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

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 (IC50’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 thro...