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Cancer Therapy: Clinical |
Authors' Affiliations: 1 University of Colorado Cancer Center, Aurora, Colorado; 2 Progen Industries Ltd., Darra, Queensland, Australia; 3 Centre for Studies in Drug Disposition, School of Medicine, University of Queensland, Brisbane, Queensland, Australia; and 4 McMaster University, Hamilton, Ontario, Canada
Requests for reprints: S. Gail Eckhardt, University of Colorado Cancer Center, 12801 East 17th Avenue, Campus Box 8117, Aurora, CO 80010. Phone: 303-724-3850; Fax: 303-724-3892; E-mail: gail.eckhardt{at}uchsc.edu.
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Abstract |
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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 Cmax 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.
PI-88 is a mixture of highly sulfated oligosaccharides derived from the yeast Pichia (Hanensula) holstii NRRL Y-2448 (14, 15). It was selected for development because it is a potent inhibitor of heparanase. PI-88 has shown antiangiogenic activity in vitro and in vivo, which is attributable to three distinct mechanisms: (a) inhibition of heparanase, an endoglycosidase that releases vascular endothelial growth factor (VEGF) and active complexes of fibroblast growth factor by cleaving heparan sulfate proteoglycans in blood vessel basement membranes and the extracellular matrix; (b) direct inhibition of heparan sulfate binding to the growth factors VEGF and fibroblast growth factor; and (c) stimulation of the release of tissue factor pathway inhibitor, an endogenous antiangiogenic protein (16–18).
Previously, PI-88 was tested in healthy volunteers by s.c. injection and in cancer patients by prolonged continuous infusion. First, a phase I trial was conducted in cancer patients evaluating PI-88 administered by prolonged i.v. infusion at doses between 0.57 and 2.28 mg/kg/d. Dose-limiting grade 3 thrombocytopenia occurred in two of six patients treated with 2.28 mg/kg/d as a 14-day infusion. 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. Next, a phase IA study evaluated s.c. administration of PI-88 in healthy volunteers. Doses of up to 160 mg were well tolerated. Mild injection site echymosis was noted as well as dose-dependent prolongation of the APTT. The maximum increase in APTT occurred 1 to 2 hours after dosing, and the levels returned to baseline within 14 hours after dosing. Mean ± SD bioavailability was 96 ± 22% (20). These results supported the evaluation of PI-88 by s.c. administration along with premedication with dexamethasone to potentially ameliorate immune-mediated thrombocytopenia. A fixed dose was evaluated because at the time there were no data available to support dosing by weight or body surface area.
Based on evidence showing the role of heparanase in angiogenesis and metastasis, encouraging preclinical data, and the favorable safety and pharmacokinetic profiles of PI-88 in healthy volunteers, the present phase I dose escalation study was undertaken in patients with advanced solid tumors. The objectives of this study were to (a) characterize the toxicities of PI-88 when administered s.c. daily for 4 consecutive days bimonthly or weekly, (b) determine the maximum tolerated dose (MTD) and recommended dose for subsequent phase II trials, (c) characterize the pharmacokinetic profile of PI-88 administered s.c. in this population, (d) seek preliminary evidence of antitumor activity in patients with advanced solid tumors, and (e) assess the effects of PI-88 on soluble biomarkers, including VEGF and basic fibroblast growth factor (bFGF).
