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Annals of Oncology 13:770-776, 2002
© 2002 European Society for Medical Oncology

Original Paper

Treatment with the novel anti-angiogenic agent PI-88 is associated with immune-mediated thrombocytopenia

M. A. Rosenthal1,+, D. Rischin2, G. McArthur2, K. Ribbons3, B. Chong4, J. Fareed5, G. Toner2, M. D. Green1 and R. L. Basser1

From the Center for Developmental Cancer Therapeutics, Parkville, Victoria, Australia affiliates: 1Department of Medical Oncology and Clinical Hematology, Royal Melbourne Hospital, Melbourne; 2Department of Medical Oncology, Peter MacCallum Cancer Institute, East Melbourne, Victoria; 3Progen Industries, Brisbane, Queensland; 4Department of Hematology, Prince of Wales Hospital, NSW, Australia; 5Hemostasis and Thrombosis Research Laboratories, Loyola University Medical Center, IL, USA

Received 19 June 2001; revised 1 October 2001; accepted 23 October 2001.

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.

Patients and 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.

Key words: anti-angiogenic, PI-88, thrombocytopenia


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