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) (GSK 204697).
Johns Hopkins Kimmel Cancer Center in Baltimore
This research is being done to evaluate the safety and effects of the study drug GSK525762 when taken with either abiraterone + prednisone or with enzalutamide, drugs that are options for standard treatmentfor mCRPC, and to figure out the highest dose of GSK525762 that can be used in future studies that include these combinations of drugs. The study drug targets a class of proteins known as BET (called bromodomain extra terminal) that are important for cell growth. Successful targeting may decrease the growth of cancer cells. The main goal of the study is to determine the highest dose of GSK525762 in combination with abiraterone + prednisone or enzalutamide that can be given safely and with the least harmful side effects. We also want to know how the body handles the drugs when GSK525762 and abiraterone + prednisone or GSK525762 and enzalutamide are given together and what effect GSK525762 and abiraterone + prednisone or enzalutamide have on each other in the body.
Males subjects must be 18 years of age (at the time written consent is obtained for screening) with histologically confirmed adenocarcinoma of the prostate and have surgically or medically castrated disease, with testosterone levels of ??50 ng/dL ( less than 2.0 nM). Subjects must have failed prior therapy with abiraterone, enzalutamide, or both and must have completed at least 12 weeks of prior continuous therapy with abiraterone or enzalutamide, or both. Patients should have documented prostate cancer progression and must also havean Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and have a life expectancy greater than 12 weeks. Patients should have the ability to be able to swallow and retain orally administered medication. Patients should also have adequate organ function. Subjects with neuroendocrine and/or small cell CRPC, 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 will be ineligible for the study. Subjects with a systolic blood pressure higher than 150 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 and subjects will be excluded. Also, 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 will be an exclusion criteria. Subjects with history of known bleeding disorder(s) or history of clinically significant hemorrhage (e.g., GI, neurologic), within the past 6 months will NOT be eligible for the study. Subjects with known bleeding diathesis will also be excluded from the study. Subjects with gastrointestinal disorders likely to interfere with absorption of the study medication, history of loss of consciousness or transient ischemic attack within 12 months prior to enrollment or subjects who have experienced a seizure or seizures within 6 months of study treatment will be excluded.
There will be 2 arms to this study - Arm A & Arm B. Enrollment to Arm A or Arm B will depend on the patient's most recent treatment. If the most recent treatment before enrollment to the study was abiraterone, then the patient will be enrolled on Arm A. Alternatively, if the most recent treatment before enrollment to the study was enzalutimide, then the patient will be enrolled to Arm B. Patients on Arm A will receive GSK525762 in combination with abiraterone + prednisone while patients on Arm B will be treated with GSK525762 in combination with enzalutimide. There will be 2 parts to the study: Dose Escalation & Dose Expansion. During dose escalation on Arm A, a small number of about 3 to 10 subjects will receive the first dose level (DL60), which includes 60 mg of GSK525762, taken with abiraterone. In addition, prednisone will be given. If DL60 (60mg) is shown to be tolerated without serious side effects, a small number of about 6 to 10 subjects will be enrolled to start a second, higher dose level of GSK525762(study drug), taken with abiraterone + prednisone. This dose level is planned to be 80 mg of GSK525762 (study drug), taken with abiraterone + prednisone.However, if DL60 is not tolerated, a lower dose level of 40 mg GSK525762(study drug), taken with abiraterone + prednisone, will be given. For the dose expansion phase, granted the patients enrolled on the 80mg dose (DL80),in the dose escalation phase,overall tolerated that dose level well, patients will be randomized to either 60DL (60mg) or 80DL (80mg). For Arm B, during the dose escalation phase, 3-10 patients will receive GSK525762(study drug)at a starting dose of 80mg (DL80).If DL80 is shown to be tolerated without serious side effects, a small number of about 3 to 10 subjects will be enrolled to start a second, higher dose level of GSK525762(study drug)DL100 (100mg), taken with enzalutimide. If DL80 is not tolerated, a lower dose, DL60 (60mg) of GSK525762(study drug), will be taken with enzalutimide. Depending on information obtained after patients enrollment on DL80 and DL100, DL120 (120mg of GSK525762 - study drug) may be opened. Once all patients enrolled on DL100 or DL120 are noted to have tolerated the study drug well with minimal or no side effects, the dose expansion phase of Arm B will be open at the selected higher dose of either DL100 or DL120 and the lower dose of DL80. Patients will be randomized to either higher dose - DL100/DL120 or the lower dose DL80mg
03/05/2019 05:03 AM