Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer.
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.
Khasraw
M
M
Department of Oncology, Royal North Shore Hospital. Electronic address: mkhasraw@med.usyd.edu.au.
Pavlakis
N
N
Department of Oncology, Royal North Shore Hospital.
McCowatt
S
S
Department of Oncology, Royal North Shore Hospital; Sydney New South Wales Haematology and Oncology Clinics, Sydney, New South Wales.
Underhill
C
C
Border Medical Oncology, Wodonga, Victoria.
Begbie
S
S
Department of Oncology, Port Macquarie Base Hospital, Port Macquarie.
de Souza
P
P
UNSW, St George Hospital Clinical School, Sydney.
Boyce
A
A
Department of Oncology, Lismore Base Hospital, Lismore, New South Wales.
Parnis
F
F
Ashford Cancer Centre, Adelaide, South Australia, Australia.
Lim
V
V
Department of Oncology, Royal North Shore Hospital.
Harvie
R
R
Department of Oncology, Royal North Shore Hospital.
Marx
G
G
Department of Oncology, Royal North Shore Hospital; Sydney New South Wales Haematology and Oncology Clinics, Sydney, New South Wales.
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
D000077143:Docetaxel; D005966:Glucuronidase; D009844:Oligosaccharides; D043823:Taxoids; D000099175:Heparanase; C120158:phosphomannopentaose sulfate