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

Basche, Michele, Gustafson, Daniel L., Holden, Scott N., O'Bryant, Cindy L., Gore, Lia, Witta, Samir, Schultz, Mary Kay, Morrow, Mark, Levin, Adrah, Creese, Brian R., kangas, Michael, Roberts, Kaye, Nguyen, Thu, Davis, Kat and Addison, Russell S. (2006) A phase I biological and pharmacologic study of the heparanase inhibitor PI-88 in patients with advanced solid tumors. Clinical Cancer Research, 12 18: 5471-5480. doi:10.1158/1078-0432.CCR-05-2423


Author Basche, Michele
Gustafson, Daniel L.
Holden, Scott N.
O'Bryant, Cindy L.
Gore, Lia
Witta, Samir
Schultz, Mary Kay
Morrow, Mark
Levin, Adrah
Creese, Brian R.
kangas, Michael
Roberts, Kaye
Nguyen, Thu
Davis, Kat
Addison, Russell S.
Title A phase I biological and pharmacologic study of the heparanase inhibitor PI-88 in patients with advanced solid tumors
Journal name Clinical Cancer Research   Check publisher's open access policy
ISSN 1078-0432
Publication date 2006-09
Sub-type Article (original research)
DOI 10.1158/1078-0432.CCR-05-2423
Volume 12
Issue 18
Start page 5471
End page 5480
Total pages 10
Place of publication Philadelphia
Publisher American Association for Cancer Research.
Collection year 2006
Language eng
Subject CX
1112 Oncology and Carcinogenesis
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 >= 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.
Keyword Recombinant Human Endostatin
Pancreatic Adenocarcinoma
Gene-expression
Growth-factors
Angiogenesis
Metastasis
Cancer
Sulfate
Invasion
Q-Index Code CX
Additional Notes Michele Basche1, Daniel L. Gustafson1, Scott N. Holden1, Cindy L. O'Bryant1, Lia Gore1, Samir Witta1, Mary Kay Schultz1, Mark Morrow1, Adrah Levin1, Brian R. Creese2, Michael Kangas2, Kaye Roberts2, Thu Nguyen2, Kat Davis2, Russell S. Addison3, Jane C. Moore4 and S. Gail Eckhardt

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
 
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Created: Wed, 15 Aug 2007, 08:18:15 EST