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Patients and Methods |
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18 years; (b) Eastern Cooperative Oncology Group performance status 
2; (c) adequate hematopoietic function [absolute neutrophil count >1,500/µL, platelet count >100,000/µL, APTT within normal limits (20-34 seconds), prothrombin time <1.5 times the institutional upper limit of normal], adequate hepatic function (total bilirubin level <1.5 times the institutional upper limit of normal, aspartate aminotransferase and alanine aminotransferase concentrations 2.0 times the institutional upper limit of normal, unless due to hepatic metastases, in which case elevations 5.0 times the institutional upper limit of normal were permitted), and adequate renal function (calculated creatinine clearance >60 mL/min using the Cockcroft-Gault formula); (d) no concomitant use of aspirin, nonsteroidal anti-inflammatory medications (except selective cyclooxygenase-2 inhibitors), heparin, low molecular weight heparin, or warfarin; (e) no heparin within 2 weeks before enrollment; (f) no chemotherapy, investigational therapy, or hormonal therapy in the previous 4 weeks; and (g) no evidence of anti-heparin antibodies by the serotonin release assay (SRA). Patients with the following were excluded: (a) history of brain metastases, (b) history of platelet diseases or allergy to anticoagulants, (c) significant cardiovascular history (including myocardial infarction, stroke, or congestive heart failure within 3 months before enrolling in the study), (d) history of acute gastrointestinal bleeding within the past 2 years, or (e) concomitant illnesses of sufficient severity to limit participation or full compliance with the study guidelines. Female subjects of childbearing age were required to have a negative pregnancy test, and informed consent was obtained from all patients in compliance with federal and institutional guidelines. Drug administration. Patients received PI-88 on one of two dosing schedules. Patients enrolled in part 1 of the trial were dosed bimonthly starting at 80 mg PI-88 daily for 4 consecutive days (i.e., days 1-4 and 15-18 of a 28-day cycle). The starting dose was one half of the maximum dose evaluated in healthy volunteers. In an attempt to observe and potentially limit immune-mediated thrombocytopenia, PI-88 was administered for a maximum of 4 consecutive days followed by a 10-day observation period, and patients received 10 mg dexamethasone p.o. on the evening before starting each 4-day PI-88 treatment period. PI-88 was administered as a s.c. injection into the stomach, thigh, or arm. The starting dose of PI-88 (80 mg/d) was increased 33% for each subsequent dose level and there was no intrapatient dose escalation. Three patients were enrolled per cohort until DLT was experienced by one of the three patients in the cohort. DLT was defined as any of the following adverse events, which occurred during the first treatment course and were possibly related to treatment: (a) grade 3/4 nonhematologic toxicity (excluding nausea and vomiting), (b) grade 3/4 nausea or vomiting despite aggressive antiemetic support, (c) grade 4 neutropenia or neutropenia complicated by fever, (d) grade 3/4 thrombocytopenia, (e) APTT more than three times the upper limit of the institutional normal, or (f) grade 3 injection site reaction. In addition, inability to receive >75% of the planned study drug dose for the treatment period or inability to begin the next course of treatment within 2 weeks of the last dose due to unresolved toxicity qualified as dose limiting. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. If DLT was experienced by one patient, the treatment cohort was expanded to include up to six patients. If no others experienced DLT, dose escalation continued. If another patient experienced DLT within that cohort (for a total of two of six patients), the dose level before that was defined as the MTD. A total of 12 patients were treated at the determined MTD before advancing to part 2 of the study.
Once the MTD was established in part 1 of the study, the observation period between periods of consecutive daily dosing was reduced from 10 to 3 days, and the safety and tolerability of PI-88 was reevaluated. Patients enrolled in part 2 of the trial were dosed weekly in the same manner, starting at one dose level below the MTD determined from part 1 of the trial (cohort 4 = 190 mg). Part 2 then followed the same dose escalation scheme as part 1 until MTD was determined for the weekly dosing regimen. Dose escalation in part 2 was stopped at the MTD for the bimonthly regimen (250 mg/d), as it was considered unlikely that the increased dose frequency would be associated with reduced toxicity. Patients were allowed to continue on treatment until criteria for study withdrawal were met. If a patient experienced a positive result on the functional serotonin release anti-heparin antibody test (SRA) at any time during his or her participation on the trial, treatment was discontinued.
PI-88 was provided by Progen Industries Ltd. (Darra, Queensland, Australia) in glass vials containing 400 mg sterile lyophilized powder. PI-88 was reconstituted to give a final concentration of 140 mg/mL solution for doses of 250 mg or a 350 mg/mL solution for doses of 250 to 315 mg. The total daily dose was then prepared by the hospital pharmacy for the patient's 4 consecutive days of home treatment before dispensing the drug in 1.0 or 2.0 mL syringes.
Pretreatment and follow-up studies. Before each cycle, complete medical histories, physical examinations, current medication profiles, assessments of performance status, and routine laboratory studies were done. Routine laboratory assessments included a complete blood count, differential WBC count, electrolytes, blood urea nitrogen, serum creatinine, glucose, total protein, albumin, calcium, phosphate, uric acid, lactate dehydrogenase, alkaline phosphatase, total bilirubin, alanine aminotransferase, aspartate aminotransferase, prothrombin time/international normalized ratio, APTT, fibrinogen, and D-dimer. In addition, before entering the study and at study discontinuation, electrocardiogram, routine urinalysis, and pregnancy test, when appropriate, were done. A 24-hour urine sample was collected following days 1 and 15 of treatment during the first cycle for analysis of creatinine and urinary excretion of PI-88. Weekly, the patient underwent a toxicity assessment, review of concomitant medications, and routine laboratory assessments.
