Dose Escalation and Dose Expansion Study of GSK525762 in Combination With Androgen Deprivation Therapy and Other Agents in Subjects With Castrate-resistant Prostate Cancer

Inclusion Criteria

- Written informed consent provided

- Males >=18 years of age (at the time written consent is obtained for screening)

- Histologically confirmed adenocarcinoma of the prostate: screening and on-treatment
biopsy is mandatory. If adequate number of paired biopsy samples are collected (>=20
paired samples for each dose level in each Arm, unless an Arm is closed early), then
further biopsy sampling will be considered based on available data; screening biopsy
can be waived if patient had a recent biopsy after failure of ADT therapy (within 30
days) and the biopsy sample is secured to be sent as screening biopsy for this study.

- Surgically or medically castrated, with testosterone levels of <=50 nanograms per
deciliter (ng/dL) (<2.0 nanometer [nM]). If the patient is being treated with
luteinizing hormone-releasing hormone (LHRH) agonists/antagonists (patient who have
not undergone orchiectomy) this therapy must have been initiated at least 4 weeks
prior to Cycle 1 Day 1 and must be continued throughout the study.

- Subjects must have failed prior therapy with abiraterone, enzalutamide, or both: has
completed at least 12 weeks of prior continuous therapy with abiraterone or
enzalutamide; has not been without abiraterone or enzalutamide treatment for >30 days
prior to initiation of study treatment; lead-in dosing period for enzalutamide only
will be required under the following circumstance:

1. If the subject has enzalutamide discontinuation for >7 days prior to dosing start
with GSK525762 plus enzalutamide on trial, then a enzalutamide only lead-in
dosing of 28 days is required

2. If the subject has enzalutamide discontinuation for <=7 days prior to dosing
start with GSK525762 plus enzalutamide on trial, then a enzalutamide only lead-in
dosing of 14 days is required

3. If the subject is on continuous dosing with enzalutamide prior to dosing start
with GSK525762 plus enzalutamide on trial, then subject can start on combined
dosing at end of screening period; Lead-in dosing period for abiraterone only
will be required: if the subject has abiraterone discontinuation for more than 3
days prior to dosing start with GSK525762 plus abiraterone on trial, then
abiraterone only lead-in dosing of 7 days is required.

- One to two line(s) of prior taxane-based chemotherapy allowed. If docetaxel
chemotherapy is used more than once, this will be considered as one regimen.

- Documented prostate cancer progression as assessed by the investigator with one of the
following: PSA progression defined by a minimum of 3 rising PSA levels with an
interval of >=1 week between each determination. The PSA value at screening must be
>=5 microgram (µg)/L (5 ng/mL) if PSA is the only indication of progression; subjects
on systemic glucocorticoids for control of symptoms must have documented PSA
progression by PCWG3 while on systemic glucocorticoids prior to commencing Cycle 1 Day
1 treatment.

- Radiographic progression of soft tissue disease by PCWG3-modified RECIST 1.1 criteria
or bone metastasis with 2 or more documented new bone lesions on a bone scan with or
without PSA progression

- Eastern Cooperative Oncology Group performance status of 0 or 1

- Life expectancy >12 weeks

- Able to swallow and retain orally administered medication

- Must have adequate organ function as defined by the following values: white blood
cells >3 x 10^9/liter(L); absolute neutrophil count (ANC) >= 1.5 x 10^9/L; hemoglobin
>= 9 grams per decilitre (g/dL) subjects that required transfusion or growth factor
need to demonstrate stable hemoglobin for 7 days of 9 g/dL; platelets >=100 x 10^9/L;
prothrombin time (PT)/International normalized ration (INR) and partial thromboplastin
time (PTT) <= 1.5 x upper limit of normal (ULN); albumin >=2.5 g/dL; total bilirubin
<=1.5 x ULN; aspartate transaminase (AST) <=2.5 x ULN; alanine transaminase (ALT)
<=2.5 x ULN OR <5 x ULN; creatinine <=1.5 x ULN is acceptable for subjects with
documented liver metastases/tumor infiltration; creatinine clearance >= 50 mL/min;
ejection fraction>= lower limit of normal (LLN) by echocardiogram or multigated
acquisition (MUGA) and minimum of 50% left ventricular ejection fraction (LVEF);
testosterone <=50 nanograms per deciliter (ng/dL)

- Male subject with a female partner of childbearing potential or pregnant must agree to
use two acceptable methods of contraception from time of first dose of study treatment
until 4 months after the last dose of study treatments

Exclusion Criteria

- Surgery or local prostatic intervention (excluding a prostatic biopsy) less than 28
days of Cycle 1 Day 1.

