Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of GSK2881078 in Single and Repeat Doses
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of GSK2881078 in Single and Repeat Doses
This study is the first administration of GSK2881078 to humans. The intention of this study
 is to provide sufficient confidence in the safety of the molecule to inform progression to
 further repeat dose and proof of concept studies. This study will include approximately 52
 subjects and consist of 2 parts. Part A will consist of two cohorts of 8 subjects to assess
 the safety, tolerability, and pharmacokinetic (PK) of ascending single oral doses of
 GSK2881078. Cohorts 1 and 2 will include healthy male subjects. Part B (Cohorts 3, 4 and 5)
 will include three cohorts of 12 healthy male subjects to examine the safety, tolerability,
 PK, and pharmacodynamic (PD) of repeated doses of GSK2881078 over 14 days. The total duration
 of the study including screening and follow-up, is not expected to exceed 70 days.
Inclusion Criteria:

 -  Males between 18 and 50 years of age (inclusive), at the time of signing the informed
 consent form

 -  Body weight >= 50 kilogram (kg) and Body Mass Index (BMI) within the range 19 - 32
 kg/meter square (m^2) (inclusive), where BMI= weight in kg/ height in m^2

 -  Healthy as determined by a responsible and experienced physician, based on a medical
 evaluation including medical history, physical examination, laboratory tests and
 cardiac monitoring. A subject with a clinical abnormality or laboratory parameters
 outside the reference range for the population being studied may be included only if
 the Investigator and the GSK Medical Monitor agree that the finding is unlikely to
 introduce additional risk factors and will not interfere with the study procedures.

 -  Male subjects with female partners of child-bearing potential must agree to use one of
 the contraception methods listed in the Lifestyle Section of the protocol. This
 criterion must be followed through the completion of the follow-up visit.

 -  Average QTcF <450millisecond (msec); or QTcF <480msec in subjects with Bundle Branch
 Block.

 -  Capable of giving written informed consent, which includes compliance with the
 requirements and restrictions listed in the consent form.

 Exclusion Criteria:

 -  Subjects with a history of clinically significant endocrine, gastrointestinal,
 hepatic, cardiovascular, neurological, haematological, immunological, renal,
 respiratory, or genitourinary abnormalities or diseases.

 -  Subjects with a history at any time in the past of coronary artery disease, congestive
 heart failure, angina, myocardial infarction, any cardiac surgery, valvular heart
 disease, clinically significant arrhythmia, dyspnea, pulmonary edema, stroke, or
 transient ischemic attack. ECG exclusion criteria: Heart rate-<40 and >100 beats per
 minute, PR Interval-<120 and >200msec, QRS duration-<70 and >110msec.

 -  Subjects with a history of malignancy that is not in complete remission for at least 5
 years or 1 year for non-melanoma skin carcinoma

 -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
 (with the exception of Gilbert's syndrome or asymptomatic gallstones).

 -  History of drug or alcohol abuse within 5 years prior to the Screening Period.

 -  History of regular alcohol consumption within 6 months of the study defined as an
 average weekly intake of >14 drinks for males or >7 drinks for females. One drink is
 equivalent to 12 g of alcohol: 12 ounces (360 milliliter [mL]) of beer, 5 ounces (150
 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

 -  History of sensitivity to any of the study medications, or components thereof or a
 history of drug or other allergy that, in the opinion of the investigator or GSK
 Medical Monitor, contraindicates their participation.

 -  Subjects with a family history of early onset prostate cancer or multiple members with
 prostate cancer.

 -  A positive pre-study drug or alcohol screen.

 -  Cotinine levels indicative of smoking or history or regular use of tobacco- or
 nicotine-containing products within 6 months prior to screening.

 -  Subjects with values outside the specified ranges for the following Key Clinical
 Laboratory Tests must be excluded from the study:

 Liver function tests - Alanine aminotransferase, Direct Bilirubin, or Albumin more than 10%
 outside the normal reference range (<0.9 x lower limit of normal [LLN] or >1.1 x upper
 limit of normal [ULN]) Renal function - Creatinine >1.6milligrams (mg)/deciliter (dL) with
 an age appropriate glomerular filtration rate<=60 (mL/minute/1.73 m^2).

 Electrolytes - Sodium more than ± 5milliequivalents/Liter outside the normal reference
 range, Potassium or Calcium more than 10% outside the normal reference range (<0.9 x LLN or
 >1.1 x ULN) Metabolic - Glucose more than 10% outside the normal reference range (<0.9 x
 LLN or >1.1 x ULN) and Total Cholesterol > 240mg/dL Muscle - creatine phosphokinase >2.0 x
 ULN Hematology - Hemoglobin, white blood cells, Neutrophils, or Platelets more than 10%
 outside the normal reference range (<0.9 x LLN or >1.1 x ULN) Prostate Specific Antigen
 >2.5nanogram/mL

 -  A positive test for human immuno virus antibody

 -  A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
 result within 3 months of screening.

 -  Exposure to more than four new chemical entities within 12 months prior to the first
 dosing day

 -  Unable to refrain from prescription or non-prescription drugs, including vitamins,
 herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if
 the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to
 the first dose of study medication and throughout the study, unless in the opinion of
 the Investigator and GSK Medical Monitor the medication will not interfere with the
 study procedures or compromise subject safety.

 -  The subject has participated in a clinical trial and has received an investigational
 product within the following time period prior to the first dosing day in the current
 study: 3 months (12 weeks), 5 half-lives or twice the duration of the biological
 effect of the investigational product (whichever is longer).

 -  Where participation in the study would result in donation of blood or blood products
 in excess of 500mL within a 56-day period.

 -  Unable to refrain from consumption of red wine, seville oranges, grapefruit or
 grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit
 juices from 7 days prior to the first dose of study medication