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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03150056




Registration number
NCT03150056
Ethics application status
Date submitted
9/05/2017
Date registered
11/05/2017

Titles & IDs
Public title
Dose Escalation and Dose Expansion Study of GSK525762 in Combination With Androgen Deprivation Therapy in Participants With Castrate-resistant Prostate Cancer
Scientific title
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)
Secondary ID [1] 0 0
2016-003416-13
Secondary ID [2] 0 0
204697
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Solid Tumours 0 0
Condition category
Condition code
Cancer 0 0 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - GSK525762
Treatment: Drugs - Abiraterone
Treatment: Drugs - Enzalutamide
Treatment: Drugs - Prednisone

Experimental: GSK525762 + Abiraterone (+ Prednisone) (Arm A) -

Experimental: GSK525762 + Enzalutamide (Arm B) -


Treatment: Drugs: GSK525762
GSK525762 will be administered.

Treatment: Drugs: Abiraterone
Abiraterone will be administered.

Treatment: Drugs: Enzalutamide
Enzalutamide will be administered.

Treatment: Drugs: Prednisone
Prednisone will be administered as a concomitant medication in combination with abiraterone
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
Timepoint [1] 0 0
Up to 21.3 months
Primary outcome [2] 0 0
Number of Participants With AEs Leading to Any Dose Reduction or Delays
Timepoint [2] 0 0
Up to 21.3 months
Primary outcome [3] 0 0
Number of Participants Who Withdrew Due to Toxicity and Changes in Safety Assessment
Timepoint [3] 0 0
Up to 21.3 months
Primary outcome [4] 0 0
Percentage of Participants With Greater Than or Equals to (>=)50 Percent (%) Decrease in Prostate-specific Antigen From Baseline (PSA50)
Timepoint [4] 0 0
Up to 21.3 months
Secondary outcome [1] 0 0
Maximum Observed Plasma Concentration (Cmax) of GSK525762 and Its Active Metabolites GSK3529246
Timepoint [1] 0 0
Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3
Secondary outcome [2] 0 0
Time to Cmax (Tmax) of GSK525762 and Its Active Metabolites GSK3529246
Timepoint [2] 0 0
Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3
Secondary outcome [3] 0 0
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
Timepoint [3] 0 0
Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3
Secondary outcome [4] 0 0
Trough Concentration (Ctrough) of GSK525762 and Its Active Metabolites GSK3529246
Timepoint [4] 0 0
Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3
Secondary outcome [5] 0 0
Cmax of Abiraterone
Timepoint [5] 0 0
Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3
Secondary outcome [6] 0 0
Tmax of Abiraterone
Timepoint [6] 0 0
Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3
Secondary outcome [7] 0 0
AUC(0-tau) of Abiraterone
Timepoint [7] 0 0
Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3
Secondary outcome [8] 0 0
Ctrough of Abiraterone
Timepoint [8] 0 0
Pre-dose, 30 minutes, 1, 3, 6 to 12, 24 hours post-dose on Day 1 of Weeks 1 and 3
Secondary outcome [9] 0 0
Cmax of Enzalutamide
Timepoint [9] 0 0
Pre-dose on Day 1 of Weeks 1, 3, 5, 9, 17 and 25
Secondary outcome [10] 0 0
Tmax of Enzalutamide
Timepoint [10] 0 0
Pre-dose on Day 1 of Weeks 1, 3, 5, 9, 17 and 25
Secondary outcome [11] 0 0
AUC(0-tau) of Enzalutamide
Timepoint [11] 0 0
Pre-dose on Day 1 of Weeks 1, 3, 5, 9, 17 and 25
Secondary outcome [12] 0 0
Ctrough of Enzalutamide
Timepoint [12] 0 0
Pre-dose on Day 1 of Weeks 1, 3, 5, 9, 17 and 25
Secondary outcome [13] 0 0
Disease Control Rate at Week 24
Timepoint [13] 0 0
Week 24
Secondary outcome [14] 0 0
Composite Response Rate
Timepoint [14] 0 0
Up to 21.3 months
Secondary outcome [15] 0 0
Objective Response Rate
Timepoint [15] 0 0
Up to 21.3 months
Secondary outcome [16] 0 0
Circulating Tumor Cells (CTC) Response Rate
Timepoint [16] 0 0
Up to 21.3 months
Secondary outcome [17] 0 0
Prostate-specific Antigen (PSA) Response Rate at Week 4
Timepoint [17] 0 0
Week 4
Secondary outcome [18] 0 0
Time to Disease Progression
Timepoint [18] 0 0
Up to 21.3 months
Secondary outcome [19] 0 0
Radiographic Progression-free Survival (rPFS)
Timepoint [19] 0 0
Up to 21.3 montths
Secondary outcome [20] 0 0
Number of Participants With Worst-Case Post Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status
Timepoint [20] 0 0
Up to 21.3 months
Secondary outcome [21] 0 0
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)
Timepoint [21] 0 0
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
Secondary outcome [22] 0 0
Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF): Pain Intensity- Pain at Worst in Last 24 Hours
Timepoint [22] 0 0
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

