Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer

J Clin Oncol. 2016 May 20;34(15):1764-71. doi: 10.1200/JCO.2015.64.5788. Epub 2016 Apr 4.

Abstract

Purpose: The primary objective was to determine safety, toxicity, and a recommended phase II dose regimen of LY2606368, an inhibitor of checkpoint kinase 1, as monotherapy.

Patients and methods: This phase I, nonrandomized, open-label, dose-escalation trial used a 3 + 3 dose-escalation scheme and included patients with advanced solid tumors. Intravenous LY2606368 was dose escalated from 10 to 50 mg/m(2) on schedule 1 (days 1 to 3 every 14 days) or from 40 to 130 mg/m(2) on schedule 2 (day 1 every 14 days). Safety measures and pharmacokinetics were assessed, and pharmacodynamics were measured in blood, hair follicles, and circulating tumor cells.

Results: Forty-five patients were treated; seven experienced dose-limiting toxicities (all hematologic). The maximum-tolerated doses (MTDs) were 40 mg/m(2) (schedule 1) and 105 mg/m(2) (schedule 2). The most common related grade 3 or 4 treatment-emergent adverse events were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. Grade 4 neutropenia occurred in 73.3% of patients and was transient (typically < 5 days). Febrile neutropenia incidence was low (7%). The LY2606368 exposure over the first 72 hours (area under the curve from 0 to 72 hours) at the MTD for each schedule coincided with the exposure in mouse xenografts that resulted in maximal tumor responses. Minor intra- and intercycle accumulation of LY2606368 was observed at the MTDs for both schedules. Two patients (4.4%) had a partial response; one had squamous cell carcinoma (SCC) of the anus and one had SCC of the head and neck. Fifteen patients (33.3%) had a best overall response of stable disease (range, 1.2 to 6.7 months), six of whom had SCC.

Conclusion: An LY2606368 dose of 105 mg/m(2) once every 14 days is being evaluated as the recommended phase II dose in dose-expansion cohorts for patients with SCC.

Trial registration: ClinicalTrials.gov NCT01115790.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Checkpoint Kinase 1 / antagonists & inhibitors*
  • Female
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrazines / pharmacokinetics
  • Pyrazines / therapeutic use*
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / therapeutic use*

Substances

  • Protein Kinase Inhibitors
  • Pyrazines
  • Pyrazoles
  • prexasertib
  • Checkpoint Kinase 1

Associated data

  • ClinicalTrials.gov/NCT01115790