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© 2000 American Society for Clinical Oncology Randomized, Dose-Escalation Study of SD/01 Compared With Daily Filgrastim in Patients Receiving ChemotherapyFrom the Thoracic Oncology Program, Duke Comprehensive Cancer Center, Durham, NC, and Amgen, Inc, Thousand Oaks, CA. Address reprint requests to Jeffrey Crawford, MD, Duke University Medical School, Box 3198, Durham, NC 27710; email crawf006@ mc.duke.edu.
PURPOSE: To explore the use of SD/01 (a polyethylene glycol–conjugated filgrastim shown in preclinical studies to have a prolonged half-life) in patients with chemotherapy-induced neutropenia. PATIENTS AND METHODS: Thirteen patients with non–small-cell lung cancer were randomized to receive daily filgrastim (5 µg/kg/d) or a single injection of SD/01 (30, 100, or 300 µg/kg) 2 weeks before chemotherapy and again 24 hours after administration of carboplatin and paclitaxel. Pharmacodynamic, pharmacokinetic, and safety analyses were performed. RESULTS: Peak serum concentrations of SD/01 and the duration of increased serum concentrations were dependent on the SD/01 dose. SD/01 concentrations remained increased longer in patients with chemotherapy-induced neutropenia. Prechemotherapy median absolute neutrophil counts (ANCs) in patients receiving SD/01 were increased in a dose-dependent fashion, with the duration of this effect also being dose dependent. After chemotherapy, median ANC nadirs were similar in the filgrastim cohort and the cohort receiving SD/01 30 µg/kg, with higher nadirs seen in the cohorts receiving SD/01 100 or 300 µg/kg. Dose-limiting toxicities were not noted. CD34+ cells were mobilized in all cohorts. CONCLUSION: A single dose of SD/01 increases the serum concentration of SD/01 for several days in a dose-dependent fashion and is not associated with significant toxicity. The effects of SD/01 on ANC and CD34+ cell mobilization are comparable or greater than those achieved with daily filgrastim. The self-regulation of this molecule provides a potential therapeutic advantage in a variety of clinical settings associated with neutropenia.
IN 1991, FILGRASTIM (recombinant methionyl human granulocyte colony-stimulating factor [G-CSF]) received approval from the United States Food and Drug Administration (FDA). Since then, more than 1.9 million patients worldwide have received filgrastim, and multiple indications have been approved for use in other therapeutic settings.1 In most clinical situations, daily subcutaneous (SC) injections are required for full benefits of filgrastim therapy to be obtained. SD/01 is a polyethylene glycol (PEG)-derivatized form of filgrastim. Historically, PEG-conjugated proteins have displayed decreased plasma clearance, with a resultant increase in half-life.2 This decreased plasma clearance potentially can translate into enhanced clinical efficacy. If SD/01 acts in a manner predicted by other pegylated proteins, a single injection of SD/01 would be expected to provide clinical benefits similar or superior to those of standard filgrastim therapy. In preclinical studies, SD/01 was administered to nonneutropenic animals, and these animals had dose-dependent increases in absolute neutrophil counts (ANCs), in both peak ANCs and the duration of ANC increases over baseline values (data on file, Amgen, Thousand Oaks, CA). Mice were made neutropenic by injection of fluorouracil and then treated with SD/01 or standard filgrastim. Neutrophil recovery patterns were similar in both groups, with both groups showing more rapid return to baseline ANC than a control group of mice that received no growth factor (data on file, Amgen). Rats given SD/01 every other day during a 2-week toxicology study experienced no adverse events attributable to the study drug. We designed this first clinical study in humans to determine the pharmacokinetic, safety, and preliminary efficacy profiles of SD/01 in patients with non–small-cell lung cancer (NSCLC) who were to receive myelosuppressive chemotherapy. Clinical end points were analyzed before and after chemotherapy.
Patient Population The institutional review board of the participating center approved the protocol, and all patients gave written, informed consent before study entry. Patients were eligible for the study if they were  18 years of age, had a diagnosis of NSCLC, and had a Karnofsky performance status 70%, ANCs 1.5 x 109 cells/L, and platelet counts of more than 100 x 109 cells/L. Patients also were required to have adequate renal and hepatic function and hemoglobin values of at least 9 g/dL. Patients were excluded from the study if they had had previous systemic chemotherapy or extensive radiotherapy, had current uncontrolled infection (ie, ANC > 12.0 x 109 cells/L and/or temperature > 38.2°C), or had cancer other than NSCLC that was not in remission, known human immunodeficiency virus infection, or known sensitivity to Escherichia coli–derived products. Women could not be pregnant or breast-feeding and had to take adequate measures to avoid becoming pregnant while on study.
