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Heparanase Inhibitor May Inhibit Angiogenesis, Promote Response to Cancer Treatment: Presented at EORTC-NCI-AACR

By Paula Moyer
Special to DG News

FRANKFURT, GERMANY -- November 25, 2002 -- Patients who receive a heparanase inhibitor may have a more robust response to chemotherapy.

Dr. Scott N. Holden, an oncologist with the University of Colorado Cancer Center in Denver, Colorado, and a consultant with Developmental Therapeutics, in Aurora, Colorado, United States, presented the finding here November 22 at the 14^th joint meeting of the European Organisation for the Research and Treatment of Cancer - National Cancer Institute - American Association for Cancer Research (EORTC-NCI-AARC): Symposium on Molecular Targets and Cancer Therapeutics.

"Our results show that a heparanase inhibitor administered subcutaneously on the schedule used in our research is well tolerated, achieves plasma concentrations capable of biologic activity, and demonstrates antitumour activity," said Dr. Holden.

The rationale for their study of a heparanase inhibitor, in this case the investigative agent PI-88, was that heparin sulphates of the extracellular matrix bind and sequester pro-angiogenic growth factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). Further, heparanase is over expressed in many cancers and promotes angiogenesis by facilitating tissue remodeling and growth release from the extracellular matrix.

The investigative agent, PI-88, is a highly sulphated oligosaccharide that interferes with growth factor binding to heparin sulphates and also inhibits the release of heparanase. Previous animal studies showed it inhibits angiogenesis, tumour growth, and metastasis.

Dr. Holden and colleagues wanted to determine the safety, pharmacokinetic behaviour, and biological effects of 80 to 250 mg of PI-88 when given subcutaneously on days 1 through 4 and on days 15 to 19 of a 28-day cycle to patients with several types of advanced cancer.

They also gave the patients 20 mg of dexamethasone orally on the day before PI-88 treatment began, on the first day of treatment, and on days 14 and 15 to guard against immune-mediated thrombocytopaenia. The rationale for the regimen included the convenience of subcutaneous administration and the possible identification of a toxicity profile that would be distinct from that associated with prolonged intravenous administration.

The researchers collected data on 21 patients with a median age 56 years old and who range from 19 to 77 years old. The patients received a total of 40 courses of treatment, ranging from one to 11 per patient.

They documented certain grade 1 and 2 toxicities, including grade 1 bruising at the injection site in 36 courses of treatment, grade 1-2 pain at known tumour sites in 12 courses and grade 3 pain at such sites in two courses, grade 1-2 fatigue in 13 courses, and grade 1-2 peripheral neuropathy in four courses. They documented two severe adverse events, a case of pneumonia and the development of a second malignancy, neither of which was considered related to the study drug.

Dr. Holden and his co-investigators noted that all patients except for one have had elevations in glucose levels, consisting of grade 1-2 elevations in 31 courses and grade 3-4 elevations -- considered true hyperglycaemia -- in four courses. They attributed these elevations to the dexamethasone.

"At this point, we have encountered no haematological or dose-limiting toxicity," he said. "Although there have been no partial or complete responses, 3 of the 15 evaluable patients have maintained stable disease through 2, 4, and 10 courses, respectively. One patient with melanoma refractory to biochemotherapy has had a decrease in the size and number of pulmonary metastases."

Pharmacokinetic analysis showed no evidence of drug accumulation with ongoing dosing. Patients in future studies will need to undergo dose escalation until the investigators identify a maximum tolerable dose. Phase II studies will soon begin in refractory or relapsing multiple myeloma, according to the researchers.

The study was funded by Progen Industries Limited, based in Darra, Australia, and by Developmental Therapeutics, which is developing PI-88.

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