title: Phase I study of GSK461364, a specific and competitive Polo-like kinase 1 inhibitor, in patients with advanced solid malignancies.
abstract: OBJECTIVE
  GSK461364 is an ATP-competitive inhibitor of polo-like kinase 1 (Plk1). A phase I study of two schedules of intravenous GSK461364 was conducted.
  
  
  METHODS
  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.
authors: Drug Development Unit, Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Downs Road, Sutton, Surrey, United Kingdom.
authors: David
authors: D
authors: Olmos
authors: Douglas
authors: D
authors: Barker
authors: Rohini
authors: R
authors: Sharma
authors: Andre T
authors: AT
authors: Brunetto
authors: Timothy A
authors: TA
authors: Yap
authors: Anne B
authors: AB
authors: Taegtmeyer
authors: Jorge
authors: J
authors: Barriuso
authors: Hanine
authors: H
authors: Medani
authors: Yan Y
authors: YY
authors: Degenhardt
authors: Alicia J
authors: AJ
authors: Allred
authors: Deborah A
authors: DA
authors: Smith
authors: Sharon C
authors: SC
authors: Murray
authors: Thomas A
authors: TA
authors: Lampkin
authors: Mohammed M
authors: MM
authors: Dar
authors: Richard
authors: R
authors: Wilson
authors: Johann S
authors: JS
authors: de Bono
authors: Sarah P
authors: SP
authors: Blagden
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D001562:Benzimidazoles / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001667:Binding, Competitive; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity; D013876:Thiophenes / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013876:Thiophenes; D000097869:Polo-Like Kinase 1; C561573:GSK 461364; C544835:GSK 461364A