phosphomannopentaose-sulfate and Neoplasms

The heparan sulfate mimetic PI-88 (muparfostat) is a complex mixture of sulfated oligosaccharides that was identified in the late 1990s as a potent inhibitor of heparanase. In preclinical animal models it was shown to block angiogenesis, metastasis and tumor growth, and subsequently became the first heparanase inhibitor to enter clinical trials for cancer. It progressed to Phase III trials but ultimately was not approved for use. Herein we summarize the preparation, physicochemical and biological properties of PI-88, and discuss preclinical/clinical and structure-activity relationship studies. In addition, we discuss the PI-88-inspired development of related HS mimetic heparanase inhibitors with improved properties, ultimately leading to the discovery of PG545 (pixatimod) which is currently in clinical trials.

Topics: Animals; Antineoplastic Agents; Glucuronidase; Heparitin Sulfate; Humans; Neoplasms; Neovascularization, Pathologic; Oligosaccharides; Structure-Activity Relationship

Topics: Animals; Cell Proliferation; Gene Expression Regulation, Enzymologic; Glucuronidase; Humans; Myocytes, Smooth Muscle; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Oligosaccharides

Topics: Animals; Antineoplastic Agents; Carbohydrate Sequence; Cloning, Molecular; DNA, Complementary; Endopeptidases; Enzyme Precursors; Extracellular Matrix; Gene Expression Regulation, Enzymologic; Glucuronidase; Heparitin Sulfate; Humans; Molecular Sequence Data; Neoplasms; Oligosaccharides

The aim of this study was to investigate typical population pharmacokinetic (PK) parameters, potential covariates, and interindividual and residual variabilities of PI-88, a heparanase endoglycosidase enzyme inhibitor being developed for the treatment of cancer.. A population PK model of PI-88 was developed and evaluated using nonlinear mixed effects modeling (NONMEM). Plasma concentration versus time data was obtained from a total of 76 subjects that participated in phase I trials of PI-88 delivered subcutaneously (SC) at doses ranging from 80 to 315 mg. Overall, the PK effects of 12 clinical covariates were evaluated, including weight, age, creatinine clearance, body surface area, body mass index, sex, cancer (vs. healthy subject), docetaxel coadministration, prior chemotherapy, prior investigational therapy, prior radiotherapy and prior surgery.. Population PK analysis of the data-set showed that apparent clearance (CL/F) and apparent volume of distribution (V/F) of PI-88 were positively correlated with body surface area and the absorption rate constant (KA) was positively correlated with body mass index. In addition, CL/F was found to be significantly lower in patients with malignancies versus healthy subjects. By incorporating these covariates into the PK parameter equations, the interindividual variability of CL/F was reduced from 30.6 to 20.2% (decrease of 34%), V/F was reduced from 31.4 to 20.7% (decrease of 34.1%) and KA was reduced from 52.6 to 46.2% (decrease of 12.2%).. This population PK model indicates that the PK variability of PI-88 can be significantly reduced by taking BSA into account when dosing this drug SC.

Topics: Adult; Aged; Algorithms; Area Under Curve; Enzyme Inhibitors; Female; Glucuronidase; Humans; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Neoplasms; Oligosaccharides; Time Factors; Young Adult

This study evaluated the safety, toxicity, pharmacological properties and biological activity of PI-88, a heparanase endoglycosidase enzyme inhibitor, with fixed weekly docetaxel in patients with advanced solid malignancies.. This was a phase I study to determine the maximal-tolerated dose of escalating doses of PI-88 administered subcutaneously for 4 days per week, along with docetaxel 30 mg/m(2) given on days 1, 8, 15 of a 28-day schedule.. Sixteen patients received a total of 42 courses of therapy. No dose-limiting toxicities were observed despite escalation to the highest planned dose level of PI-88 (250 mg/day). Frequent minor toxicities included fatigue (38%), dysgeusia (28.5%), thrombocytopenia (12%), diarrhea (14%), nausea (12%), and emesis (10%) in the 42 courses. No significant bleeding complications were observed. One patient developed a positive anti-heparin antibody test/serotonin releasing assay with positive anti-platelet factor 4/PI-88 antibodies and grade 1 thrombocytopenia in cycle 5, and was withdrawn from the study without any sequelae. PI-88 plasma concentrations (mirrored by APTT) and urinary elimination were linear and dose-proportional. Docetaxel did not alter the pharmacokinetic (PK) profile of PI-88, nor did PI-88 affect docetaxel PK. No significant relationship was determined between plasma or urine FGF-2, or plasma VEGF levels and PI-88 dose/response. Although no objective responses were observed; 9 of the 15 evaluable patients had stable disease for greater than two cycles of therapy.. PI-88 administered at 250 mg/day for 4 days each week for 3 weeks with docetaxel 30 mg/m(2) on days 1, 8 and 15, every 28 days, was determined to be the recommended dose level for phase II evaluation. This combination was well tolerated without severe toxicities or PK interactions.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Docetaxel; Drug Administration Schedule; Fatigue; Female; Fibroblast Growth Factor 2; Gastrointestinal Diseases; Glucuronidase; Heparin; Humans; Male; Maximum Allowable Concentration; Middle Aged; Neoplasm Proteins; Neoplasms; Oligosaccharides; Partial Thromboplastin Time; Platelet Factor 4; Taxoids; Vascular Endothelial Growth Factor A

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.. 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).. 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.. 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.

Topics: Adult; Aged; Antibody Formation; Antineoplastic Agents; Carcinoid Tumor; Carcinoma, Renal Cell; Colorectal Neoplasms; Female; Fibroblast Growth Factors; Glucuronidase; Humans; Leiomyosarcoma; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Neoplasms; Oligosaccharides; Partial Thromboplastin Time; Vascular Endothelial Growth Factor A

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.. 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.. 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.. 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.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Incidence; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Oligosaccharides; Risk Assessment; Survival Analysis; Thrombocytopenia; Treatment Outcome

Growth factors that stimulate angiogenesis are vital in tumor development and maintenance. Inhibitors of angiogenesis are emerging as key elements in anticancer treatments, and now antibodies and small molecule kinase inhibitors are approved in the treatment of a variety of solid tumors. These have shown modest but statistically significant benefit in colon, breast and lung cancers. PI-88 has a novel mechanism of action compared to the drugs on the market today. By inhibiting heparanase, PI-88 blocks angiogenesis on several different cellular and biological levels. Promising results from Phase I/II trials are being seen with PI-88 in a variety of tumor types including melanoma and hepatocellular carcinoma. However, the development of antibody-induced thrombocytopenia has limited its use in some patients.

Topics: Angiogenesis Inhibitors; Animals; Clinical Trials as Topic; Humans; Neoplasms; Oligosaccharides; Signal Transduction; Treatment Outcome