title: Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer.
abstract: BACKGROUND
  Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We studied the combination of PI-88, an inhibitor of angiogenesis and heparanase activity, and docetaxel in chemotherapy-naive CRPC.
  
  
  METHODS
  We conducted a multicentre open-label phase I/II trial of PI-88 in combination with docetaxel. The primary end point was PSA response. Secondary end points included toxicity, radiologic response and overall survival. Doses of PI-88 were escalated to the maximum tolerated dose; whereas docetaxel was given at a fixed 75 mg/m(2) dose every three weeks
  
  
  RESULTS
  Twenty-one patients were enrolled in the dose-escalation component. A further 35 patients were randomly allocated to the study to evaluate the two schedules in phase II trial. The trial was stopped early by the Safety Data Review Board due to a higher-than-expected febrile neutropenia of 27%. In the pooled population, the PSA response (50% reduction) was 70%, median survival was 61 weeks (6-99 weeks) and 1-year survival was 71%.
  
  
  CONCLUSIONS
  The regimen of docetaxel and PI-88 is active in CRPC but associated with significant haematologic toxicity. Further evaluation of different scheduling and dosing of PI-88 and docetaxel may be warranted to optimise efficacy with a more manageable safety profile.
authors.affiliation: Department of Oncology, Royal North Shore Hospital. Electronic address: mkhasraw@med.usyd.edu.au.
authors.forename: M
authors.initials: M
authors.lastname: Khasraw
authors.affiliation: Department of Oncology, Royal North Shore Hospital.
authors.forename: N
authors.initials: N
authors.lastname: Pavlakis
authors.affiliation: Department of Oncology, Royal North Shore Hospital; Sydney New South Wales Haematology and Oncology Clinics, Sydney, New South Wales.
authors.forename: S
authors.initials: S
authors.lastname: McCowatt
authors.affiliation: Border Medical Oncology, Wodonga, Victoria.
authors.forename: C
authors.initials: C
authors.lastname: Underhill
authors.affiliation: Department of Oncology, Port Macquarie Base Hospital, Port Macquarie.
authors.forename: S
authors.initials: S
authors.lastname: Begbie
authors.affiliation: UNSW, St George Hospital Clinical School, Sydney.
authors.forename: P
authors.initials: P
authors.lastname: de Souza
authors.affiliation: Department of Oncology, Lismore Base Hospital, Lismore, New South Wales.
authors.forename: A
authors.initials: A
authors.lastname: Boyce
authors.affiliation: Ashford Cancer Centre, Adelaide, South Australia, Australia.
authors.forename: F
authors.initials: F
authors.lastname: Parnis
authors.affiliation: Department of Oncology, Royal North Shore Hospital.
authors.forename: V
authors.initials: V
authors.lastname: Lim
authors.affiliation: Department of Oncology, Royal North Shore Hospital.
authors.forename: R
authors.initials: R
authors.lastname: Harvie
authors.affiliation: Department of Oncology, Royal North Shore Hospital; Sydney New South Wales Haematology and Oncology Clinics, Sydney, New South Wales.
authors.forename: G
authors.initials: G
authors.lastname: Marx
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D002369:Castration; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005966:Glucuronidase / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009844:Oligosaccharides / Q000008:administration & dosage* / Q000009:adverse effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects; D017211:Treatment Failure; D000099175:Heparanase
chemical_list: D000077143:Docetaxel; D005966:Glucuronidase; D009844:Oligosaccharides; D043823:Taxoids; D000099175:Heparanase; C120158:phosphomannopentaose sulfate