- Subjects with neuroendocrine and/or small cell CRPC

- Recent prior therapy, defined as: Any investigational or approved non-biologic
anti-cancer drug (see exception below) within 14 days prior to the first dose of
GSK525762 and abiraterone/enzalutamide. Exception: For allowed androgen deprivation
therapy (hormonal, abiraterone, enzalutamide. Concomitant prednisone (or equivalent)
allowed in combination with abiraterone dosing, any nitrosoureas or mitomycin C within
42 days prior to the first dose of GSK525762 and abiraterone/enzalutamide, any
anti-cancer biologic agents within five half-lives prior to the first dose of
GSK525762 and abiraterone/enzalutamide, if the subject received radiotherapy <90 days
prior to study treatment, the irradiated lesion cannot be the only lesion used for
evaluating response. Exception: Any radiotherapy within 14 days prior to the first
dose of GSK525762 and abiraterone/enzalutamide must be limited to a single fraction of
radiotherapy for the purpose of palliation (confined to one field) is permitted, any
major surgery within 28 days prior to the first dose of GSK525762 and
abiraterone/enzalutamide

- 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),
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; systolic blood pressure higher than 150 millimeter of mercury (mmHg)
or diastolic blood pressure higher than 90 mmHg found on 2 separate occasions
separated by 1 week, despite adequate therapy, will be defined as uncontrolled
hypertension; uncontrolled diabetes mellitus (despite therapeutic, compliance
intervention) as defined by a hemoglobin A1c (HbA1c) level more than 8% and/or
occurrence of more than 2 episodes of ketoacidosis in the 12 months prior to the first
dose of study drug.

- Cardiac abnormalities as evidenced by any of the following: Baseline QT interval
corrected for heart rate by Fridericia's formula (QTcF) interval >=450 milliseconds
(msec), clinically significant conduction abnormalities or arrhythmias, such as
subjects with second degree (Type II) or third degree atrio-ventricular block, 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.
Subjects with a history of stent placement requiring ongoing anti-coagulant therapy
(e.g., clopidogrel, prasugrel) will not be permitted to enroll, known cardiac
metastasis.

- Subjects with history of known bleeding disorder(s) or history of clinically
significant hemorrhage (e.g., gastrointestinal , neurologic), within the past 6
months.

- Therapeutic-dose anticoagulation (e.g., warfarin, low-molecular weight heparin [LMWH],
or novel oral anticoagulants) must be discontinued and coagulation parameters must be
normalized prior to the first dose of abiraterone/enzalutimide. Prophylactic
anticoagulation, with low doses (per standard practice) of agents such as low
molecular weight heparin (LMWH), direct thrombin inhibitors, or factor Xa inhibitors
is permitted.

- Concurrent use of high dose aspirin (doses up to 81 mg oral dose daily allowed) and
non-steroidal anti-inflammatory drugs (NSAIDS), except for where NSAIDs provide
documented benefit over other analgesics, and then to be used with caution including
concomitant use of proton pump inhibitors).

- Any acute toxicities due to prior chemotherapy and / or radiotherapy that have not
resolved to a Common Terminology Criteria for Adverse Events version 4.0 grade <=1
with the exception of chemotherapy induced alopecia and grade 2 peripheral neuropathy.

- The patient has an active second malignancy other than curatively resected basal cell
or squamous cell carcinoma of the skin, in situ carcinoma of the bladder, or other
cancers for which they are treated with curative intent with no active disease in the
3 years prior to enrollment.

- Subjects with known symptomatic brain metastasis are not suitable for enrolment.
Subjects with asymptomatic, stable, treated brain metastases are eligible for study
entry.

- History of seizure or any condition that may predispose subject to seizure (e.g.,
prior cortical stroke or significant brain trauma).

- History of loss of consciousness or transient ischemic attack within 12 months prior
to enrollment

- Subjects with symptomatic or impending cord compression unless appropriately treated
beforehand and clinically stable and asymptomatic.

- Subjects who have experienced a seizure or seizures within 6 months of study treatment
or who are currently being treated with cytochrome P450 enzyme inducing anti-epileptic
drugs for seizures (use of anti-epileptic drugs to control pain is allowed in subjects
not suffering from seizures unless drug is excluded due to Cytochrome P450 3A4
induction - phenytoin, carbamazepine, Phenobarbital.

- Current use of a prohibited medication or planned use of any forbidden medications
during treatment with GSK525762 and abiraterone/enzalutamide. This includes
medications with significant risk of Torsades de pointes as well as those that are
potent inducers or inhibitors of CYP3A4 enzymes or strong inhibitors of CYP2C8.

- Subjects with gastrointestinal disorders likely to interfere with absorption of the
study medication.

- Subjects with known bleeding diathesis will be excluded from the study.

- Current active liver or biliary disease (with the exception of Gilbert's syndrome or
asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease
per investigator assessment).

- Initiating bisphosphonate or denosumab therapy or adjusting dose/regimen within 3
months prior to Cycle 1 Day 1. Subjects on a stable bisphosphonate or denosumab
therapy are eligible and may continue.

- Any serious known immediate or delayed hypersensitivity reaction to GSK525762 or
idiosyncrasy to drugs chemically related to the investigational drugs. Additionally,
any known hypersensitivity to either enzalutamide, abiraterone or any excipients would
be excluded.

- Known history of human immunodeficiency virus (HIV)

- Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test
result at screening. Subjects with positive hepatitis C antibody due to prior resolved
disease can be enrolled only if a confirmatory negative hepatitis C ribonucleic acid
polymerase chain reaction is obtained.