Prostate cancer Cancer Malignant neoplasm of prostate
Conditions
Interventions
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
Sponsors
University Hospital Southampton NHS Foundation Trust
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: 1. Histologically or cytologically proven castrate resistant prostate cancer 2. Metastatic disease. Measurable or evaluable disease is acceptable 3. Serum testosterone 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
Exclusion criteria
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 | — |
Countries
United Kingdom
Contacts
Public ContactDenise Dunkley
Outcome results
None listed