A Phase IB Open-label, Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK525762 in Combination With Androgen Deprivation Therapy and Other Agents in Subjects With Castrate-resistant Prostate Cancer (CRPC)
DescriptionThe study aims to evaluate the combination of GSK525762 with other agents that have been shown to be effective in the treatment of CRPC or metastatic CRPC, including approved agents (e.g., abiraterone, enzalutamide) as well as investigational agents for mCRPC that have proven to show efficacy and can be combined based on complimentary mechanism of action. As a first step, the combination of GSK525762 will be evaluated as a combination with abiraterone or enzalutamide in men with metastatic or advanced castrate-resistant prostate cancer who have progressed on at least one line of prior androgen receptor (AR)-targeted therapy. This study is designed to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) based on safety, tolerability, pharmacokinetic, and efficacy profiles of GSK525762 in combination with either abiraterone (Arm A) or enzalutamide (Arm B). Arm A and Arm B will further have 2 cohorts: A1, A2 and B1, B2 respectively based on prior lines of therapy (L2 [chemo-naive subjects treated with a second androgen-deprivation therapy] and Lx [subjects treated with both prior androgen-deprivation therapy and chemotherapy]). During dose escalation, both the treatment arms (A and B) will follow a modified Toxicity Probability Interval (mTPI) design. Approximately 130 subjects will be enrolled worldwide in this study. Subjects from both dose escalation and dose expansion may be combined to reach 30 subjects. The total duration of study will be approximately 2 to 3 years. A subject will be considered to have completed the study if they are followed until death.
Inclusion and Exclusion Criteria
- 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:
- 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
- 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
- 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
- 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.
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