Study Design and Laboratory Monitoring
Cycle 0 was a 14-day prechemotherapy cycle, and cycle 1 was a 21-day postchemotherapy cycle. Each patient randomized to filgrastim therapy received five daily injections beginning on day 1 of cycle 0. In cycle 1, filgrastim therapy was initiated 24 hours after completion of chemotherapy and was continued until neutrophil recovery (ANC 10 x 109 cells/L). Each patient randomized to SD/01 received a single SC injection during each cycle. These injections were given on day 1 of cycle 0 and day 3 (24 hours after completion of chemotherapy) of cycle 1. In cycle 0, daily complete blood cell counts were performed (WBC count, RBC count, hemoglobin level, hematocrit, and platelet count), and blood for chemistry panels was drawn on days 1, 8, and 15. Samples for pharmacokinetic analysis were obtained at various intervals during the first 48 hours and then daily through day 15. CD34+ cells were assayed daily.
In cycle 1, biochemistry panels were performed on days 1, 8, and 15; and serum samples for antibody testing were taken on days 1 and 22. CD34+ cell counts were performed daily, starting on day 1 and continuing through day 15 or until neutrophil recovery (ANC
Serum samples for pharmacokinetic analysis were analyzed using an enzyme-linked immunosorbent assay that does not distinguish filgrastim or SD/01 from endogenous G-CSF. Serum samples were analyzed for filgrastim and SD/01 using standard curves constructed with filgrastim and SD/01, respectively. Pharmacokinetic parameters were estimated using noncompartmental methods. Patients receiving SD/01 who experienced prolonged neutropenia (
Safety Analysis
Chemotherapy
Study Drug
Statistical Analysis
Patient Population Thirteen patients were entered onto the trial. The eight women and five men ranged in age from 48 to 76 years (median, 62 years) (Table 1). The patients randomized to the filgrastim treatment group had slightly more favorable prognostic factors, with a lower incidence of metastatic disease and a higher overall performance status (data not shown).
Study Drug Administration One patient assigned to treatment with SD/01 300 µg/kg was removed from the study after cycle 0 when she developed an atrial arrhythmia during paclitaxel infusion. An additional patient was accrued to the trial and was given SD/01 300 µg/kg; data from both patients are included in the analysis.
Neutrophil Response
The peak ANC obtained also seemed to be dose dependent within the SD/01 treatment cohorts. Patients administered 300 µg/kg had a median peak ANC of nearly 54 x 109 cells/L; patients given SD/01 100 µg/kg had a median peak ANC most closely approximating that in the standard filgrastim therapy cohort (ie, 32 x 109 cells/L); and patients treated with SD/01 30 µg/kg had a median peak ANC of 24 x 109 cells/L. The ANC data for cycle 1 are presented logarithmically in Fig 3. SD/01 was given as a one-time dose, and filgrastim was given daily until the postchemotherapy ANC was more than 10 x 109 cells/L (9 or 10 days). Shortly after filgrastim or SD/01 administration, there was an initial increase in ANC in all groups (that was similar in magnitude), followed by the ANC nadir. Median nadir ANC in patients receiving filgrastim and those receiving SD/01 30 µg/kg were identical (0.1 x 109 cells/L). The SD/01 treatment cohorts receiving higher doses (100 and 300 µg/kg) had nearly identical median ANC nadirs (0.65 and 0.70 x 109 cells/L, respectively). There were no episodes of neutropenic fever (temperature > 38.2°C and ANC < 0.5 x 109/L) and no patient required filgrastim rescue. Postnadir neutrophil recovery among the patients receiving filgrastim was completed by day 10 and was closely mimicked by the patients given SD/01 100 or 300 µg/kg. In this small patient population, patients receiving SD/01 30 µg/kg had a slower neutrophil recovery.
CD34+ Cell Mobilization CD34+ cell mobilization was measured in individual patients. Significant interpatient variability was apparent. Nonetheless, administration of either filgrastim or SD/01 did result in CD34+ cell mobilization in both the pre- and postchemotherapy cycles. In cycle 0, the median peak CD34+ cell count was similar in the filgrastim therapy cohort and the cohort receiving SD/01 30 µg/kg (14.6 cells/µL and 12.3 cells/µL, respectively). The cohorts receiving SD/01 100 or 300 µg/kg had higher median peaks (60.5 cells/µL and 42.7 cells/µL, respectively). Mobilization was also noted after administration of chemotherapy, with a median peak CD34+ cell count of 56.8 cells/µL in the filgrastim treatment group and median peaks of 4.8 cells/µL, 67.8 cells/µL, and 27.9 cells/µL in the cohorts receiving SD/01 30, 100, or 300 µg/kg, respectively.
Pharmacokinetics
Laboratory Monitoring Median hemoglobin values were unchanged throughout the trial in all cohorts. There was a modest, transient decrease in platelet counts in all groups (Fig 5). All patients experienced a transient increase in uric acid, lactate dehydrogenase, and alkaline phosphatase levels.