A formal assessment of disease by the Response Evaluation Criteria in Solid Tumors was done before treatment and every 8 weeks thereafter (21). Patients continued on treatment in the absence of disease progression or intolerable toxicity.
Measurement of antibodies to PF4 and PI-88 or heparin. Anti-PI-88/PF4 IgG antibody production was measured in patients treated in part 1 of the study. Blood samples were obtained from patients before treatment and days 15 and 28 of course 1. In part 1, anti-PI-88/PF4 IgG antibody production was measured with an enzyme-linked immunoassay (EIA) as well as with the functional SRA as described previously (22). The EIA was based on the assay described by Amiral et al. (23).
Pharmacokinetic sampling and assay. To study the pharmacokinetics of PI-88, whole blood samples were obtained from an indwelling i.v. catheter. Samples were taken on days 1 to 4 and, in part 1 only, on day 5. On the first day of treatment, samples were taken before dosing and at 0.5, 1, 1.5, 2 to 4, 6, and 8 hours after PI-88 administration. On days 2 to 5, only a pre-dose sample was drawn. Samples were also taken during the third week of the course on days 15, 16, and 18 for both parts and additionally on days 17 and 19 for part 1 patients. Day 15 samples were drawn before dose and at 0.5, 1, 1.5, 2 to 4, 6, and 8 hours after dose. Pre-dose samples were again drawn on days 16 to 19. The samples were collected in tubes containing EDTA, inverted several times, and immediately placed on ice. Within 15 minutes of blood collection, samples were centrifuged at 4°C to separate plasma, and then frozen at –70°C. Urine samples were also collected over 24 hours on days 1 and 15 of dosing for analysis of urinary excretion of PI-88; analysis of these samples is delayed pending the validation of a suitable assay for PI-88 in human urine.
A fluorescence quenching assay was used to measure plasma concentrations of PI-88. PI-88 was extracted from plasma samples by treatment with 1 mol/L guanidine (1 hour at room temperature) followed by filtration through a Microcon YM-30 concentrator in a microcentrifuge (15,300 x g, 40 minutes at room temperature). The filtrate and/or appropriate dilutions (1:6, 1:36, or 1:216 in 1 mol/L guanidine) were transferred to a 96-well microplate in duplicate (40 µL/replicate). The plate was placed in a fluorescence microplate reader (FLUOstar Galaxy, BMG Labtechnologies, Offenburg, Germany), which was programmed to add 210 µL protamine-FITC solution per well followed by mixing. Quenching of fluorescence (by binding of PI-88 to protamine) was measured at 520 nm following excitation at 485 nm. Standard curves were prepared by adding known concentrations of PI-88 to control plasma samples from healthy volunteers. Typically, standards in the range 0.05 to 75.6 µg/mL were prepared and processed without dilution (0.05-0.35 µg/mL) or after dilution of the filtrate 1:6, 1:36, or 1:216 (0.3-2.1, 1.8-12.6, and 10.8-75.6 µg/mL, respectively). At these dilutions, the standards produce linear responses in the fluorescence quenching assay. The precision and accuracy of the PI-88 assay in plasma were determined to be within acceptable ranges for assay validation and cross-validation showed the robustness of the assay.
Pharmacokinetic analysis. The pharmacokinetic profile of PI-88 was analyzed using compartmental methods. The equation for this model is
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Data were fit to the model equation using WinNonlin software version 4.1 (Pharsight Corp., Mountain View, CA) with 1 / y2 weighting. Pharmacokinetic variables were calculated in a model-dependent manner. Linear regression and correlation of patient characteristics with pharmacokinetic variables was done using GraphPad Prism version 4.02 (GraphPad Software, San Diego, CA).
Measurement of systemic and urinary angiogenic growth factor levels. To measure angiogenic growth factor levels, whole blood and urine samples were collected on days 1 and 15 before administering PI-88 dose, day 28, and, for part 1 of the study only, days 5 and 19. Blood samples were placed on ice and then centrifuged at 1,950 x g for 10 minutes in a precooled centrifuge. Plasma and urine samples were stored at –70°C before analysis.
Plasma VEGF and urine bFGF were measured using reliable and validated sandwich immunoassays (R&D Systems, Minneapolis, MN). Each control and sample was run in triplicate according to the manufacturer's specifications. Quality control samples containing known amounts of the substrate were run in parallel with other samples to determine the interday coefficient of variation. Only assays exhibiting <20% coefficient of variation were considered valid.
