NCIC CTG IND.181: phase I study of AT9283 given as a weekly 24 hour infusion in advanced malignancies

Invest New Drugs. 2013 Dec;31(6):1522-9. doi: 10.1007/s10637-013-0018-9. Epub 2013 Sep 27.

Abstract

Purpose: AT9283 is a potent inhibitor of the mitotic regulators, Aurora-kinases A and B, and has shown anti-tumor activity in patients with solid and haematological malignancies. This phase I study assessed safety, tolerability, pharmacokinetic and pharmacodynamic properties of AT9283.

Patients and methods: Patients with advanced, incurable solid tumors or non-Hodgkin's lymphoma received AT9283 as a continuous 24-hour infusion on days 1, 8 of a 21-day cycle. A 3 + 3 dose escalation design was used with a starting dose of 1.5 mg/m(2)/day. Pharmacokinetic samples were collected from all patients on cycle one, and pharmacodynamic samples were collected from 4 patients at the recommended phase II dose (RP2D).

Results: 35 patients were evaluable for toxicity and 32 were evaluable for response. AT9283 was well tolerated, with main toxicities being reversible dose-related fatigue, gastrointestinal disturbance, anemia, lymphocytopenia and neutropenia. The dose limiting toxicities were febrile neutropenia (two patients) and neutropenia with grade 3 infection (1 patient) at 47 mg/m(2)/day (established as the maximum tolerated dose). The RP2D was 40 mg/m(2)/day. Pharmacokinetic analyses showed AT9283 appeared to follow linear kinetics, with a mean elimination half-life of 8.2 h. Pharmacodynamic analyses showed no consistent or significant changes, but trends suggested evidence of AT9283 inhibition and anti-proliferative activity. One patient had partial response and four patients experienced RECIST stable disease (median 2.6 months).

Conclusion: In this study, AT9283 was well tolerated. The RP2D is 40 mg/m(2)/day on days 1, 8 of a 21-day cycle. Ongoing AT9283 trials will assess efficacy and safety in solid and haematological cancers.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Benzimidazoles / administration & dosage*
  • Benzimidazoles / adverse effects
  • Benzimidazoles / pharmacokinetics
  • Drug Administration Schedule
  • Female
  • Histones / metabolism
  • Humans
  • Infusions, Intravenous
  • Ki-67 Antigen / metabolism
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Proliferating Cell Nuclear Antigen / metabolism
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacokinetics
  • Skin / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Urea / administration & dosage
  • Urea / adverse effects
  • Urea / analogs & derivatives*
  • Urea / pharmacokinetics

Substances

  • 1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea
  • Antineoplastic Agents
  • Benzimidazoles
  • Histones
  • Ki-67 Antigen
  • Proliferating Cell Nuclear Antigen
  • Protein Kinase Inhibitors
  • Tumor Suppressor Protein p53
  • Urea