Phase I study of ECO-4601, a novel Ras pathway inhibitor

Abstract

14128 Background: ECO-4601 is a structurally novel farnesylated dibenzodiazepinone with broad μM in vitro cytotoxic activity, and in vivo antitumor efficacy in rat glioma, hormone-independent human prostate, breast tumor xenograft tumor models. 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. Greatest efficacy was observed with continuous exposure, and a target plasma ECO-4601 efficacy concentration was determined. Preclinical toxicity studies did not demonstrate significant or dangerous side-effects. ECO-4601 is currently in phase I clinical trial testing to determine toxicity, pharmacologic profile and antitumor efficacy. Methods: ECO-4601 is administered as a 2-week continuous i.v. infusion (CIV), followed by 1 week off in repeated 21 day cycles. The trial includes dose- escalation and dose-extension portions, with comprehensive pharmacokinetics (PK) during the first cycle. Dose-escalation consists of increased doses in single pts until grade 3 toxicity is observed during cycle 1 of treatment, with up to five additional pts dosed to confirm dose-limiting toxicity (2/6 pts with grade 3 toxicities). The extension portion includes up to 15 pts at the dose determined in the first portion. Patients with a variety of cancers have been treated, including colorectal (10), ovarian (2), duodenal (1), and glioma (1). Results: ECO-4601 doses of 30, 60, 120, 180, 270, 360, and 480 mg/m2/day were evaluated in 14 patients. The number of cycles ranged from 1 to 8 with 7 pts completing at least 3 cycles of treatment. ECO-4601 is well tolerated and a maximum tolerated dose (MTD) has not been reached. Stable disease was observed in 6 of 7 evaluable pts; 4 colorectal, 1 ovarian, 1 duodenal. Preliminary PK shows steady state concentrations following 24 h CIV, dose proportionality, plasma concentrations above the preclinical efficacy threshold, rapid elimination post-infusion. Conclusions: ECO-4601 is a bifunctional targeting agent, against a novel combination of targets, that is well tolerated and demonstrates evidence of biological activity in an early phase clinical trial. The extension portion is currently ongoing. [Table: see text]