The study of pexidartinib and enzalutamide as a combined treatment in men with prostate cancer resistant to other treatments

ISRCTN	ISRCTN13103155
DOI	https://doi.org/10.1186/ISRCTN13103155
EudraCT/CTIS number	2016-003291-47
Secondary identifying numbers	32858

Submission date: 27/03/2017
Registration date: 28/03/2017
Last edited: 21/06/2019

Recruitment status: Stopped
Overall study status: Stopped
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Study website

Contact information

Mrs Denise Dunkley
Public

Southampton Clinical Trials Unit
University of Southampton
MP131
Southampton
SO16 6YD
United Kingdom

ORCID ID	0000-0003-2220-3987

Study information

Study design	Non-randomised; Interventional; Design type: Treatment, Drug
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
Scientific title	A phase Ib/IIa clinical trial to combine the CSF1 receptor inhibitor pexidartinib with the androgen receptor antagonist enzalutamide in metastatic castration resistant prostate cancer
Study acronym	POLERISE
Study objectives	The dose escalation phase aims to establish the maximum tolerated dose for the study treatment pexidartinib when given to patients in combination with the already liscensed drug enzalutamide. Patients may be enzalutamide naïve or refractory. The aim is to determine a safe biologically effective dose (bed) and a recommended phase ii dose (rp2d). The dose expansion phase will then use the rp2d of pexidartinib in combination with enzalutamide to determine the anti-tumour activity (composite response rate) in enzalutamide refractory patients and provide further information on the safety and toxicity of the combined treatment for patients with metastatic castration resistant prostate cancer.
Ethics approval(s)	West Midlands - Coventry & Warwickshire Research Ethics Committee, 25/01/2017, ref: 16/WM/0480
Health condition(s) or problem(s) studied	Prostate cancer
Intervention	Dose escalation phase: All patients will receive enzalutamide (current standard of care treatment) in combination with pexidartinib. There are five potential cohorts to the escalation phase with a rolling 6 trial design which means a minimum of three evaluable patients and a maximum of six per cohort will receive a dose level. Escalation to the next dose will be dependent on the number of dose limiting toxicities (dlts) as assessed by a safety review committee. For cohorts 1 and 2, there will be a 2-week run-in period with single agent pexidartinib, followed by the combination therapy. Cohorst 3-5 begin treatment immediately on the combination therapy. Patients will receive up to 5 cycles of treatment (28 days each cycle) and may continue beyond if positive response and will be followed up until progression. The primary endpoint will be assessed at 6-weeks of treatment. Dose expansion phase: Patients will receive combination therapy using the rp2d established during phase Ib (escalation phase) for up to 5 cycles of treatment (28 days each cycle) and may continue beyond if a positive response is determined. Patients will be followed up until progression. The primary endpoint will be assessed at 12-weeks of treatment. Patients who have prior evidence of PSA and/or radiological progression on enzalutamide, and where there has been a treatment break of greater than 8 weeks prior to restarting enzalutamide on this trial, will receive a 4-week run-in of enzalutamide, single treatment, prior to the combination therapy commencing. This is to exclude a PSA response.
Intervention type	Other
Primary outcome measure	Dose escalation phase: 1. Maximum tolerated dose (MTD) for pexidartinib is measured using treatment emergent adverse events data (dose limiting toxicity) measured according to CTCAEv4.03 at screening and at each study visit until end of treatment (EoT) 2. Biologically Effective Dose for pexidartinib is measured by plasma CSF-1 rise at 6 weeks (cycle 2 day 15) of combination therapy compared to baseline Dose expansion phase: Anti-tumour activity (composite response rate) for pexidartinib at the RP2D is measured by: 1. PSA reduction from baseline by > 50% (PSA measured at Day 1 of each cycle. Additionally, at run-in of days 1, 8, 15 and 22) 1. RECIST objective response (measured by disease progression at Cycle 4 Day 1 and at EoT/progression) 1. Circulating tumour cell (CTC) conversion: change from unfavourable (≥ 5 cells per 7.5 mL of blood) to favourable (≤ 4 cells per 7.5 mL) as measured at cycle 1 day 1, cycle 4 day 1 and at EoT/progression
Secondary outcome measures	Dose escalation phase: 1. Pharmacokinetics of pexidartinib is measured from blood plasma testing at run-in, then on cycle 1 day 1, cycle 2 day 1 (pre-dose, 1,2,4,8 hours). Pre-dose PK on day 1 of all subsequent cycles and at EoT 2. Efficacy is measured from blood sampling to measure PSA reduction from baseline by > 50% (PSA measured at Day 1 of each cycle). Additionally, at run-in day 1 (cohort 1 and 2 only) and RECIST objective response (measured by disease progression at Cycle 4 Day 1 and at EoT/progression) Dose expansion phase: Safety and toxicity profile of pexidartinib at the RP2D measure by blood sampling of PSA and CTC: 1. PSA progression free survival and radiological progression-free survival by PCWG3 criteria (measured at run-in for single agent enzalutamide at day 1,8,15 and 22). Then cycle day 1 for all other cycles 2. CTC conversion: change from unfavourable (≥ 5 cells per 7.5 mL of blood) to favourable (≤ 4 cells per 7.5 mL) as measured at cycle 1 day 1, cycle 4 day 1 and at EoT/progression 3. Objective response rate by RECIST version 1.1 at 12 weeks and best response (measured by disease progression at Cycle 4 Day 1 and at EoT/progression) 4. PSA reduction from baseline by > 50% at 12 weeks and best response
Overall study start date	01/10/2016
Completion date	31/12/2019

