title: A phase I pharmacological and biological study of PI-88 and docetaxel in patients with advanced malignancies.
abstract: OBJECTIVE
  This study evaluated the safety, toxicity, pharmacological properties and biological activity of PI-88, a heparanase endoglycosidase enzyme inhibitor, with fixed weekly docetaxel in patients with advanced solid malignancies.
  
  
  METHODS
  This was a phase I study to determine the maximal-tolerated dose of escalating doses of PI-88 administered subcutaneously for 4 days per week, along with docetaxel 30 mg/m(2) given on days 1, 8, 15 of a 28-day schedule.
  
  
  RESULTS
  Sixteen patients received a total of 42 courses of therapy. No dose-limiting toxicities were observed despite escalation to the highest planned dose level of PI-88 (250 mg/day). Frequent minor toxicities included fatigue (38%), dysgeusia (28.5%), thrombocytopenia (12%), diarrhea (14%), nausea (12%), and emesis (10%) in the 42 courses. No significant bleeding complications were observed. One patient developed a positive anti-heparin antibody test/serotonin releasing assay with positive anti-platelet factor 4/PI-88 antibodies and grade 1 thrombocytopenia in cycle 5, and was withdrawn from the study without any sequelae. PI-88 plasma concentrations (mirrored by APTT) and urinary elimination were linear and dose-proportional. Docetaxel did not alter the pharmacokinetic (PK) profile of PI-88, nor did PI-88 affect docetaxel PK. No significant relationship was determined between plasma or urine FGF-2, or plasma VEGF levels and PI-88 dose/response. Although no objective responses were observed; 9 of the 15 evaluable patients had stable disease for greater than two cycles of therapy.
  
  
  CONCLUSIONS
  PI-88 administered at 250 mg/day for 4 days each week for 3 weeks with docetaxel 30 mg/m(2) on days 1, 8 and 15, every 28 days, was determined to be the recommended dose level for phase II evaluation. This combination was well tolerated without severe toxicities or PK interactions.
authors.affiliation: University of Colorado Heath Sciences Center, Aurora, CO, USA. laurachow@hotmail.com
authors.forename: Laura Q M
authors.initials: LQ
authors.lastname: Chow
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gustafson
authors.forename: Cindy L
authors.initials: CL
authors.lastname: O'Bryant
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
authors.forename: Michele
authors.initials: M
authors.lastname: Basche
authors.forename: Scott N
authors.initials: SN
authors.lastname: Holden
authors.forename: Mark C
authors.initials: MC
authors.lastname: Morrow
authors.forename: Stacy
authors.initials: S
authors.lastname: Grolnic
authors.forename: Brian R
authors.initials: BR
authors.lastname: Creese
authors.forename: Kaye L
authors.initials: KL
authors.lastname: Roberts
authors.forename: Kat
authors.initials: K
authors.lastname: Davis
authors.forename: Russell
authors.initials: R
authors.lastname: Addison
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000652:urine; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D005966:Glucuronidase / Q000037:antagonists & inhibitors; D006493:Heparin / Q000276:immunology; D006801:Humans; D008297:Male; D008452:Maximum Allowable Concentration; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D009844:Oligosaccharides / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D010314:Partial Thromboplastin Time; D010978:Platelet Factor 4 / Q000276:immunology; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D042461:Vascular Endothelial Growth Factor A / Q000652:urine; D000099175:Heparanase
chemical_list: D020533:Angiogenesis Inhibitors; D000077143:Docetaxel; D016222:Fibroblast Growth Factor 2; D005966:Glucuronidase; D006493:Heparin; D009363:Neoplasm Proteins; D009844:Oligosaccharides; D010978:Platelet Factor 4; D043823:Taxoids; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase; C467484:VEGFA protein, human; C120158:phosphomannopentaose sulfate