| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castration Resistant Prostate Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062904 |
| E.1.2 | Term | Hormone-refractory prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Dose Escalation Phase: To determine safe biologically effective (BED) and recommended phase II (RP2D) doses for pexidartinib to be given in combination with full dose enzalutamide in patients with mCRPC
Dose Expansion Phase: Determination of the anti-tumour activity (composite response rate) for pexidartinib at the RP2D (and if relevant at the BED) combined with full dose enzalutamide in patients with mCRPC who have progressed on enzalutamide. |
|
| E.2.2 | Secondary objectives of the trial |
Dose Escalation Phase:
•To evaluate the safety and toxicity profile of pexidartinib when it is combined with full dose enzalutamide
•To provide pharmacokinetic data for pexidartinib exposure when combined with enzalutamide
•To provide efficacy data for those patients included in the Dose Escalation Phase who have previously progressed on enzalutamide
Dose Expansion Phase:
•To evaluate the safety and toxicity profile of pexidartinib when it is combined with full dose enzalutamide
•To evaluate other efficacy measures for pexidartinib at the RP2D (and if relevant at the BED) combined with enzalutamide in patients with mCRPC who have progressed on enzalutamide. These will be:
o PSA progression free survival
o Radiological progression-free survival
o CTC response rate
o RECIST objective response rate
o PSA response rate
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically proven castrate resistant prostate cancer
2. Metastatic disease. Measurable or evaluable disease is acceptable
3. In the dose escalation phase of the trial patients may be enzalutamide naive or refractory by either:
i.Commencing enzalutamide for the first time as a treatment for mCRPC as a result of entering this trial
ii.Receiving retreatment with enzalutamide as a result of entering this trial providing a minimum of 12 weeks has elapsed since prior enzalutamide. 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
In the dose expansion phase of the trial patients will be enzalutamide refractory by either:
i.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.
ii.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.
4.Serum testosterone <1.7 nmol/L (< 50 ng/dL)
5.No other current therapies for prostate cancer. Allowable exceptions are:
i.Use of an LHRH agonist or antagonist where required for ongoing androgen deprivation
ii.Ongoing enzalutamide for patients entering the Dose Expansion Phase
iii.Denosumab or bisphosphonates such as zoledronate or pamidronate
6.ECOG performance status 0 to 2
7.Haemoglobin ≥ 8.5 g/dL; platelets ≥ 100 x 109/L; neutrophils ≥ 1.0 x109/L; INR ≤ 1.5
8.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
10.Able to swallow oral trial drugs
11.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
12.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)
13.Life expectancy > 3 months
14.Aged 16 years or over
15.Provision of written informed consent
|
|
| E.4 | Principal 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
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose Escalation Phase
To establish a RP2D for pexidartinib in combination with enzalutamide from both:
- Maximum tolerated dose (MTD) for pexidartinib when given in combination with full dose enzalutamide will be defined based on dose limiting toxicity (DLT) according to protocol described rules based on emergent adverse events measured according to CTCAEv4.03
- BED defined by assessment at 6 weeks of combination therapy of plasma CSF-1 rise.
Dose Expansion Phase
Determination of the anti-tumour activity (composite response rate) for pexidartinib at the RP2D (and if relevant at the BED) combined with full dose enzalutamide in patients with mCRPC who have progressed on enzalutamide.
Using a composite response rate endpoint at 12 weeks of combination treatment of one or more of:
- PSA reduction from baseline by > 50%
- RECIST objective response
- Circulating tumour cell (CTC) conversion: change from unfavourable (≥ 5 cells per 7.5 mL of blood) to favourable (≤ 4 cells per 7.5 mL)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Determination of a MTD = Patients assessed for toxicity throughout treatment and a MTD decision can be made once all patients on treatment in the escalation phase have reached at least Cycle 2 Day 15 of treatment (6 weeks) This may be through reaching the final cohort or meeting the stopping rules for cohorts 1, 2, 3 or 4.
- Determination of a BED = A decision on a BED can be made once all samples for patients completing at least 6 weeks of combination therapy treatment in the escalation phase have been analysed for plasma CSF-1 rise.
- Determination of the anti-tumour activity = Cycle 4 Day 1 (12 weeks)
|
|
| E.5.2 | Secondary end point(s) |
Dose escalation:
To evaluate the safety and toxicity profile of pexidartinib when it is combined with full dose enzalutamide measured according to CTCAEv4.03
To provide pharmacokinetic data for pexidartinib exposure when combined with enzalutamide using pharmacokinetics of pexidartinib measured at first dose pexidartinib in the single agent run in (dose level cohorts 1 and 2), at the first combination dose (C1D1 in all patients) and on day 29 of combination dosing
To provide efficacy data for those patients included in the Dose Escalation Phase who have previously progressed on enzalutamide assessed by
• PSA reduction from baseline by > 50%
• RECIST objective response
Dose Expansion:
To evaluate the safety and toxicity profile of pexidartinib when it is combined with full dose enzalutamide. Measured according to CTCAEv4.03
To evaluate other efficacy measures for pexidartinib at the RP2D (and if relevant at the BED) combined with enzalutamide in patients with mCRPC who have progressed on enzalutamide. These will be:
o PSA progression free survival
o Radiological progression-free survival
o CTC response rate
o RECIST objective response rate
o PSA response rate
Measured according to:
• PSA progression free survival and radiological progression-free survival by PCWG3 criteria
• CTC conversion: change from unfavourable (≥ 5 cells per 7.5 mL of blood) to favourable (≤ 4 cells per 7.5 mL)
• Objective response rate by RECIST version 1.1 at 12 weeks and best response
• PSA reduction from baseline by > 50% at 12 weeks and best response
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Dose escalation:
Evaluate the safety and toxicity profile: Patients will be assessed for toxicity throughout treatment.
Pharmacokinetic data: following 4 weeks of combination treatment.
Efficacy data in previously progressed patients: 12 weeks of combination treatment
Dose Expansion:
Evaluate the safety and toxicity profile: Patients will be assessed for toxicity throughout treatment.
Evaluation of other efficacy measures: 12 weeks |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose finding and expansion trial |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
Print