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Results |
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Toxicity. Thrombocytopenia occurred in 15 of 238 (6%) treatment courses and was generally mild to moderate. Two episodes of grade 3 thrombocytopenia were related to PI-88, whereas the third occurrence was attributed to the development of acute myelogenous leukemia in a patient with melanoma. In three patients, thrombocytopenia was associated with DLT, and the time course is depicted in Fig. 1 . In all three of these patients, the platelet concentration decreased precipitously between days 15 and 16 of course 1, and PI-88 was discontinued on day 16. In one patient at the 315 mg/d dose level, the platelets decreased from 196,000 to 61,000 (69%) concomitant with a large, grade 4 pulmonary embolism, which was deemed to be possibly related to PI-88 and constituted DLT. Anticoagulation with a direct thrombin inhibitor was initiated, but the patient died in hospice care of rapidly progressive melanoma 10 days after the last dose of PI-88. In another patient treated at this dose level, the platelet concentration decreased from 176,000 to 48,000 (73%) without complications and the patient died 23 days after the last dose of PI-88 due to disease progression. The third patient with DLT was treated at the 250 mg/d dose level. In this patient, the platelets decreased from 217,000 to 70,000 (68%) between days 15 and 16 to a nadir of 28,000 on day 17, concomitant with a diagnosis of heart failure thought to be unrelated to PI-88. Four days later, the platelets increased to 110,000 and the patient died of complications from heart failure. No postmortem evaluation was done, but the cause of death was felt to be unrelated to PI-88.
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Anti-PI-88/PF4 IgG antibody production. Twenty-nine patients treated on part 1 of the study were assessed for the development of anti-PI-88/PF4 antibodies during the first course of treatment. There were no anti-PI-88/PF4 IgG antibodies detected in patients by EIA at baseline. Among the 26 patients that did not develop thrombocytopenia during course 1, no detectable anti-PI-88/PF4 IgG antibodies developed. Among the three patients who developed thrombocytopenia, anti-PI-88/PF4 and anti-heparin/PF4 IgG antibodies were documented by EIA, suggesting an immune-mediated etiology. One of the three patients with uncomplicated thrombocytopenia developed a positive heparin-induced thrombocytopenia (HIT)-SRA with both unfractionated heparin (0.1 units/mL) and PI-88 (10-200 µg/mL). Interestingly, the patient treated with PI-88 315 mg/d who had grade 2 thrombocytopenia and a documented pulmonary embolism had a negative HIT-SRA.
Antitumor activity. Thirty-eight patients were assessable for antitumor activity. Of these, 10 (26%) patients experienced clinical benefit as defined by a partial response (PR) or stable disease (SD) for six treatment courses: 6 of 17 patients with melanoma, 2 of 5 patients with renal cell carcinoma, 1 patient with carcinoid, and 1 patient with adenoid cystic carcinoma. Four patients received >1 year of therapy. One patient, a 47-year-old man with metastatic melanoma, had a PR (see Fig. 2 ) and has received treatment with PI-88 for >50 months. Additional details regarding patients who experienced clinical benefit are presented in Table 4 .
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6 months were compared with patients with disease progression within 6 months of treatment initiation, no significant differences were found in mean plasma VEGF, plasma bFGF, and urine bFGF concentrations at baseline or at days 15 and 28 of course 1 (Table 7
). Within each group of patients, there was no significant change in growth factor levels during course 1.
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Discussion |
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Although thrombocytopenia was a DLT in this study, no bleeding complications were observed, whereas grade 2/3 thrombocytopenia was associated with the development of antibodies to PF4 by EIA in all patients with thrombocytopenia and DLT. HIT is a serious, immunologic, prothrombotic disorder mediated by complexes of PF4, anti-PF4 IgG, and heparin. Thrombosis occurs in 35% to 75% of patients with HIT (24). The diagnosis of rapid-onset HIT requires the following: (a) thrombocytopenia, defined as a 50% decrease in platelet count; (b) an abrupt decrease in platelet count within 24 hours of starting heparin in patients recently exposed to heparin; and (c) positive EIA and SRA for HIT antibodies (i.e., anti-PF4/heparin antibodies). PI-88 is structurally similar to heparin and, like heparin, binds PF4. Development of antibodies to PI-88/PF4 could theoretically give a HIT-like immune disorder.
