number of Participants With Worst Case Vital Signs Results Relative to Baseline: Pulse Rate and Body Temperature
Participants	Part 1: GSK525762 5 mg QD	Part 1: GSK525762 10 mg QD	Part 1: GSK525762 20 mg QD	Part 1: GSK525762 30 mg QD MM	Part 1: GSK525762 40 mg QD	Part 1: GSK525762 40 mg QD MM	Part 1: GSK525762 60 mg QD AML	Part 1: GSK525762 60 mg QD NHL	Part 1: GSK525762 60 mg QD MM	Part 1: GSK525762 75 mg QD AML	Part 1: GSK525762 80 mg QD	Part 1: GSK525762 80 mg QD AML	Part 1: GSK525762 80 mg QD NHL	Part 1: GSK525762 100 mg QD AML	Part 1: GSK525762 120 mg QD AML
Pulse rate, To Low	0	0	1	0	0	0	2	0	0	0	0	0	0	1	0
Pulse rate, To Normal or No change	0	1	0	2	0	2	4	8	1	5	1	1	1	8	4
Pulse Rate, To High	1	0	0	3	1	2	2	10	2	3	0	6	6	8	2
Temperature, To Low	0	0	0	0	0	1	0	0	0	0	0	0	1	1	0
Temperature, To Normal or No Change	0	1	1	4	1	2	3	15	3	7	1	1	6	7	6
Temperature, To High,	1	0	0	1	0	1	4	3	0	1	0	6	0	8	0

PrimaryPart 1: Number of Participants With Increase to Grade 3 From Baseline in Vital Signs: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)

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.

Time frame:: Up to 86.9 weeks
Reported as:: Count of participants · Participants

Part 1: Number of Participants With Increase to Grade 3 From Baseline in Vital Signs: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
Participants	Part 1: GSK525762 5 mg QD	Part 1: GSK525762 10 mg QD	Part 1: GSK525762 20 mg QD	Part 1: GSK525762 30 mg QD MM	Part 1: GSK525762 40 mg QD	Part 1: GSK525762 40 mg QD MM	Part 1: GSK525762 60 mg QD AML	Part 1: GSK525762 60 mg QD NHL	Part 1: GSK525762 60 mg QD MM	Part 1: GSK525762 75 mg QD AML	Part 1: GSK525762 80 mg QD	Part 1: GSK525762 80 mg QD AML	Part 1: GSK525762 80 mg QD NHL	Part 1: GSK525762 100 mg QD AML	Part 1: GSK525762 120 mg QD AML
DBP	0	0	0	0	1	0	0	1	0	0	0	0	1	0	0
SBP	0	0	0	1	1	0	1	1	0	1	1	4	1	4	4

PrimaryPart 1: Number of Participants With Worst-case Post-Baseline Abnormal Electrocardiogram (ECG) Findings (Investigator Reading)

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.

Time frame:: Up to 86.9 weeks
Reported as:: Count of participants · Participants

Part 1: Number of Participants With Worst-case Post-Baseline Abnormal Electrocardiogram (ECG) Findings (Investigator Reading)
Participants	Part 1: GSK525762 5 mg QD	Part 1: GSK525762 10 mg QD	Part 1: GSK525762 20 mg QD	Part 1: GSK525762 30 mg QD MM	Part 1: GSK525762 40 mg QD	Part 1: GSK525762 40 mg QD MM	Part 1: GSK525762 60 mg QD AML	Part 1: GSK525762 60 mg QD NHL	Part 1: GSK525762 60 mg QD MM	Part 1: GSK525762 75 mg QD AML	Part 1: GSK525762 80 mg QD	Part 1: GSK525762 80 mg QD AML	Part 1: GSK525762 80 mg QD NHL	Part 1: GSK525762 100 mg QD AML	Part 1: GSK525762 120 mg QD AML
Abnormal-Clinically significant	0	0	1	1	0	1	1	1	0	3	0	0	2	4	1
Abnormal-Not Clinically significant	1	1	0	4	1	3	6	17	3	5	1	7	5	12	5

PrimaryPart 2: Objective Response Rate (ORR) (MDS Cohort)

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.

Time frame:: Up to 36.4 weeks
Reported as:: Number · Percentage of participants

Part 2: Objective Response Rate (ORR) (MDS Cohort)
Percentage of participants	Part 2: GSK525762 75 mg QD MDS
Part 2: Objective Response Rate (ORR) (MDS Cohort)	25 (7.3 to 52.4)

PrimaryPart 2: Objective Response Rate Lasting at Least 4 Months (ORR4) (CTCL Cohorts)

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.

Time frame:: Up to 36.4 weeks
Reported as:: Number · Percentage of participants

Part 2: Objective Response Rate Lasting at Least 4 Months (ORR4) (CTCL Cohorts)
Percentage of participants	Part 2: GSK525762 60 mg QD CTCL	Part 2: GSK525762 80 mg QD CTCL
Part 2: Objective Response Rate Lasting at Least 4 Months (ORR4) (CTCL Cohorts)	0 (0 to 41)	0 (0 to 97.5)

SecondaryPart 1: Overall Response Rate (ORR)- Investigator Assessment

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.