Safety The toxicity on this study was reflective of the chemotherapy administered (Table 3). Clinical adverse events attributed to the study drug were limited to mild-to-moderate bone pain whose severity and duration were similar for patients treated with SD/01 and those receiving standard filgrastim therapy. There was no apparent relationship between SD/01 dose and patient frequency of bone pain.
Seroreactivity was detected in four of 19 samples collected from SD/01-treated patients. No clinical sequelae were reported, and no evidence of neutralizing antibodies was found.
When filgrastim was initially approved by the FDA, the FDA approved labeling the drug for use as prophylaxis for chemotherapy-induced neutropenia, because randomized trials had demonstrated reductions, when the growth factor was used, in the number of episodes of neutropenic fever, the duration of grade IV neutropenia, the depth of ANC nadirs, and the number of hospitalizations due to infection.3-7 In several of these trials, chemotherapy dose-intensity was superior, because of fewer dose reductions and treatment delays in patients randomized to receive filgrastim, which led to ongoing investigations of the value of dose-intensity or dose density in oncology.8 Filgrastim has also demonstrated utility in other clinical situations, and additional indications for the use of the drug include peripheral-blood progenitor cell mobilization, marrow reconstitution after bone marrow transplantation, and enhancement of neutrophil counts in states of chronic neutropenia and myeloid leukemias. In all of these settings, daily injections have been required for clinical benefits of filgrastim or other neutrophil factors to be obtained. Given the broad clinical utility of hematopoietic growth factors, the potential clinical benefit of an agent requiring only a single injection is evident. SD/01 is manufactured by the covalent attachment of a 20-kd PEG moiety to the amino terminus of E coli–derived filgrastim. Other such pegylated proteins, including PEG-asparaginase and megakaryocyte growth and development factor, have a reduced clearance, an increased plasma half-life, and sustained biologic activity compared with their nonpegylated counterparts. Likewise, preclinical trials of SD/01 in rodents and nonhuman primates have demonstrated sustained plasma concentrations of SD/01 after a single dose, with no identifiable toxicity. Furthermore, neutrophil response, correlating with SD/01 serum concentration, was confirmed in the animals.9 Retained efficacy without added toxicity in human subjects treated with SD/01 would mean fewer injections, increased patient compliance, and a reduced burden on medical support systems. The 13 patients accrued to this trial were chemotherapy-naïve and had not had significant portions of bone marrow irradiated. Such a population allows for preliminary evaluation of the pharmacokinetics and pharmacodynamics of SD/01. The pharmacokinetics of SD/01 in patients with NSCLC are nonlinear over the dose range evaluated in this trial. The serum clearance of SD/01 decreased with the increasing of the dose. This phenomenon is likely the result of saturation of receptor-binding sites on neutrophils at higher SD/01 doses, resulting in a decrease in the rate of receptor-mediated clearance of the growth factor. Findings obtained from comparison of the pharmacokinetic data before and after chemotherapy lend support to this conclusion. After chemotherapy (cycle 1), SD/01 was administered at the same doses as those that had been given before chemotherapy (cycle 0), and the peak serum concentrations of SD/01 by cohort were nearly identical in the two cycles. However, this peak serum concentration is maintained until the time of neutrophil recovery in cycle 1. This longer duration of increased serum concentrations of SD/01 in patients with neutropenia has been the subject of pharmacokinetic and pharmacodynamic modeling of this agent, described in more detail elsewhere.10 Pegylation of filgrastim decreases the renal clearance of the molecule so that SD/01 clearance is almost entirely dependent on neutrophil receptor–mediated clearance. This self-regulation of SD/01 suggests there is broad applicability of a single injection of the molecule in other conditions associated with even more prolonged neutropenia, such as leukemia. In both cycles, SD/01 levels had almost returned to baseline by day 12 and were well below the estimated EC50 (plasma concentration at 50% maximal effect) of 10 ng/mL within 10 days of growth factor administration. This leads to the prediction that SD/01 administration will not result in enhanced marrow toxicity with multicycle chemotherapy when cycles are delivered at intervals of 2 weeks or more. However, this premise will require confirmation in a multicycle trial. Several multicycle trials are ongoing.
