A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK2849466 in Healthy Male Subjects

This study is the first administration of GSK2849466 in humans. This will be a single centre, randomized, double-blind, placebo-controlled study, to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GSK2849466, given as single and repeat oral doses up to 14 days to healthy male subjects. Part A will be a randomized placebo controlled and 4-way crossover study. It will include two cohorts of 8 subjects each. In each cohort there will be 4 study periods each approximately of 1 week including 6 days of washout. Each subject will receive a total of 3 active doses as ascending single oral dose of GSK2849466 and 1 placebo dose during the course of their participation in the study. The first ("bridging dose") dose provided to subjects in Cohort 2 will be the same as the last dose provided to subjects in Cohort 1. The single doses of GSK2849466 planned in Part A of this study are: 0.01, 0.03, 0.1, and 0.3 milligram (mg) in Cohort 1 and 0.3, 1, 3, and 10 mg in Cohort 2. In cohorts 1 and 2 all available safety, tolerability, and PK data will be reviewed prior to each dose escalation. The dosing schedule in Part A may be adjusted to expand a cohort or to add an additional cohort(s) in order to further evaluate additional doses or repeat evaluation of a dose level already studied. Part B will be a randomized placebo controlled, parallel group study. It will include three cohorts of 12 subjects each. Each subject will receive repeat doses of GSK2849466 over 14 days. The doses chosen for Part B will be based on the safety, tolerability, and PK data from Part A. Subjects in Cohort 4 (and/or an another cohort \[s\] as determined based on Part A PK data) will be dosed in the fasted state on Days 1 and 14 and in the fed state on Day 7 when subjects will receive a standard meal 30 minutes prior to dosing. Part B will provide sufficient safety and tolerability data to bridge to longer duration studies. The study duration, including screening and follow-up, is not expected to exceed 70 days for subjects in the study.


Eligibility Criteria:
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 (m)\^2 (inclusive), where BMI = (weight in kg)/(height in meters)\^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 GlaxoSmithKline (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.
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
* Average corrected QT interval using Fridericia's formulas (QTcF) \<450 milliseconds (msec); or QTcF \<480 msec in subjects with Bundle Branch Block.

Exclusion Criteria:

* Subjects with a history of clinically significant endocrine, gastrointestinal, hepatic, cardiovascular, neurological, hematological, 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 \>200 msec; QRS duration \<70 and \>110 msec.
* 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 grams (g) of alcohol: 12 ounces (360 millilitre \[mL\]) 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.
* 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 transaminase (ALT), Direct Bilirubin, or Albumin \>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 \<1.6 mg/ deciliter (dl) with an age appropriate Glomerular filtration rate (GFR) \>=60 mL/min/1.73 m\^2), Electrolytes - Sodium \> +,- 5 milliequivalents of solute per litre of solvent (mEq/L) outside the normal reference range, Potassium or Calcium \>10% outside the normal reference range (\<0.9 x LLN or \>1.1 x ULN), Metabolic - Glucose \>10% outside the normal reference range (\<0.9 x LLN or \>1.1 x ULN) and Total Cholesterol \>240 mg/dl, Muscle - creatine phosphokinase \>2.0 x ULN, Hematology - Hemoglobin, WBC, Neutrophils, or Platelets \>10% outside the normal reference range (\<0.9 x LLN or \>1.1 x ULN), Prostate Specific Antigen (PSA) \>=2.5 nanogram (ng)/mL.
* A positive test for human immunodeficiency virus (HIV) 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 500 mL within a 56-day period.
* Unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication.
* Unwillingness or inability to follow the procedures outlined in the protocol