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A phase 1 and dose-finding study of LY2523355 (litronesib), an Eg5 inhibitor, in Japanese patients with advanced

Hiroshi Wakui1, Noboru Yamamoto, Satoru Kitazono

  • 1Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Cancer Chemotherapy and Pharmacology
|April 23, 2014
PubMed
Abstract

Insights

The recommended dose of litronesib (LY2523355) for advanced solid tumors in Japanese patients is 5 mg/m²/day, with therapeutic G-CSF support. This phase 1 study assessed safety, pharmacokinetics, and preliminary efficacy.

Area of Science:

  • Oncology
  • Pharmacology
  • Cell Biology

Background:

  • Eg5 is a crucial mitotic motor kinesin protein essential for bipolar spindle formation during M phase.
  • Litronesib (LY2523355) is an allosteric inhibitor targeting Eg5, a key player in cell division.
  • Advanced solid tumors represent a significant challenge in cancer therapy, necessitating novel treatment strategies.

Purpose of the Study:

  • To determine the safety and tolerability of LY2523355 in Japanese patients with advanced solid tumors.
  • To establish the recommended dose for further clinical studies based on safety and pharmacokinetic data.
  • To evaluate the preliminary efficacy and pharmacokinetic profile of LY2523355 in this patient population.

Main Methods:

  • A phase 1, dose-finding study administering LY2523355 at 2, 4, or 5 mg/m²/day on days 1-3 every 3 weeks.
  • Toxicity assessment using NCI-CTCAE v4.0; tumor response evaluated per RECIST v1.1.
  • Granulocyte colony-stimulating factor (G-CSF) utilized for managing severe neutropenia.

Main Results:

  • Twelve patients received LY2523355; most frequent adverse events were neutropenia and leukopenia (100%).
  • Grade 4 neutropenia occurred in 83% but resolved within 7 days; G-CSF was required for patients at 4 and 5 mg/m²/day.
  • No dose-limiting toxicities were observed up to 5 mg/m²/day; LY2523355 exposure showed dose-dependency and was similar to Western populations. No objective tumor responses were noted.

Conclusions:

  • The recommended dose of LY2523355 for further investigation in Japanese patients with advanced solid tumors is 5 mg/m²/day, with therapeutic G-CSF use.
  • LY2523355 demonstrated a manageable safety profile and predictable pharmacokinetics in this population.
  • Further studies are warranted to explore the therapeutic potential of LY2523355 in advanced solid tumors.

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