Treatment with the novel anti-angiogenic agent PI-88 is associated with immune-mediated thrombocytopenia

Rosenthal, Mark; Rischin, Danny; McArthur, Grant A.; Ribbons, Karen; Chong, Beng H.; Fareed, Jawed; Toner, Guy C.; Green, M. D.; Basser, Russell L.

doi:10.1093/annonc/mdf117

Cited by 56 publications

(40 citation statements)

References 12 publications

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“…PI-88 was not associated with clinically significant bleeding. We suspect no correlation between PI-88 dose and APTT was found in the initial phase I trial because insufficient doses were evaluated in that trial (19). Prior studies have shown that PI-88 prolongs the APTT by potentiating heparin cofactor II -mediated inhibition of thrombin activity.…”

Section: Discussionmentioning

confidence: 96%

“…Both patients developed anti-heparin platelet factor 4 (PF4) complex antibodies, suggesting that the thrombocytopenia was immune mediated. Only 2 of 14 patients developed prolongation of the activated partial thromboplastin time (APTT), a pharmacodynamic marker of PI-88 (19). Thus, because of the development of dose-limiting toxicity (DLT) in the absence of appreciable pharmacodynamic effects, an alternative dosing strategy was evaluated using a s.c. formulation.…”

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confidence: 99%

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A Phase I Biological and Pharmacologic Study of the Heparanase Inhibitor PI-88 in Patients with Advanced Solid Tumors

Basche

Gustafson

Holden

et al. 2006

Clinical Cancer Research

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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.

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

A Phase I Biological and Pharmacologic Study of the Heparanase Inhibitor PI-88 in Patients with Advanced Solid Tumors

Basche

Gustafson

Holden

et al. 2006

Clinical Cancer Research

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“…It is known that one or more neoepitopes on PF4 18,36,37 are created when PF4 forms complexes with heparin (or certain other polyanions 36,[38][39][40] ) at an optimal PF4-heparin stoichiometric ratio. However, unlike these other molecules, our studies show fondaparinux is unique in that although its administration can be associated with formation of anti-PF4/heparin antibodies that are indistinguishable from those generated during LMWH therapy, these antibodies do not bind well to PF4/fondaparinux, at least under the physicochemical conditions we used.…”

Section: Discussionmentioning

confidence: 99%

Anti–platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin

Warkentin

Cook

Marder

et al. 2005

Blood

256

177

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Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating IgG antibodies that recognize platelet factor 4 (PF4) bound to heparin. Immunogenicity of heparins differs in that unfractionated heparin (UFH) induces more anti-PF4/heparin antibodies than low-molecular-weight heparin (LMWH) and UFH also causes more HIT. Fondaparinux, a synthetic anticoagulant modeled after the antithrombin-binding pentasaccharide, is believed to be nonimmunogenic. We tested 2726 patients for anti-PF4/heparin antibodies after they were randomized to receive antithrombotic prophylaxis with fondaparinux or LMWH (enoxaparin) following hip or knee surgery. We also evaluated in vitro cross-reactivity of the IgG antibodies generated against PF4 in the presence of UFH, LMWH, danaparoid, or fondaparinux. We found that anti-PF4/heparin antibodies were generated at similar frequencies in patients treated with fondaparinux or enoxaparin. Although antibodies reacted equally well in vitro against PF4/UFH and PF4/ LMWH, and sometimes weakly against PF4/danaparoid, none reacted against PF4/fondaparinux, including even those sera obtained from patients who formed antibodies during fondaparinux treatment. At high concentrations, however, fondaparinux inhibited binding of HIT antibodies to PF4/polysaccharide, indicating that PF4/ fondaparinux interactions occur. No patient developed HIT. We conclude that despite similar immunogenicity of fondaparinux and LMWH, PF4/fondaparinux, but not PF4/ LMWH, is recognized poorly by the antibodies generated, suggesting that the risk of HIT with fondaparinux likely is very low.

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“…15), PI-88 (16,28), and pentosan polysulfate (29). These studies have revealed that the principal toxicities of this class of compound are overanticoagulation and immune-mediated thrombocytopenia.…”

Section: Discussionmentioning

confidence: 99%

“…Several attempts to generate saccharide inhibitors of this mechanism have yielded molecules that have been associated with dose-limiting anticoagulation (15), thrombocytopenia (16), or other toxicities. Thus, in this study, we also present in vitro data on the safety of short oligosaccharides with respect to anticoagulation at clinically relevant concentrations.…”

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confidence: 99%

Heparin Octasaccharides Inhibit Angiogenesis In vivo

Hasan

Shnyder

Clamp

et al. 2005

Clinical Cancer Research

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Background: In previous experiments, we showed that heparin oligosaccharides inhibit the angiogenic cytokine fibroblast growth factor-2. Here, we present the first in vivo study of sizefractionated heparin oligosaccharides in four models of angiogenesis that are progressively less dependent on fibroblast growth factor-2. Experimental Design: Heparin oligosaccharides were prepared using size-exclusion gel filtration chromatography and characterized through depolymerization and strong anion exchange high-performance liquid chromatography. Size-defined oligosaccharides (20 mg/kg/d) were given to mice bearing s.c. sponges that were injected with fibroblast growth factor-2 (100 ng/d). After 14 days, octasaccharides and decasaccharides reduced the microvessel density to levels below control. In a second experiment, HEC-FGF2 human endometrial cancer cells that overexpress fibroblast growth factor-2 were implanted in a hollow fiber placed s.c. in vivo. Oligosaccharides were given at 20 mg/kg/d for 2 weeks and the data again showed that octasaccharides significantly reduced microvessel density around the fiber (P = 0.03). In a more complex model, where angiogenesis was induced by a broad spectrum of growth factors, including vascular endothelial growth factor, we implanted H460 lung carcinoma cells in hollow fibers and treated the animals with oligosaccharides at 20 mg/kg/d over 3 weeks. Octasaccharides reduced the microvessel density to that of control. Preliminary investigation of 6-O-desulfated heparins showed that these also had antiangiogenic activity. Results: Finally, we examined the inhibitory potential of hexasaccharides and octasaccharides given at 20 mg/kg/d and these inhibited the growth of H460 lung carcinoma in vivo. At clinically attainable concentrations, significant anticoagulation (activated partial thromboplastin time, anti^factor Xa, and anti^factor IIa) was not observed in vitro unless species containing z16 saccharide residues were investigated. Conclusions: Thus, our preclinical data show that heparin octasaccharides represent novel antiangiogenic compounds that can be given without the anticoagulant effects of low molecular weight heparin.

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Treatment with the novel anti-angiogenic agent PI-88 is associated with immune-mediated thrombocytopenia

Abstract: 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.

Cited by 56 publications

References 12 publications

A Phase I Biological and Pharmacologic Study of the Heparanase Inhibitor PI-88 in Patients with Advanced Solid Tumors

A Phase I Biological and Pharmacologic Study of the Heparanase Inhibitor PI-88 in Patients with Advanced Solid Tumors

Anti–platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin

Heparin Octasaccharides Inhibit Angiogenesis In vivo

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