A phase I biological and pharmacologic study of the heparanase inhibitor PI-88 in patients with advanced solid tumors.

Abstract

PURPOSE:

PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to heparan sulfate. This agent showed potent inhibition of placental blood vessel angiogenesis as well as growth inhibition in multiple xenograft models, thus forming the basis for this study.

EXPERIMENTAL DESIGN:

This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive days bimonthly (part 1) or weekly (part 2).

RESULTS:

Forty-two patients [median age, 53 years (range, 19-78 years); median performance status, 1] with a range of advanced solid tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin time and injection site echymosis. The pharmacokinetics were linear with dose. Intrapatient variability was low and interpatient variability was moderate. Both AUC and C(max) correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point can be used as a surrogate for drug exposure. No association between PI-88 administration and vascular endothelial growth factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which was maintained for >50 months, and 9 patients had stable disease for >or=6 months.

CONCLUSION:

The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials.

• Authors: Michele Basche, Daniel L Gustafson, Scott N Holden, Cindy L O'Bryant, Lia Gore, Samir Witta, Mary Kay Schultz, Mark Morrow, Adrah Levin, Brian R Creese, Michael Kangas, Kaye Roberts, Thu Nguyen, Kat Davis, Russell S Addison, Jane C Moore, S Gail Eckhardt
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 18 Pg. 5471-80 (Sep 15 2006) ISSN: 1078-0432 [Print] United States
• PMID: 17000682 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Oligosaccharides
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• phosphomannopentaose sulfate
• Fibroblast Growth Factors
• heparanase
• Glucuronidase

Topics

• Adult
• Aged
• Antibody Formation (drug effects)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoid Tumor (drug therapy)
• Carcinoma, Renal Cell (drug therapy)
• Colorectal Neoplasms (drug therapy)
• Female
• Fibroblast Growth Factors (blood)
• Glucuronidase (antagonists & inhibitors)
• Humans
• Leiomyosarcoma (drug therapy)
• Male
• Maximum Tolerated Dose
• Melanoma (drug therapy)
• Middle Aged
• Neoplasms (drug therapy)
• Oligosaccharides (blood, pharmacokinetics, therapeutic use, toxicity)
• Partial Thromboplastin Time
• Vascular Endothelial Growth Factor A (blood)