A phase I trial of sns-314, a novel and selective pan-aurora kinase inhibitor, in advanced solid tumor patients.

Academic Article

Abstract

  • 2536 Background: Aurora Kinases are a family of serine/threonine kinases (Aurora Kinases (AK) A, B, and C) critical for mitosis. Elevated AKs expression occurs in a high percentage of melanoma, colon, breast, ovarian, gastric, and pancreatic tumors; in a subset of these tumors the AURKA locus (20q13) is amplified. SNS-314 is a selective pan-AK inhibitor with low nanomolar IC50s. METHODS: Study design is 3+3 phase 1 dose escalation by modified Fibonacci. Patients (pts) with advanced solid tumors received SNS-314 by 3 hour infusion qweek X 3 (28 day cycle). Primary endpoints: safety, tolerability, and DLT assessment. Secondary endpoints: MTD, pharmacokinetics (PK), pharmacodynamics, and antitumor activity. Pharmacodynamic endpoint was inhibition of Histone H3 phosphorylation (pHH3) evaluated by immunohistochemistry of skin punch biopsies taken pre- and 2 hours post-infusion. RESULTS: Thirty-two pts (16M/16F; median age = 58.5 years) were enrolled into 8 cohorts: dose range 30-1800 mg/m(2). Median cycles received =2. SNS-314 was generally well tolerated with Grade 1-2 toxicities ≥ 15% incidence: nausea (31%), fatigue (28%), vomiting, constipation, and pain (16% each), and no Grade 3+ toxicities of ≥ 15% incidence. A DLT of Grade 3 neutropenia preventing administration of all 3 doses was observed at 1440 mg/m(2). Plasma PK were dose proportional for exposure with no accumulation of SNS-314 following weekly administration. Clearance was moderate (5.65 L/hr/m(2), CV 39.4%); Vss approximated total body water (21.5 L/m(2), CV 78.1%); terminal half-life was 10.4 hours (CV 66.8%). Six patients had stable disease as their best response. Inhibition of pHH3 by SNS-314 was observed in skin biopsies of patients treated at doses of 240 mg/m(2) and greater. CONCLUSIONS: SNS-314 is a novel inhibitor of AKs A, B, and C. The compound has been generally well tolerated; MTD was not established. No objective responses were observed. Pharmacodynamic activity was demonstrated by inhibition of pHH3. [Table: see text].
  • Published In

    Pubmed Id

  • 3908030
  • Author List

  • Robert F; Verschraegen C; Hurwitz H; Uronis H; Advani R; Chen A; Taverna P; Wollman M; Fox J; Michelson G
  • Start Page

  • 2536
  • Volume

  • 27
  • Issue

  • 15_suppl