The three patients who developed grade 2/3 thrombocytopenia associated with DLT possessed many features of HIT, including a decrease in the platelet count of 50% and a time course consistent with rapid-onset HIT. Only one patient had a positive SRA result, whereas in the other two patients the diagnosis was suspected based on clinical features. One patient with grade 2/3 thrombocytopenia and a large pulmonary embolism may have had HIT-like immune-mediated thrombocytopenia with thrombosis, assuming that the sensitivity of the standard SRA for detecting anti-PI-88/PF4 is not 100%. Alternatively, the patient may have had anti-PI-88/PF4 antibodies that did not result in platelet activation and thrombocytopenia; rather, the thrombocytopenia may have been secondary to the pulmonary embolism itself (24).
This study shows that PI-88 can cause immune-mediated thrombocytopenia with or without thrombosis, similar to heparin. The extent to which dexamethasone reduced the risk of developing PI-88-induced immune-mediated thrombocytopenia is unknown, as patients were not randomly assigned to receive dexamethasone versus placebo. However, patients who did continue on study for multiple cycles and were allowed to discontinue dexamethasone did not develop HIT.
PI-88 treatment results in prolongation of the APTT that was found to be linearly correlated to the AUC and Cmax. 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. PI-88 has no effect on the prothrombin time (14, 18).
In this study, we explored the effects of PI-88 on circulating angiogenic growth factors, because this agent is thought to mediate its effect, in part, through the inhibition of VEGF and bFGF release from the extracellular matrix (25). However, no significant effect of PI-88 administration on angiogenic growth factor levels was observed, nor was clinical benefit associated with baseline growth factor levels or changes in these levels. Interpreting systemic growth factor levels is difficult because of the multiple sites of production and storage of these growth factors and their complex cross-regulation (26). Although PI-88 may have effectively reduced the release of growth factors from heparan sulfate proteoglycans by inhibiting heparanase, this may not be manifested as a change in systemic growth factors due to a potential increase in growth factor release from other components of the extracellular matrix (such as fibronectin, fibrin, and thrombospondin), an increase in release of stored VEGF from activated platelets, or a compensatory increase in VEGF production by leukocytes, megakaryocytes, or the neoplasm itself. These results are consistent with studies of other agents, such as imatinib and endostatin, and do not rule out a biological effect of the compound (27–29). Preclinical studies are ongoing to assess whether heparanase expression before therapy may be used to preselect patients or to predict clinical benefit, but these studies are not yet validated. We recommend that future efficacy studies collect baseline tumor specimens to determine whether heparanase expression correlates with clinical benefit.
The pharmacokinetics of s.c. dosed PI-88 are best described using a one-compartment model with first-order absorption and distribution. This is similar to what has been shown with low molecular weight heparins. The PI-88 dose was linear with respect to AUC and Cmax. The data showed low intraindividual variability but considerably higher interpatient variability. These data suggest that target dosing for individuals would be best achieved by individual assessment of plasma levels or by using percent increase in APTT as a surrogate. The linear relationship between percent increase in APTT and PI-88 AUC and Cmax levels could prove useful in optimizing patient dosing based on this relatively simple clinical test as opposed to the more complicated analysis for PI-88 drug concentrations. Further, the correlations between patient weight and pharmacokinetic variables suggest that part of the interpatient variability could be corrected for by dosing by body weight with this agent.
Antitumor activity was shown in this study. One patient with metastatic melanoma had an objective response that was maintained for >50 months. Five additional patients with melanoma, most of whom had a low disease burden, had SD for 7 to >38 months. These favorable outcomes suggest that PI-88 has growth-inhibitory activity in patients with melanoma, although randomized studies are needed to confirm this. Prolonged disease stability may be related to the preclinical observation that the rate of metastasis of melanoma was dependent on the activity of heparanase (2). Prolonged disease stabilization with PI-88 treatment is also consistent with preclinical data showing that heparanase expression is increased in human metastatic melanoma and that PI-88 decreases tumor growth and invasion in a mouse model of multistage cancer in which heparanase is up-regulated (30). A phase II clinical trial evaluating the efficacy of PI-88 in patients with metastatic melanoma is ongoing.
The results of this phase I and pharmacokinetic study show that PI-88 is generally well tolerated but occasionally results in thrombocytopenia associated with anti-PF4 antibodies and HIT. The recommended dose of PI-88 administered daily for 4 days every week is 250 mg. Given the prolonged disease stabilization observed in patients with melanoma and the single PR, further randomized studies of this agent in melanoma are warranted. Additionally, future studies should incorporate preclinically validated biological assays that relate to the heparanase-inhibiting capacity of PI-88.
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 11/ 7/05; revised 3/22/06; accepted 5/30/06.
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, percent increase in APTT; 
, Max APTT.