Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Rare Diseases

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Kennedy Disease

All Drugs and Chemicals

Anti-Inflammatory Agents

Antineoplastic Agents

Androgens

Prednisone

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

GSK525762

Abiraterone

Enzalutamide

Prednisone will be administered as a concomitant medication in combination with abiraterone

GSK Clinical Trials

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).

This will be a two-arm, open-label dose escalation and dose expansion cohort study.

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

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)

IPD for this study will be made available via the Clinical Study Data Request site.

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 any AEs and SAEs collected from start of the treatment until end of the study were reported.

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 from start of the treatment until end of the study were reported.

Number of participants who withdrew due to toxicity and changes in safety assessment including laboratory parameters and vital signs from start of the treatment until end of the study were reported.

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.

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 including laboratory parameters and vital signs have been presented.

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.

Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK525762 and GSK3529246 (metabolite of GSK525762). PK parameters were calculated using standard non-compartmental analysis. PK Population consisted of all participants from the All Treated Safety Population for whom a PK sample was obtained and analyzed.

Blood samples were collected at indicated time points for PK analysis of GSK525762 and GSK3529246 (metabolite of GSK525762). PK parameters were calculated using standard non-compartmental analysis.

Blood samples were collected at indicated time points for PK analysis of abiraterone. PK parameters were calculated using standard non-compartmental analysis.

Blood samples were collected at indicated time points for PK analysis of enzalutamide. PK parameters were calculated using standard non-compartmental analysis.

Disease control rate (DCR) is defined as the percentage of participants with \>=1 post-Baseline disease assessment who showed either a confirmed complete response (CR), partial response (PR) or stable disease (SD) observed at \>=24 weeks per prostate cancer working group 3 (PCWG3)-modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; where CR: disappearance of all target lesions. Any pathological lymph nodes must be \<10 millimeter in the short axis; PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive diseases. Confidence interval (CI) was computed using exact two sided 95% CI.

Composite response rate was defined as the percentage of participants with one of the following: a) Response based on PCWG3-modified RECIST version 1.1, b) PSA decrease of \>=50% from Baseline at Week 12 and thereafter, or c) Circulating Tumor-cell Count Conversion from unfavorable (\>=5/7.5 milliliter \[mL\]) at Baseline to favorable (\<5/7.5 mL) confirmed by a second assessment at least 4 weeks later. If a participant met at least one of the above requirements, then that participant was considered a composite responder. CI was computed using exact two sided 95% CI.

Objective response rate (ORR) is defined as the percentage of participants with a confirmed CR or PR at any time as per PCWG3-modified RECIST version 1.1; where CR: Disappearance of all target lesions. Any pathological lymph nodes must be \<10 millimeter (mm) in the short axis and PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters.

CTC response rate is defined as the percentage of participants with a CTC conversion to \<5/7.5 mL blood at nadir (confirmed by a second consecutive value obtained four or more weeks later) for participants with unfavourable CTC (\>=5/7.5 mL) at Baseline. CI was computed using exact two sided 95% CI.

PSA Response Rate is defined as percentage of participants achieving \>=30% decrease from Baseline PSA after 4 weeks of study treatment. The CI was calculated using exact two sided 95% CI for the percentage of participants with Baseline PSA values who show \>=30% reduction in PSA at \>=4 weeks post-Baseline.

Time to disease progression is defined as the time from date of first dose of study treatment to date of disease progression defined as one or more of the following criteria: 1. Radiographic progression by PCWG3-modified RECIST version 1.1 for participants with measurable disease, 2. Bone progression on bone scan according to the PCGW3 criteria, 3. PSA progression according to the PCWG3 criteria accompanied by any one of the following: investigator-defined clinical progression or either of the above RECIST version 1.1 radiographic progression or bone progression.

rPFS is defined as the time from study treatment start until the first date of either disease progression or death due to any cause. The date of disease progression is defined as the earliest date of disease progression as assessed by the investigator using PCWG3-modified RECIST, version 1.1 or progression on bone scan. Progressive disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started.