Time frame:: Up to 86.9 weeks
Reported as:: Number · Percentage of participants

Part 1: Overall Response Rate (ORR)- Investigator Assessment
Percentage of participants	Part 1: GSK525762 5 mg QD	Part 1: GSK525762 10 mg QD	Part 1: GSK525762 20 mg QD	Part 1: GSK525762 30 mg QD MM	Part 1: GSK525762 40 mg QD	Part 1: GSK525762 40 mg QD MM	Part 1: GSK525762 60 mg QD AML	Part 1: GSK525762 60 mg QD NHL	Part 1: GSK525762 60 mg QD MM	Part 1: GSK525762 75 mg QD AML	Part 1: GSK525762 80 mg QD	Part 1: GSK525762 80 mg QD AML	Part 1: GSK525762 80 mg QD NHL	Part 1: GSK525762 100 mg QD AML	Part 1: GSK525762 120 mg QD AML
Part 1: Overall Response Rate (ORR)- Investigator Assessment	0 (0 to 97.5)	0 (0 to 97.5)	0 (0 to 97.5)	0 (0 to 52.2)	0 (0 to 97.5)	0 (0 to 60.2)	25 (3.2 to 65.1)	6 (0.1 to 27.3)	0 (0 to 70.8)	0 (0 to 36.9)	0 (0 to 97.5)	14 (0.4 to 57.9)	29 (3.7 to 71.0)	13 (1.6 to 38.3)	17 (0.4 to 64.1)

SecondaryPart 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

Plasma samples for pharmacokinetic (PK) analysis of GSK525762 were collected at the indicated time points. PK parameters were calculated by standard non-compartmental analysis.

Time frame:: Week 1 Day 1: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Reported as:: Geometric mean · Hours*nanograms per milliliter

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
Hours*nanograms per milliliter	Part 1: GSK525762 5 mg QD	Part 1: GSK525762 10 mg QD	Part 1: GSK525762 20 mg QD	Part 1: GSK525762 30 mg QD MM	Part 1: GSK525762 40 mg QD	Part 1: GSK525762 40 mg QD MM	Part 1: GSK525762 60 mg QD AML	Part 1: GSK525762 60 mg QD NHL	Part 1: GSK525762 60 mg QD MM	Part 1: GSK525762 75 mg QD AML	Part 1: GSK525762 80 mg QD	Part 1: GSK525762 80 mg QD AML	Part 1: GSK525762 80 mg QD NHL	Part 1: GSK525762 100 mg QD AML	Part 1: GSK525762 120 mg QD AML
AUC(0-24), n=1,1,1,5,1,4,8,18,3,8,1,6,7,16, 6	460.48 ± NA	1024.49 ± NA	2881.41 ± NA	2146.54 ± 31.68	3317.10 ± NA	2510.55 ± 71.29	6424.74 ± 22.42	5918.90 ± 52.85	3695.32 ± 62.01	7980.72 ± 45.28	5944.52 ± NA	8394.69 ± 34.31	5017.96 ± 44.17	13520.57 ± 46.29	13688.54 ± 43.80
AUC(0-inf), n=1,1,1,5,1,4,7,17,3,8,1,5,7,16,5	466.81 ± NA	1092.28 ± NA	3054.11 ± NA	2217.32 ± 32.55	3465.49 ± NA	2546.49 ± 72.05	6951.06 ± 25.12	6214.97 ± 60.67	3874.05 ± 63.27	8248.45 ± 47.87	6032.36 ± NA	9734.83 ± 29.60	5114.61 ± 44.76	14635.17 ± 52.35	17021.44 ± 35.37

SecondaryPart 1: AUC(0-24) and Area Under the Concentration-time Curve Over the Dosing Interval (AUC[0-tau]) of GSK525762 Following Repeat Dose Administration

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.

Time frame:: Week 2 Day 7: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Reported as:: Geometric mean · Hours*nanograms per milliliter

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
Hours*nanograms per milliliter	Part 1: GSK525762 5 mg QD	Part 1: GSK525762 10 mg QD	Part 1: GSK525762 20 mg QD	Part 1: GSK525762 30 mg QD MM	Part 1: GSK525762 40 mg QD	Part 1: GSK525762 40 mg QD MM	Part 1: GSK525762 60 mg QD AML	Part 1: GSK525762 60 mg QD NHL	Part 1: GSK525762 60 mg QD MM	Part 1: GSK525762 75 mg QD AML	Part 1: GSK525762 80 mg QD	Part 1: GSK525762 80 mg QD AML	Part 1: GSK525762 80 mg QD NHL	Part 1: GSK525762 100 mg QD AML	Part 1: GSK525762 120 mg QD AML
AUC(0-24)	476.71 ± NA	656.93 ± NA	1855.07 ± NA	1908.18 ± 27.53	2490.25 ± NA	1702.37 ± 58.17	6271.43 ± 38.76	3576.49 ± 30.59	931.02 ± 53.64	5883.76 ± 48.48	5188.25 ± NA	6892.57 ± 71.96	2994.24 ± 37.27	9440.98 ± 84.11	5296.46 ± 8.89
AUC(0-tau)	476.71 ± NA	656.93 ± NA	1855.07 ± NA	1908.18 ± 27.53	2490.25 ± NA	1702.37 ± 58.17	6271.43 ± 38.76	3576.49 ± 30.59	931.02 ± 53.64	5883.76 ± 48.48	5188.25 ± NA	6892.57 ± 71.96	2994.24 ± 37.27	9440.98 ± 84.11	5296.46 ± 8.89

SecondaryPart 1: Maximum Observed Concentration (Cmax) and Minimum Plasma Concentration (Cmin) of GSK525762 Following Single Dose Administration