A phase I clinical and pharmacokinetic (PK) trial of the aurora kinase (AK) inhibitor MK-0457 in cancer patients

Abstract

3009 Background: The AKs are essential for mitotic progression, spindle formation, centrosome maturation, chromosomal segregation, and cytokinesis. Elevated expression occurs frequently in tumors. MK-0457 (VX-680) is a potent AK inhibitor, with Ki values of 0.66, 18 and 4.6 nM for AKs A, B and C, respectively. MK-0457 inhibits proliferation of transformed cells in vitro (IC 50 ’s 15–113 nM), and induces colon and pancreatic cancer xenograft regressions. Methods: After IRB approval, consenting patients (pts) with refractory solid tumors (median 3 prior regimens, range 2–6) and adequate hematologic and organ function were enrolled using an accelerated dose escalation scheme with 1–2 pts/dose level until ≥ grade 2 toxicity, followed by 3–6 pts/level. MK-0457 was administered by continuous 5-day intravenous infusion every 28 days. Dose-limiting toxicity (DLT) was grade 3 non-hematologic or grade 4 hematologic toxicity ≥ 5 days, or grade 4 febrile neutropenia (FN) during cycle 1. PKs were collected pre-dose through 168 h and analyzed for MK-0457 and metabolites by HPLC/mass spec. Steady state volume of distribution (Vd ss ), clearance (CL), maximal concentration (Cmax) and terminal half-life (t 1/2 ) were determined by WinNonLin. Results: 16 pts received MK-0457 dosed at 0.5, 1, 2, 4, 8, and 12 mg/m 2 /h. Median number of cycles was 2 (range 1–6). DLT was asymptomatic neutropenia ≥ 5 days at 12 mg/m 2 /h. At 8 mg/m 2 /h, 1 pt experienced FN in cycle 2; a second developed a grade 2 allergic reaction. Three pts achieved stable disease as best response, and two of them completed 6 cycles. Plasma concentrations reached steady state rapidly (i.e., within 24 h) and declined biexponentially after the end of infusion; after a rapid initial decay, a slower decaying terminal phase demonstrated a t 1/2 ∼15 h. PK parameters include Vd ss = 237 ± 107 (SD) L/m 2 and CL = 517 ± 141 ml/min/m 2 . At 8 mg/m 2 /h, Cmax was ∼650 nM. Conclusion: MK-0457 is generally well tolerated and achieves plasma levels similar to those causing regressions in xenografts. CL is high and exposures achieved are roughly dose proportional. Because 8 mg/m 2 /h was well tolerated in heavily pre-treated pts, escalation to 10 mg/m 2 /h is underway. Baseline tumor samples will be assessed for predictive biomarkers at the recommended phase II dose. [Table: see text]