title: Treatment with the novel anti-angiogenic agent PI-88 is associated with immune-mediated thrombocytopenia.
abstract: BACKGROUND
  The novel molecule PI-88 is a highly sulfonated oligosaccharide which inhibits heparanase activity and competes with heparan sulfate binding of growth factors such as FGF and VEGF. Preclinical data demonstrates that PI-88 inhibits angiogenesis and has anti-metastatic effects. The aim of this phase I study was to determine the recommended dose and toxicity profile of PI-88.
  
  
  METHODS
  PI-88 was given intravenously in increasing duration of administration (0.57 mg/kg for 2 h, 0.57 mg/kg/day for 1 day, 4, 7 and 14 consecutive days) and then increasing dose for 14 consecutive days (1.14 mg/kg/day and 2.28 mg/kg/day) in patients with advanced malignancies until dose-limiting toxicity (DLT) was observed. Fourteen assessable patients with advanced malignancies received PI-88 intravenously.
  
  
  RESULTS
  DLT was thrombocytopenia. The thrombocytopenia appeared to be immunologically mediated with the development of anti-heparin platelet factor 4 complex antibodies. There were no other significant toxicities. At the final dose and schedule (2.28 mg/kg/day for 14 days), there was limited evidence of biological activity as measured by the surrogate marker activated partial thromboplastin time (APTT), although two patients had stabilisation of disease.
  
  
  CONCLUSIONS
  In conclusion, PI-88 at a dose of 2.28 mg/kg/day for 14 days resulted in dose-limiting thrombocytopenia which appeared to be immune related. Limited evidence of biological activity was noted. Alternate scheduling and routes of administration are now being explored.
authors.affiliation: Department of Medical Oncology and Clinical Hematology, Royal Melbourne Hospital, Parkville, Victoria, Australia. mark.rosenthal@mh.org.au
authors.forename: M A
authors.initials: MA
authors.lastname: Rosenthal
authors.forename: D
authors.initials: D
authors.lastname: Rischin
authors.forename: G
authors.initials: G
authors.lastname: McArthur
authors.forename: K
authors.initials: K
authors.lastname: Ribbons
authors.forename: B
authors.initials: B
authors.lastname: Chong
authors.forename: J
authors.initials: J
authors.lastname: Fareed
authors.forename: G
authors.initials: G
authors.lastname: Toner
authors.forename: M D
authors.initials: MD
authors.lastname: Green
authors.forename: R L
authors.initials: RL
authors.lastname: Basser
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009844:Oligosaccharides / Q000008:administration & dosage* / Q000009:adverse effects*; D018570:Risk Assessment; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000453:epidemiology; D016896:Treatment Outcome
chemical_list: D009844:Oligosaccharides; C120158:phosphomannopentaose sulfate