GSK2269557 is potent and highly selective inhaled phosphoinositides 3-kinases -delta (PI3K-delta) inhibitor being developed as an anti-inflammatory agent for the treatment of inflammatory airway diseases. GSK2269557 has already been administered as a nebulized solution in single and repeat doses to humans and has been well tolerated across the range of doses used. The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of single and repeat inhaled doses of GSK2269557 as a dry powder. This study is the first administration of dry powder GSK2269557 in humans.

Part A will consist of four treatment periods separated by at least 14 days wash out periods. In each treatment period there will be 12 subjects receiving GSK2269557 and 4 subjects receiving placebo. The doses of GSK2269557 planned for Part A are 100 micrograms (mcg), 500 mcg and 3000 mcg. Blinded safety and available pharmacokinetic (PK) data will be reviewed before each dose escalation. Part B will be a parallel group design conducted in a separate group of subjects from Part A. Nine subjects will receive repeat doses of GSK2269557 and 3 subjects will receive repeat doses of placebo for 14 days. The total daily dose will be the same as the dose that was well tolerated in Part A. The study duration, including screening and follow-up, is not expected to exceed 82 days for subjects in part A and 55 days for subjects in part B of the study.

Inclusion Criteria:

• Subjects who are current daily cigarette smokers. Must have smoked regularly in the 12-month period preceding the screening visit and have a pack history of >= 5 pack years (number of pack years = number of cigarettes per day/20 x number of years smoked
• Normal spirometry (FEV1 >= 80% of predicted) at screening.
• Single QTcF < 450 milliseconds (msec); or QTcF< 480 msec in subjects with Right Bundle Branch Block
• Currently healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac testing. A subject with a clinical abnormality or laboratory parameters outside the reference range expected for them and the population being studied may be included only if the Investigator believes that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures or outcomes
• Between 18 and 50 years of age inclusive, at the time of signing the informed consent
• A female subject is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented hysterectomy, bilateral oophorectomy or bilateral salpingectomy or postmenopausal defined as 12 months of spontaneous amenorrhea. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods f they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method
• Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods.
• Body weight >= 50 kilogram (kg) and body mass index (BMI) within the range 18 to 31 kg/meter^2 (inclusive).
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

Exclusion Criteria:

• Subjects who are unable to produce a total weight of at least 0.100 grams (g) of selected sputum at screening
• Subjects whose primary consumption of tobacco is via methods other than cigarettes (manufactured or self-rolled). Primary methods of tobacco consumption that are excluded include, but are not limited to pipes and cigars
• Urinary cotinine levels at screening < 30 nanograms (ng)/mL
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
• A history of congestive heart failure, coronary insufficiency or clinically significant cardiac arrhythmia that would contraindicate the subject's participation in the study
• A positive pre-study drug/alcohol screen
• A positive test for HIV antibody
• History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint ( approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits
• 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: 90 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer)
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day
• Unable to refrain from the use of prescription or non-prescription drugs (except simple analgesics), including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GlaxoSmithKline (GSK) Medical Monitor the medication will not interfere with the study procedures or compromise subject safety
• The subject has received any type of vaccination within 4 weeks of their first dose of investigational product, or are expected to be vaccinated within 4 weeks after their last dose of investigational product
• 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
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 90 day period
• Unwillingness or inability to follow the procedures outlined in the protocol
• Subject is mentally or legally incapacitated
• Subjects who have asthma or a history of asthma (except in childhood and which has now remitted)
• Unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids from 7 days prior to the first and subsequent doses of study medication and until collection of the last PK sample for that study period

Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.