The isoflavone compound idronoxil has previously been studied as a potential sensitizer of chemotherapy agents in multiple tumour types. Whilst phase 1 and 2 studies of oral and IV idronoxil showed promising results, development was halted during a phase 3 study of oral idronoxil in combination with carboplatin due to slow recruitment and a lack of evidence to suggest efficacy. A primary reason for the lack of efficacy is believed to be the rapid and extensive metabolism of idronoxil to inactive metabolites. In order to avoid first pass metabolism and to protect idronoxil from complete phase 2 metabolism a formulation of idronoxil (known as NOX66) has been developed whereby the active ingredient is compounded in a lipophilic base for rectal administration. Studies in rats of the pharmacokinetic profile of idronoxil administered as NOX66 shows a lower Cmax with extended t1/2 compared with orally administered idronoxil.
A first in human study of NOX66 was commenced in March 2017 (NOX66-001; NCT02941523) – a phase 1a study investigating the safety and pharmacokinetics of NOX66 as monotherapy, with patients continuing in to a Phase 1b study where NOX66 is administered in combination with carboplatin. Patients were allocated to receive either NOX66 once daily (400mg per day) or NOX66 twice daily (800mg per day) for 14 consecutive days. Plasma samples were collected at the following time points to measure idronoxil levels: Day 1 – 0, 30min, 60min, 2h; Day 8 – 0, 1h, 2h; Day 15 - single sample post final dose. At the time of abstract submission, 13/16 patients have commenced the study, with phase 1a expected to complete for all patient in September 2017. Plasma levels of idronoxil for all patients at the two dose levels, and a safety data overview for the phase 1a component of this study, are to be presented.