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	Male
Target number of participants	Planned Sample Size: 100; UK Sample Size: 100
Key inclusion criteria	1. Histologically or cytologically proven castrate resistant prostate cancer 2. Metastatic disease. Measurable or evaluable disease is acceptable 3. Serum testosterone <1.7 nmol/L (< 50 ng/dL) 4. No other current therapies for prostate cancer. Allowable exceptions are: 4.1. Use of an LHRH agonist or antagonist where required for ongoing androgen deprivation 4.2. Ongoing enzalutamide for patients entering the Dose Expansion Phase 4.3. Denosumab or bisphosphonates such as zoledronate or pamidronate 5. ECOG performance status 0 to 2 6. Haemoglobin ≥ 8.5 g/dL; platelets ≥ 100 x 109/L; neutrophils ≥ 1.0 x109/L; INR ≤ 1.5 7. Bilirubin ≤ ULN; ALT and AST ≤ 1.5 x ULN 9. For patients entering the Dose Expansion Phase of the trial: PSA of ≥ 2 ng/mL 9. Able to swallow oral trial drugs without crushing 10. Able to safely provide both an archival formalin fixed paraffin embedded (FFPE) prostate cancer tissue sample and a prostate cancer fresh tissue sample from either the prostate or a metastatic site 11. Fertile men must agree to use a highly effective method of birth control while on study drug and up to 3 months after the last dose of study drug (see section 4.7) 12. Life expectancy > 3 months 13. Aged 16 years or over 14. Provision of written informed consent Dose escalation phase: Patients may be enzalutamide naive or refractory by either: 1. Commencing enzalutamide for the first time as a treatment for mCRPC as a result of entering this trial 1. Receiving retreatment with enzalutamide as a result of entering this trial providing a minimum of 12 weeks has elapsed since prior enzalutamide dosing. Prior enzalutamide in these circumstances may have been given for either hormone sensitive prostate cancer (for example within the STAMPEDE or ENZAMET clinical trials) or as a conventional treatment for mCRPC. There are no restrictions on other treatments used during this period. Such patients should have tolerated an enzalutamide dose of 160mg once daily. Dose expansion phase: Patients will be enzalutamide refractory by either: 1. Currently receiving enzalutamide (for a minimum of 12 weeks) and with evidence of PSA and/or radiological progression according to RECIST 1.1 and PCWG3 criteria as judged by the investigator. These patients should have tolerated an enzalutamide dose of 160mg once daily. These patients may continue enzalutamide through the screening period. 2. Have previously had evidence of PSA and/or radiological progression during a minimum of 12 weeks of enzalutamide treatment according to RECIST 1.1 and PCWG3 criteria as judged by the investigator. There are no restrictions on the time period since this prior use of enzalutamide or other treatments used during this period. These patients must have tolerated an enzalutamide dose of 160mg once daily. Where there has been a break of >8 weeks between prior enzalutamide and restarting it in this trial, patients will initially receive a four week run in period of single agent enzalutamide before commencing combination therapy to exclude a PSA response. Patients who exhibit a PSA decrease during the first four weeks will have the option to continue enzalutamide until the point of subsequent disease progression and could then enter the trial to commence combination therapy after discussion with the sponsor.
Key exclusion criteria	1. Patients with predominantly small cell or neuroendocrine differentiated prostate cancer 2. Administration of an investigational agent, chemotherapy or major surgery within 28 days of first dose of trial medication 3. Receiving a known CYP3A4 or CYP2C8 inducer or inhibitor (see appendix) within 2 weeks of starting trial treatment 4. Use of systemic corticosteroids within 2 weeks of starting trial treatment (topical and inhaled corticosteroids are acceptable) 5. Malabsorption syndrome, previous gastrointestinal surgery or other gastrointestinal condition that may affect drug absorption 6. Clinically significant cardiac arrhythmias including bradyarrhythmias and/or patients who require anti-arrhythmic therapy (excluding beta blockers or digoxin) 7. Congenital long QT syndrome or patients taking concomitant medications known to prolong the QT interval 8. Patients with a prolonged QTc interval > 480msec 9. History of clinically significant cardiac disease or congestive heart failure > New York Heart Association (NYHA) class 2. Patients must not have unstable angina (anginal symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months 10. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study medication 11. Patients taking warfarin. (Use of low molecular weight heparin is acceptable as an alternative for anticoagulation.) 12. For patients entering the Dose Expansion Phase of the trial: Prior malignancy with an estimated > = 30% chance of relapse within 2 years in the view of the investigator with the exception of surgically treated basal or squamous cell carcinoma of the skin, melanoma in-situ or non-muscle invasive bladder cancer 13. History of seizures or any condition that may predispose to seizure including, but not limited to, underlying brain injury, stroke, primary brain tumours, brain metastases or alcoholism 14. History of loss of consciousness within the previous 12 months 15. Known brain or leptomeningeal involvement 16. Unresolved clinically significant toxicity from prior therapy (except alopecia and grade 1 peripheral neuropathy) 17. Inability to comply with trial and follow up procedures
Date of first enrolment	31/12/2018
Date of final enrolment	30/04/2019

