Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer

Jeffrey R. Infante, Amita Patnaik, Claire F. Verschraegen, Anthony J. Olszanski, Montaser Shaheen, Howard A. Burris, Anthony W. Tolcher, Kyriakos P. Papadopoulos, Muralidhar Beeram, Scott M. Hynes, Jennifer Leohr, Aimee Bence Lin, Lily Q. Li, Anna McGlothlin, Daphne L. Farrington, Eric H. Westin, Roger B. Cohen

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Purpose: This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. Methods: Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125–16 mg/m2/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels. Results: One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/m2/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies. Conclusions: On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/m2/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/m2/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle.

Original languageEnglish (US)
Pages (from-to)315-326
Number of pages12
JournalCancer Chemotherapy And Pharmacology
Volume79
Issue number2
DOIs
StatePublished - Feb 1 2017
Externally publishedYes

Keywords

  • Antimitotic
  • Eg5
  • Kinesin spindle protein (KSP)
  • KSP inhibitor
  • Phase 1

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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