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 z6 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.

Phase I Study and Preliminary Pharmacology of the Novel Innate Immune Modulator rBBX-01 in Gynecologic Cancers

“…The increase to peak levels and the decay from the blood is typical of other proteins and peptides given as subcutaneous treatments (e.g., see refs. 21,22). Preliminary estimates of the pharmacokinetic variables from two individuals are as follows: volume of distribution, Vd = f0.72 L/kg; plasma half-life, s 1/2 = 5.7 hours; maximum plasma concentration, C max = f0.03 ng/ mL; and area under the concentration  time curve, AUC = 0.4 Ag/L/h.…”

“…The drug is well tolerated over a 1,000-fold range of doses, with no observable toxicity or discomfort. Pharmacokinetic analysis indicated a plasma concentration profile and clearance typical for subcutaneously injected proteins and peptides (21,22). Limited pharmacodynamic analysis revealed increases in IL-12 in some patients during the week of injections, which tended to correlate with delayed reductions in CA125 following the 30-day time frame.…”

Expression of Heparanase in Renal Cell Carcinomas: Implications for Tumor Invasion and Prognosis

“…PI-88 is a representative of heparanase inhibitors and is being evaluated in a phase II clinical trial (23). However, due to the toxicity consisted of thrombocytopenia and pulmonary embolism, clinical trials using heparanase inhibitors require further investigations (24). Therefore, a blockade of the gene expression of heparanase by siRNA may be a promising alternative strategy.…”

Role of Angiogenesis and Microenvironment in Melanoma Progression

“…Moreover, preclinical data strongly support the use of a combination of Bevacizumab and Erlotinib, a tyrosine kinase receptors inhibitor (Varker et al, 2007;Perez et al, 2009;Vásquez et al, 2009;Schicher et al, 2009). PI-88, a potent inhibitor of heparanase, demonstrates an overall survival and time to progression similar to standard chemotherapy (Basche et al, 2006). In a phase II trial (Lewis et al, 2008) a total of 44 patients were enrolled with about 60% of them previously treated.…”