Study design and treatment
The was a multi-centre, open-label study with randomised cross-over
design. There were two treatment periods: in the oPac+E treated group,
patients were to receive encequidar 15mg daily for three days a week and
oral paclitaxel 615mg/m2 divided over 3 days with
rounding to the nearest 30mg capsule. At the completion of the two
treatment periods, patients were eligible to return to usual care with
weekly paclitaxel, or enter into an extension study of oPac+E three days
per week at the dose administered in the current study. The encequidar
tablet was administered 1 hour before the oral paclitaxel capsules. In
the IV paclitaxel group, patients received weekly Taxol®
80mg/m2 IV infused over one hour. Patients were
randomised by computer generated central randomization scheme to receive
oPac+E followed by IV Taxol, or the reverse sequence. Subjects were
instructed to fast for at least 8 hours before and 4 hours after oPac+E
dosing.
Intravenous paclitaxel was administered according to standard local
practice. oPac+E was administered in an inpatient clinical research
unit. Patients receiving IV PAC were administered standard prophylactic
steroids and antihistamines. No premedication was allowed before the
first dose of oPac+E; in the follow-up extension study premedication was
permitted before subsequent doses for hypersensitivity reactions and/or
nausea or vomiting. Intensive blood sampling was undertaken for the
first 3 days while on oPac+E, with samples taken pre-dose, after dosing
(0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, and 18 hours), on Day
2 to Day 5 or 9 to Day 12, samples were taken predose, after dosing
(0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 32, 48, 56,
72, 96, 120 and 144 hours). With Taxol® administration blood sampling
was performed pre-dose, during infusion (2, 5, 8, 12, 20, 40, and 60
minutes), after infusion (0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, and 24
hours, then at 32, 48, 56, 72 and 96 hours post dose. Standard baseline
investigations were performed including physical exam, ECG, pregnancy
test in pre-menopausal female subjects, haematology and biochemistry
samples, and urinalysis. After completing both treatment periods
patients were asked which treatment they preferred. Adverse events were
collected and graded according to CTCAE 4.03, and causality assessed by
investigators.