Eligibility
Key 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:

1. Has completed at least 12 weeks of prior continuous therapy with abiraterone or enzalutamide in any prior line.
2. 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:

1. 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.
2. 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.
* ECOG performance status of 0 or 1.
* Life expectancy >12 weeks.
* Able to swallow and retain orally administered medication.
* Must have adequate organ function.
* Male participants are eligible to participate if they agree to use contraceptive methods.
Minimum age
18 Years
Maximum age
No limit
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
* 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:

1. Any investigational or approved non-biologic anti-cancer drug within 14 days prior to the first dose of GSK525762 and abiraterone/enzalutamide.
2. Any nitrosoureas or mitomycin C within 42 days prior to the first dose of GSK525762 and abiraterone/enzalutamide.
3. Any anti-cancer biologic agents within five half-lives prior to the first dose of GSK525762 and abiraterone/enzalutamide.
4. If the participant received radiotherapy <90 days prior to study treatment, the irradiated lesion cannot be the only lesion used for evaluating response.
5. 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:

1. Baseline QT interval corrected for heart rate by Fridericia's formula (QTcF) interval >=480 milliseconds (msec).
2. Clinically significant conduction abnormalities or arrhythmias, such as participants with second degree (Type II) or third degree atrio-ventricular block.
3. History or evidence of current >=Class II congestive heart failure as defined by New York Heart Association (NYHA).
4. 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.
5. Known cardiac metastasis.
* Participants 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 GSK525762 and abiraterone/enzalutimide. Prophylactic anticoagulation, with low doses (per standard practice) of agents such as LMWH, direct thrombin inhibitors, or factor Xa inhibitors is permitted.
* Concurrent use of high dose aspirin (doses up to 81 milligrams (mg) oral dose daily allowed, or 100 mg, as per country standards) 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 National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 grade <=1 with the exception of chemotherapy induced alopecia and grade 2 peripheral neuropathy.
* The participant 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.
* Participants with known symptomatic brain metastasis are not suitable for enrolment. Participants with asymptomatic, stable, treated brain metastases are eligible for study entry.
* History of seizure within 6 months of study treatment initiation or any condition that may predispose participant to seizure (e.g., prior cortical stroke or significant brain trauma) 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 participants not suffering from seizures unless drug is excluded due to Cytochrome (CY)P3A4 induction - phenytoin, carbamazepine, phenobarbital).
* History of loss of consciousness or transient ischemic attack within 12 months prior to enrollment.
* Participants with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable and asymptomatic.
* Current use of a prohibited medication or planned use of any forbidden medications during treatment with GSK525762 and abiraterone/enzalutamide. This includes medications that are potent inducers or inhibitors of CYP3A4 enzymes or strong inhibitors of CYP2C8.
* Participants with gastrointestinal disorders likely to interfere with absorption of the study medication.
* Participants with known bleeding diathesis.
* 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 months prior to Week 1 Day 1. Participants 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
18/07/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
22/06/2021
Sample size
Target
Accrual to date
Final
73
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
GSK Investigational Site - Sydney
Recruitment hospital [2] 0 0
GSK Investigational Site - Clayton
Recruitment hospital [3] 0 0
GSK Investigational Site - Melbourne
Recruitment postcode(s) [1] 0 0
2050 - Sydney
Recruitment postcode(s) [2] 0 0
3168 - Clayton
Recruitment postcode(s) [3] 0 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Maryland
Country [3] 0 0
United States of America
State/province [3] 0 0
Massachusetts
Country [4] 0 0
United States of America
State/province [4] 0 0
Michigan
Country [5] 0 0
United States of America
State/province [5] 0 0
Missouri
Country [6] 0 0
United States of America
State/province [6] 0 0
New York
Country [7] 0 0
United States of America
State/province [7] 0 0
Pennsylvania
Country [8] 0 0
United States of America
State/province [8] 0 0
Wisconsin
Country [9] 0 0
Spain
State/province [9] 0 0
Barcelona
Country [10] 0 0
Spain
State/province [10] 0 0
Madrid
Country [11] 0 0
Spain
State/province [11] 0 0
Malaga
Country [12] 0 0
Spain
State/province [12] 0 0
Sabadell (Barcelona)
Country [13] 0 0
Spain
State/province [13] 0 0
Santander
Country [14] 0 0
United Kingdom
State/province [14] 0 0
London
Country [15] 0 0
United Kingdom
State/province [15] 0 0
Glasgow

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
IPD for this study will be made available via the Clinical Study Data Request site.

Supporting document/s available: Study protocol, Statistical analysis plan (SAP), Informed consent form (ICF), Clinical study report (CSR)
When will data be available (start and end dates)?
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.
Available to whom?
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.
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: http://clinicalstudydatarequest.com


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT03150056