Performance status assessments were based on 6-point ECOG scale (from 0 to 5), where 0=fully active, able to carry on all pre-disease performance without restriction; 1=restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light house work, office work); 2=ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours; 3=capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=completely disabled, cannot carry on any self-care, totally confined to bed or chair; and 5=dead. Data for worst case post-Baseline is presented.

EORTC QLQ-C30 includes 30-items with single and multi-item scales. These included 5 functional scales (physical functioning, role functioning, cognitive functioning, emotional functioning and social functioning), 3 symptom scales (fatigue, pain and nausea/vomiting), a GHS/ Quality-of-Life (QoL) scale, and six single items (constipation, diarrhea, insomnia, dyspnea, appetite loss and financial difficulties). Response options for GHS/QoL range from 1 to 4, where 1=not at all and 4=very much. Scores were averaged and transformed to a 0 to 100 scale, with higher scores representing a high QoL. Baseline is defined as the latest non-missing assessment time-point prior to the first study treatment dose. Change from Baseline was calculated as post-Baseline visit value minus Baseline value.

BPI-SF is 9-item self-administered questionnaire. Pain intensity score was calculated from the four items (items 3, 4, 5 and 6) for worst pain, least pain, average pain and current pain. Worst pain in last 24 hours was rated from 0 (no pain) to 10 (pain as bad as you can imagine). Baseline is defined as the latest non-missing assessment time-point prior to the first study treatment dose (latest up to Week 1 Day 1). Change from Baseline was calculated as post-Baseline visit value minus Baseline value.

GlaxoSmithKline

All-cause mortality, non-SAES and SAEs were assessed using All Treated Population which consisted of all participants who received at least one dose of GSK525762 or abiraterone or enzalutamide.

Participants received once daily oral dose of GSK525762 60 milligram (mg) in combination with abiraterone 1000 mg up to maximum of 21.3 months. Participants received prednisone 5 mg orally twice daily as per abiraterone label.

GSK525762 60 mg+Abiraterone 1000 mg

Participants received an alternate dosing schedule- once daily GSK525762 60 mg + abiraterone 1000 mg tablets via the oral route for 2 weeks followed by 1 week off-treatment up to maximum of 21.3 months. Participants received prednisone 5 mg orally twice daily as per abiraterone label.

GSK525762 60 mg Alternate+Abiraterone 1000 mg

Participants received once daily oral dose of GSK525762 40 mg in combination with abiraterone 1000 mg up to maximum of 21.3 months. Participants received prednisone 5 mg orally twice daily as per abiraterone label.

GSK525762 40 mg+Abiraterone 1000 mg

Participants received once daily oral dose of GSK525762 80 mg in combination with enzalutamide 160 mg up to maximum of 21.3 months.

GSK525762 80 mg+Enzalutamide 160 mg

Participants received once daily oral dose of GSK525762 60 mg in combination with enzalutamide 160 mg up to maximum of 21.3 months.

GSK525762 60 mg+Enzalutamide 160 mg

Participants received an alternate dosing schedule- once daily GSK525762 60 mg + enzalutamide 160 mg tablets via the oral route for 2 weeks followed by 1 week off-treatment up to maximum of 21.3 months.

GSK525762 60 mg Alternate+Enzalutamide 160 mg

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

GSK Response Center

Any AEs

Any SAEs

All Treated Population consisted of all participants who received at least one dose of GSK525762 or abiraterone or enzalutamide.

Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)

Dose reduction

Dose delay

Number of Participants With AEs Leading to Any Dose Reduction or Delays

Number of Participants Who Withdrew Due to Toxicity and Changes in Safety Assessment

Modified All Treated Population comprised of all participants who received at least one dose of GSK525762 plus abiraterone/enzalutamide. Only those participants with data available at the indicated time points were analyzed.

Percentage of Participants With Greater Than or Equals to (>=)50 Percent (%) Decrease in Prostate-specific Antigen From Baseline (PSA50)

GSK525762:Week1 Day1,n=10,6,4,10,21,18

GSK525762:Week3 Day1,n=4,3,3,9,17,10

GSK3529246:Week1 Day1,n=10,6,4,10,21,18

GSK3529246:Week3 Day1,n=4,3,3,10,17,10

PK Population. Only those participants with data available at the indicated time points were analyzed (indicated by n=X in category titles).

