Phase I study of the aurora kinases (AKs) inhibitor PHA-739358 administered as a 6 and 3-h IV infusion on Days 1, 8, 15 every 4 wks in patients with advanced solid tumors

3507 Background: Aurora proteins belong to a family of serine/threonine kinases that are key regulators of different steps in mitosis. AKs were found to be implicated in tumorigenesis and overexpressed in cancer. Methods: Objectives were to determine the recommended dose for phase II (RP2D) and dose limiting toxicities (DLTs) during cycle 1 for each schedule, to evaluate the safety and pharmacokinetics (PK) profiles, to document antitumor activity and evaluate histone H3 phosphorylation (pH3) in skin biopsies. DLTs were defined as grade 4 neutropenia (G4 ANC) >7 days, febrile neutropenia (FN), neutropenic infection, G ≥3 thrombocytopenia (≥ 7 days or with bleeding), G ≥3 non-hematological toxicity, dose omission for ≥ G3 drug related (DR) toxicities and 2-wks delay in starting Cycle 2. Sequential cohorts of 3–6 patients (pts) were treated per dose level (DL). Results: 6-h IV infusion schedule: 42 pts were included in 7 DLs (45, 90, 135, 190, 250, 330 and 400 mg/m2). The RP2D is 330 mg/m2. DLTs were observ...