Phase I study of GSK461364, a specific and competitive Polo-like kinase 1 inhibitor, in patients with advanced solid malignancies

David Olmos, Douglas Barker, Rohini Sharma, Andre T Brunetto, Timothy A Yap, Anne B Taegtmeyer, Jorge Barriuso, Hanine Medani, Yan Y Degenhardt, Alicia J Allred, Deborah A Smith, Sharon C Murray, Thomas A Lampkin, Mohammed M Dar, Richard Wilson, Johann S de Bono, Sarah P Blagden

Research output: Contribution to journalArticlepeer-review

Abstract

PURPOSE: GSK461364 is an ATP-competitive inhibitor of polo-like kinase 1 (Plk1). A phase I study of two schedules of intravenous GSK461364 was conducted.

EXPERIMENTAL DESIGN: GSK461364 was administered in escalating doses to patients with solid malignancies by two schedules, either on days 1, 8, and 15 of 28-day cycles (schedule A) or on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (schedule B). Assessments included pharmacokinetic and pharmacodynamic profiles, as well as marker expression studies in pretreatment tumor biopsies.

RESULTS: Forty patients received GSK461364: 23 patients in schedule A and 17 in schedule B. Dose-limiting toxicities (DLT) in schedule A at 300 mg (2 of 7 patients) and 225 mg (1 of 8 patients) cohorts included grade 4 neutropenia and/or grade 3-4 thrombocytopenia. In schedule B, DLTs of grade 4 pulmonary emboli and grade 4 neutropenia occurred at 7 or more days at 100 mg dose level. Venous thrombotic emboli (VTE) and myelosuppression were the most common grade 3-4, drug-related events. Pharmacokinetic data indicated that AUC (area under the curve) and C(max) (maximum concentration) were proportional across doses, with a half-life of 9 to 13 hours. Pharmacodynamic studies in circulating tumor cells revealed an increase in phosphorylated histone H3 (pHH3) following drug administration. A best response of prolonged stable disease of more than 16 weeks occurred in 6 (15%) patients, including 4 esophageal cancer patients. Those with prolonged stable disease had greater expression of Ki-67, pHH3, and Plk1 in archived tumor biopsies.

CONCLUSIONS: The final recommended phase II dose for GSK461364 was 225 mg administered intravenously in schedule A. Because of the high incidence (20%) of VTE, for further clinical evaluation, GSK461364 should involve coadministration of prophylactic anticoagulation.

Original languageEnglish
Pages (from-to)3420-30
Number of pages11
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Volume17
Issue number10
DOIs
Publication statusPublished - 15 May 2011

Keywords

  • Adenocarcinoma/drug therapy
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents/metabolism
  • Benzimidazoles/metabolism
  • Binding, Competitive
  • Cell Cycle Proteins/antagonists & inhibitors
  • Colorectal Neoplasms/drug therapy
  • Disease Progression
  • Female
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms/drug therapy
  • Protein Kinase Inhibitors/metabolism
  • Protein-Serine-Threonine Kinases/antagonists & inhibitors
  • Proto-Oncogene Proteins/antagonists & inhibitors
  • Substrate Specificity
  • Thiophenes/metabolism

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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