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.