Neutrophil response was apparent at all doses of SD/01 tested and was dose dependent with regard to peak and duration of effect consistent with the measured serum concentrations of SD/01. In the prechemotherapy model, a SD/01 dose of 100 µg/kg produced a peak ANC closest to that obtained with 5 days of standard filgrastim therapy.11 After chemotherapy, median ANC nadirs were essentially identical in the filgrastim therapy group and the group given SD/01 30 µg/kg. Less severe median ANC nadirs occurred in the other two cohorts; however, the ranges were broadly overlapping, with at least one patient in each cohort experiencing grade IV neutropenia (ie, ANC Mobilization and collection of CD34+ cells for peripheral-blood stem-cell transplantation is an increasingly important component of oncologic care. This trial called for daily CD34+ cell counts rather than collection by apheresis, which would have allowed for a more meaningful evaluation of stem-cell yield. Nonetheless, significant numbers of CD34+ cells were present in the peripheral blood in all cohorts, both before and after chemotherapy. Again, there is the suggestion of a dose-response relationship of CD34+ mobilization with higher doses of SD/01. The dose-response relationship of CD34+ cell recovery in the peripheral blood was also evident in normal volunteers given a single injection of SD/01.12 However, significant patient variability, the limited number of patients, and the lack of data regarding yield by apheresis make drawing further conclusions difficult. Trials of SD/01 to address this issue are planned. The prolonged pharmacokinetic and pharmacodynamic effects of SD/01 have raised the concern that this agent has potential excessive toxicity; however, few toxicities were noted during this trial, and no serious adverse events were attributable to either filgrastim or SD/01. Nine of the 13 patients experienced musculoskeletal pain during cycle 0 (the pain lasting from 1 to 8 days), with six patients requiring oral analgesics for a brief time. There was also a transient decrease in platelet counts, as well as increases in uric acid, lactate dehydrogenase, and alkaline phosphatase levels that were not of clinical significance in both growth factor treatment groups. The overall toxicity profiles of filgrastim and SD/01 were indistinguishable. This trial has provided preliminary evidence that a single dose of SD/01 enhances postchemotherapy neutrophil recovery and mobilizes CD34+ cells in a manner similar to that of daily filgrastim therapy, without added toxicity. SD/01 is currently being evaluated in multicycle trials conducted to confirm these effects and establish a larger safety profile. The possibility of superior neutrophil recovery at higher doses of SD/01 compared with filgrastim is also being evaluated, and such recovery would be consistent with the higher level of saturation of G-CSF receptors noted at higher doses of SD/01. The initial trials of SD/01 suggest several potential therapeutic advantages of this molecule over standard G-CSF.
Supported by grant no. M01-RR-30, clinical research, from the National Center for Research Sources, National Institutes of Health, Bethesda, MD, and by Amgen, Inc, Thousand Oaks, CA. We thank Mary Ann Foote, PhD, for assistance with the writing of the article.
1. Welte K, Gabrilove J, Bronchud MH, et al: Filgrastim (r-metHuG-CSF): The first 10 years. Blood 88:1907-1929, 1996 2. Delgado C, Francis GE, Fisher D: The uses and properties of PEG-linked proteins. Crit Rev Ther Drug Carrier Syst 9:249-304, 1992[Medline] 3. Crawford J, Ozer H, Stoller R, et al: Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 325:164-170, 1991[Abstract] 4. Trillet-Lenoir V, Green J, Manegold C, et al: Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 29A:319-324, 1993
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Zinzani PL, Pavone E, Storti S, et al: Randomized trial with or without granulocyte colony-stimulating factor as adjunct to induction VNCOP-B treatment of elderly high-grade non-Hodgkin’s lymphoma. Blood 89:3974-3979, 1997 7. Gisselbrecht C, Haioun C, Lepage E, et al: Placebo controlled phase III study of lenograstim (glycosylated recombinant human granulocyte-stimulating factor) in aggressive non-Hodgkin’s lymphoma: Factors influencing chemotherapy administration. Leuk Lymphoma 25:289-300, 1997[Medline] 8. Frei E 3rd, Elias A, Wheeler C, et al: The relationship between high-dose treatment and combination chemotherapy: The concept of summation dose intensity. Clin Cancer Res 4:2027-2037, 1998[Abstract] 9. Cheung E, Cozenza M, Lopez O, et al: Modeling of r-metHuG-CSF-SD/01 mediated granulopoiesis in normal animals, with mathematical extrapolation to neutropenia settings. Blood 92:379a, 1998 (abstr 1563) 10. Roskos LK, Yank B, Schwab G, et al: A cytokinetic model of r-metHUG-CSF-SD/01 mediated granulopoiesis and "self-regulation" of SD-01, elimination in non-small cell lung cancer patents. Blood 92:507a, 1998 (abstr 2085) 11. Farese AM, Roskos L, Cheung E, et al: A single administration of r-metHuG-CSF-SD-01 significantly improves neutrophil recovery following autologous bone marrow transplantation. Blood 92:112a, 1998 (abstr 455) 12. Schwab G, Roskos L, Molineux G, et al: A phase 1 study of sustained-duration filgrastim in normal volunteers. Exp Hematol 26:709, 1998 (abstr 95) Submitted September 21, 1999; accepted March 2, 2000.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
0.5 x 109 cells/L) or febrile neutropenia met criteria for filgrastim rescue. 
