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)
Overview
- Phase
- Phase 1
- Intervention
- GSK525762
- Conditions
- Solid Tumours
- Sponsor
- GlaxoSmithKline
- Enrollment
- 73
- Locations
- 1
- Primary Endpoint
- Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
- Status
- Terminated
- Last Updated
- 3 years ago
Overview
Brief Summary
This 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 (m)CRPC. 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).
Investigators
Eligibility 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 participant had a recent biopsy after failure of the most recent 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 less than or equal to (\<=)50 nanograms per deciliter (ng/dL) (\<2.0 nanometer \[nM\]). If the participant is being treated with luteinizing hormone-releasing hormone (LHRH) agonists/antagonists (participant who have not undergone orchiectomy) this therapy must have been initiated at least 4 weeks prior to Week 1 Day 1 and must be continued throughout the study.
- •Participants must have failed prior therapy with abiraterone, enzalutamide, or both:
- •Has completed at least 12 weeks of prior continuous therapy with abiraterone or enzalutamide in any prior line.
- •Lead-in dosing period for enzalutamide only will be required under the following circumstance:
- •(i) If the participant 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.
- •(ii) If the participant has enzalutamide discontinuation for \<=7 days prior to dosing start with GSK525762 plus enzalutamide on trial, then an enzalutamide only lead-in dosing of 14 days is required.
- •(iii) If the participant is on continuous dosing with enzalutamide prior to dosing start with GSK525762 plus enzalutamide on trial, then participant can start on combined dosing at end of screening period.
Exclusion Criteria
- •Surgery or local prostatic intervention (excluding a prostatic biopsy) less than 28 days of Week 1 Day
- •Participants with neuroendocrine and/or small cell CRPC.
- •Recent prior therapy, defined as:
- •Any investigational or approved non-biologic anti-cancer drug within 14 days prior to the first dose of GSK525762 and abiraterone/enzalutamide.
- •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 participant received radiotherapy \<90 days prior to study treatment, the irradiated lesion cannot be the only lesion used for evaluating response.
- •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 participant'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:
Arms & Interventions
GSK525762 + Abiraterone (+ Prednisone) (Arm A)
Intervention: GSK525762
GSK525762 + Abiraterone (+ Prednisone) (Arm A)
Intervention: Abiraterone
GSK525762 + Abiraterone (+ Prednisone) (Arm A)
Intervention: Prednisone
GSK525762 + Enzalutamide (Arm B)
Intervention: GSK525762
GSK525762 + Enzalutamide (Arm B)
Intervention: Enzalutamide
Outcomes
Primary Outcomes
Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame: Up to 21.3 months
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, any other situation according to medical or scientific judgement, or is associated with liver injury and impaired liver function.
Number of Participants With AEs Leading to Any Dose Reduction or Delays
Time Frame: Up to 21.3 months
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Number of participants with AEs leading to any dose reduction or delays have been presented.
Number of Participants Who Withdrew Due to Toxicity and Changes in Safety Assessment
Time Frame: Up to 21.3 months
Number of participants who withdrew due to toxicity and changes in safety assessment including laboratory parameters and vital signs have been presented.
Percentage of Participants With Greater Than or Equals to (>=)50 Percent (%) Decrease in Prostate-specific Antigen From Baseline (PSA50)
Time Frame: Up to 21.3 months
PSA50 response rate is defined as percentage of participants with a decrease of \>=50% in the PSA concentration from the Baseline PSA value determined at least 12 weeks after start of treatment and confirmed \>=4 weeks later by an additional PSA evaluation.
Secondary Outcomes
- Cmax of Abiraterone(Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3)
- Tmax of Enzalutamide(Pre-dose on Day 1 of Weeks 1, 3, 5, 9, 17 and 25)
- Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUC[0-tau]) of GSK525762 and Its Active Metabolites GSK3529246(Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3)
- Trough Concentration (Ctrough) of GSK525762 and Its Active Metabolites GSK3529246(Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3)
- Time to Cmax (Tmax) of GSK525762 and Its Active Metabolites GSK3529246(Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3)
- Tmax of Abiraterone(Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3)
- AUC(0-tau) of Enzalutamide(Pre-dose on Day 1 of Weeks 1, 3, 5, 9, 17 and 25)
- Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30): Global Health Status (GHS)(Baseline (Week 1 Day 1, pre-dose) and on Day 1 of Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 61)
- Cmax of Enzalutamide(Pre-dose on Day 1 of Weeks 1, 3, 5, 9, 17 and 25)
- Maximum Observed Plasma Concentration (Cmax) of GSK525762 and Its Active Metabolites GSK3529246(Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3)
- AUC(0-tau) of Abiraterone(Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3)
- Ctrough of Abiraterone(Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3)
- Disease Control Rate at Week 24(Week 24)
- Composite Response Rate(Up to 21.3 months)
- Objective Response Rate(Up to 21.3 months)
- Radiographic Progression-free Survival (rPFS)(Up to 21.3 montths)
- Number of Participants With Worst-Case Post Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status(Up to 21.3 months)
- Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF): Pain Intensity- Pain at Worst in Last 24 Hours(Baseline (Pre-dose on Week 1 Day 1) and on Day 1 of Weeks 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 61, 73, 85, 97)
- Ctrough of Enzalutamide(Pre-dose on Day 1 of Weeks 1, 3, 5, 9, 17 and 25)
- Circulating Tumor Cells (CTC) Response Rate(Up to 21.3 months)
- Prostate-specific Antigen (PSA) Response Rate at Week 4(Week 4)
- Time to Disease Progression(Up to 21.3 months)