Phase I pharmacokinetic study of ECO-4601, a novel bifunctional targeting agent

B119 Background: ECO-4601 (U.S. Patent 7,101,872) is a structurally novel farnesylated dibenzodiazepinone with broad µM in vitro cytotoxic activity and in vivo antitumor efficacy in rat glioma and human hormone-independent prostate and breast tumor xenografts. Preclinical data suggest ECO-4601 is a targeted anticancer drug with dual activity: selective binding to the peripheral benzodiazepine receptor (PBR), resulting in apoptosis, and inhibition of the Ras-MAPK pathway, which is involved in cellular proliferation and migration. Antitumor activity is dependent on continuous exposure, and a target plasma ECO-4601 efficacy concentration of 2 µM was determined. The pharmacokinetic profile ECO-4601 has been tested in a Phase I clinical trial in patients with advanced solid tumors. Methods: ECO-4601 was administered as a 2-week continuous i.v. infusion (CIV) followed by 1 week off in repeated 21 day cycles. The trial included dose-escalation and dose-extension portions, with comprehensive pharmacokinetics (PK) during the first and second cycles. ECO-4601 doses of 30, 60, 120, 180, 270, 360, and 480 mg/m2/day were evaluated in 14 patients in the escalation portion and in 12 additional patients treated at 480 mg/m2/day. ECO-4601 plasmatic concentrations were determined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) using EDTA-K2 as anti-coagulant agent. The lower limit of quantitation (LLOQ) was established at 1 ng/mL. Results: The first six (6) patients dosed at 30 mg/m2/day had a mean ECO-4601 plasmatic concentration of 0.50 µM, which was in good agreement with a PK simulation calculated from PK studies in animal species (mouse, rat and monkey). Apparent volume (Vapp) of distribution was 111 ± 26 L and clearance (CL) was 9.4 ± 2.4 L/h. Inter-patient PK variability was moderate (26% CV for CL). After the infusion ceased, ECO-4601 was rapidly eliminated from the bloodstream within 24 h at all dose levels. The mean terminal half-life was ~9.4 hours and the post-infusion half-life (t1/2 alpha) was less than 30 min. ECO-4601 concentrations increased linearly as a function of dose and clearance, half-life and volume of distribution appeared to be independent of dose level. Doses of 270, 360 and 480 mg/m2/day in the dose escalation portion resulted in ECO-4601 steady-state plasma concentrations of 2.4, 3.1 and 4.7 µM, respectively. These plasma concentrations are above the estimated therapeutic threshold determined in animal efficacy studies. An additional twelve (12) patients were dosed in the dose extension portion at the selected dose of 480 mg/m2/day. Plasma concentrations varied between 4.5 and 7 µM. Blood samples were collected during cycles 1 and 2, and steady-state concentrations in human plasma were comparable between both cycles, indicating that no drug accumulation had occurred. Post-infusion half-life (t1/2 alpha) of ECO-4601 was similar in both cycles. Conclusions: ECO-4601 is a bifunctional targeting agent, against a novel combination of targets, for which estimated therapeutic plasma concentrations are reached at doses of 270 mg/m2/day or greater. ECO-4601 is well tolerated and demonstrates preliminary evidence of biological activity in an early phase clinical trial. These PK data, together with Phase I safety data, and non-clinical data, support further development of ECO-4601 in a Phase II trial.