Maximum Observed Plasma Concentration (Cmax) of GSK525762 and Its Active Metabolites GSK3529246

Time to Cmax (Tmax) of GSK525762 and Its Active Metabolites GSK3529246

GSK525762:Week1 Day1,n=8,2,2,6,9,8

GSK525762:Week3 Day1,n=4,1,3,5,6,6

GSK3529246:Week1 Day1,n=2,1,0,5,9,10

GSK3529246:Week3 Day1,n=2,2,2,4,12,7

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

GSK525762:Week1 Day1,n=8,2,3,1,3,4

GSK525762:Week3 Day1,n=2,2,2,1,0,0

GSK3529246:Week1 Day1,n=8,3,3,9,20,17

GSK3529246:Week3 Day1,n=3,3,2,7,13,8

Trough Concentration (Ctrough) of GSK525762 and Its Active Metabolites GSK3529246

Week 1 Day 1, n=10,5,4

Week 3 Day 1, n=4,4,2

Cmax of Abiraterone

Tmax of Abiraterone

Week 1 Day 1, n=5,1,1

Week 3 Day 1, n=1,2,1

AUC(0-tau) of Abiraterone

Week 1 Day 1, n=9,2,3

Week 3 Day 1, n=2,4,1

Ctrough of Abiraterone

PK Population. Cmax could not be derived as only pre-dose samples were collected.

Cmax of Enzalutamide

PK Population. Tmax could not be derived as only pre-dose samples were collected.

Tmax of Enzalutamide

PK Population. AUC(0-tau) could not be derived as only pre-dose samples were collected.

AUC(0-tau) of Enzalutamide

Week 1 Day 1, Pre-dose, n=9,20,18

Week 3 Day 1, Pre-dose, n=9,19,13

Week 5 Day 1, Pre-dose, n=10,15,18

Week 9 Day 1, Pre-dose, n=6,6,13

Week 17 Day 1, Pre-dose, n=4,2,4

Week 25 Day 1, Pre-dose, n=2,2,2

Ctrough of Enzalutamide

Modified All Treated Population. Only those participants with data available at the indicated time points were analyzed.

Disease Control Rate at Week 24

Composite Response Rate

Objective Response Rate

Modified All Treated Population. Only those participants with data available at the indicated time points were analyzed. For GSK525762 40 mg+Abiraterone 1000 mg arm, there were no unfavorable values at Baseline, hence CTC response rate (change from unfavorable to favorable) could not be derived for this arm.

Circulating Tumor Cells (CTC) Response Rate

Prostate-specific Antigen (PSA) Response Rate at Week 4

Time to Disease Progression

Radiographic Progression-free Survival (rPFS)

All Treated Population. Only those participants with data available at the indicated time points were analyzed.

Number of Participants With Worst-Case Post Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status

Week 1 Day 1,n=1,0,0,0,2,0

Week 2 Day 1,n=6,1,2,4,4,8

Week 3 Day 1,n=6,0,1,4,3,7

Week 4 Day 1,n=6,1,2,3,6,10

Week 5 Day 1,n=3,0,1,3,5,9

Week 9 Day 1,n=2,0,1,2,3,6

Week 13 Day 1,n=1,1,1,1,2,3

Week 17 Day 1,n=1,1,1,1,1,3

Week 21 Day 1,n=0,0,1,1,0,2

Week 25 Day 1,n=0,0,1,0,0,1

Week 29 Day 1,n=0,0,0,0,0,2

Week 33 Day 1,n=0,0,1,0,1,2

Week 37 Day 1,n=0,0,1,0,0,3

Week 41 Day 1,n=0,0,1,0,0,0

Week 45 Day 1,n=0,0,1,0,0,1

Week 49 Day 1,n=0,0,1,0,0,2

Week 61 Day 1,n=0,0,1,0,0,1

Modified All Treated Population. Only those participants with data available at the indicated time points were analyzed (indicated by n=X in category titles).

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)

Spots Global Cancer Trial Database for Dose Escalation and Dose Expansion Study of GSK525762 in Combination With Androgen Deprivation Therapy in Participants With Castrate-resistant Prostate Cancer

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

Useful links and downloads for this trial