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

NCT03150056 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 2046972016-003416-13
• Study Type: interventional
• Target: 73
• Locations: 4 countries
• Sites: 20

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).

Conditions

Solid Tumours

Keywords

Abiraterone; Castrate-resistant prostate cancer; Androgen receptor targeted therapy; RP2D; Enzalutamide; GSK525762

Outcome Measures

Primary Outcomes (4)

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

  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.

  Up to 21.3 months

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

  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.

  Up to 21.3 months

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

  Number of participants who withdrew due to toxicity and changes in safety assessment including laboratory parameters and vital signs have been presented.

  Up to 21.3 months

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

  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.

  Up to 21.3 months

Secondary Outcomes (22)

• 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

• 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

• 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

• Cmax of Abiraterone

  Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3

Other Outcomes (3)

• Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) Until End of the Study

  Up to 3 years and 11 months

• Number of Participants With AEs Leading to Any Dose Reduction or Delays Until End of the Study

  Up to 3 years and 11 months

• Number of Participants Who Withdrew Due to Toxicity and Changes in Safety Assessment Until End of the Study

  Up to 3 years and 11 months

Study Arms (2)

GSK525762 + Abiraterone (+ Prednisone) (Arm A)

EXPERIMENTAL

Drug: GSK525762; Drug: Abiraterone; Drug: Prednisone

GSK525762 + Enzalutamide (Arm B)

EXPERIMENTAL

Drug: GSK525762; Drug: Enzalutamide

Interventions

GSK525762 DRUG

GSK525762 will be administered.

GSK525762 + Abiraterone (+ Prednisone) (Arm A); GSK525762 + Enzalutamide (Arm B)

Abiraterone DRUG

Abiraterone will be administered.

GSK525762 + Abiraterone (+ Prednisone) (Arm A)

Enzalutamide DRUG

Enzalutamide will be administered.

GSK525762 + Enzalutamide (Arm B)

Prednisone DRUG

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

GSK525762 + Abiraterone (+ Prednisone) (Arm A)

Eligibility Criteria

• Age: 18 Years+
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• (c) Lead-in dosing period for abiraterone only will be required: if the participant 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. Participants who have not received prior chemotherapy in any setting will qualify for study if they are ineligible for or refuse chemotherapy.
• 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)/Liter (L) (5 ng/mL) if PSA is the only indication of progression; participants on systemic glucocorticoids for control of symptoms must have documented PSA progression by PCWG3 while on systemic glucocorticoids prior to commencing Week 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.

You may not qualify if:

• Surgery or local prostatic intervention (excluding a prostatic biopsy) less than 28 days of Week 1 Day 1.
• 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:
• Baseline QT interval corrected for heart rate by Fridericia's formula (QTcF) interval \>=480 milliseconds (msec).
• Clinically significant conduction abnormalities or arrhythmias, such as participants 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. Participants with a history of stent placement requiring ongoing anti-coagulant therapy (e.g., clopidogrel, prasugrel) will not be permitted to enroll.
• Known cardiac metastasis.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (20)

GSK Investigational Site

Los Angeles, California, 90033, United States

Location

GSK Investigational Site

Baltimore, Maryland, 21287, United States

Location

GSK Investigational Site

Towson, Maryland, 21204, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02215, United States

Location

GSK Investigational Site

Detroit, Michigan, 48201, United States

Location

GSK Investigational Site

St Louis, Missouri, 63110, United States

Location

GSK Investigational Site

New York, New York, 10016, United States

Location

GSK Investigational Site

Philadelphia, Pennsylvania, 19104, United States

Location

GSK Investigational Site

Madison, Wisconsin, 53792, United States

Location

GSK Investigational Site

Sydney, New South Wales, 2050, Australia

Location

GSK Investigational Site

Clayton, Victoria, 3168, Australia

Location

GSK Investigational Site

Melbourne, Victoria, 3000, Australia

Location

GSK Investigational Site

Barcelona, 08035, Spain

Location

GSK Investigational Site

Barcelona, 8036, Spain

Location

GSK Investigational Site

Madrid, 28034, Spain

Location

GSK Investigational Site

Málaga, 3075EA, Spain

Location

GSK Investigational Site

Sabadell (Barcelona), 08208, Spain

Location

GSK Investigational Site

Santander, 39008, Spain

Location

GSK Investigational Site

Sutton, London, SM2 5NG, United Kingdom

Location

GSK Investigational Site

Glasgow, G12 OYN, United Kingdom

Location

MeSH Terms

Interventions

molibresib; abiraterone; enzalutamide; Prednisone

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

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

Study Record Dates

• First Submitted: May 9, 2017
• First Posted: May 11, 2017
• Study Start: July 18, 2017
• Primary Completion: July 31, 2020
• Study Completion: June 22, 2021
• Last Updated: August 10, 2022
• Results First Posted: August 26, 2021

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted when justified, for up to another 12 months.

Locations

ES (6); US (9); AU (3); GB (2)