Locations

Countries of recruitment

England
Scotland
United Kingdom

Study participating centres

The Royal Marsden Hospital

Royal Marsden NHS Foundation Trust
Downs Road
Sutton
SM2 5PT
United Kingdom

Southampton General Hospital

University Hospital Southampton NHS Foundation Trust
Tremona Road
Southampton
SO16 6YD
United Kingdom

Churchill Hospital

Oxford University Hospitals NHS Foundation Trust
Old Road
Headington
Oxford
OX3 7LE
United Kingdom

The Beatson Institute for Cancer Research

Garscube Estate
Switchback Road
Bearsden
Glasgow
G61 1BD
United Kingdom

Sponsor information

University Hospital Southampton NHS Foundation Trust
Hospital/treatment centre

Mailpoint 18
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
England
United Kingdom

Phone	+44 2381 205078
Email	Sharon.Davies-Dear@uhs.nhs.uk
"ROR"	https://ror.org/0485axj58

Funders

Funder type

Charity

Cancer Research UK
Private sector organisation / Other non-profit organizations

Alternative name(s): CR_UK, Cancer Research UK - London, CRUK
Location: United Kingdom

Results and Publications

Intention to publish date	31/12/2019
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
Publication and dissemination plan	Planned publication in a high-impact peer reviewed journal. Findings may also be presented at scientific conferences.
IPD sharing plan	The current data sharing plans for the current study are unknown and will be made available at a later date.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No

Editorial Notes

21/06/2019: Internal review.
05/04/2019: The trial is not going ahead and has been stopped.
26/03/2019: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Prostate Cancer; UKCRC code/ Disease: Cancer/ Malignant neoplasms of urinary tract" to "Prostate cancer" following a request from the NIHR.
05/03/2019: Internal review.
07/06/2018: Recruitment start date was changed from 01/05/2017 to 31/12/2018.
06/06/2018; Internal review.
14/05/2018: internal review.
16/01/2018: Internal review.
15/09/2017: Internal review.
06/06/2017: Internal review.