A randomized, multicenter study of subcutaneous and intravenous darbepoetin alfa for the treatment of chemotherapy-induced anemia

G. Justice1,*, J. F. Kessler2, J. Jadeja3, L. Campos4, J. Weick5, C.-F. Chen6, A. C. Heatherington6 and R. G. Amado6

1 Pacific Coast Hematology Oncology Medical Group, Fountain Valley, CA; 2 Virginia Oncology Associates, Newport News, VA; 3 Hematology-Oncology Associates of Jacksonville, Jacksonville, FL; 4 Oncology Consultants, Houston, TX; 5 Hematology Oncology Associates, Lake Worth, FL; 6 Amgen Inc., Thousand Oaks, CA, USA

* Correspondence to: Dr G. Justice, Pacific Coast Hematology Oncology Medical Group, 11190 Warner Avenue, Suite 300, Fountain Valley, CA 92708, USA. Tel: +1-714-751-2600; Fax: +1-714-751-4501; Email: glen4jane{at}aol.com


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: This randomized, open-label study evaluated the efficacy, safety and pharmacokinetics of darbepoetin alfa administered intravenously (i.v.) or subcutaneously (s.c.) in chemotherapy-induced anemia.

Patients and methods: Patients received darbepoetin alfa i.v. (n=59) or s.c. (n=59) at a dose of 4.5 µg/kg once weekly for 6 weeks (correction phase) followed by 4.5 µg/kg once every 3 weeks for the remainder of the 18-week treatment period (maintenance phase).

Results: During the correction phase, the mean [95% confidence interval (CI)] change in hemoglobin (intention-to-treat) was 1.1 (0.6–1.5) g/dl in the i.v. group and 1.3 (0.9–1.7) g/dl in the s.c. group; using available data, the mean change was 1.4 (1–1.9) g/dl and 1.6 (1.2–2) g/dl, respectively. The percentage (95% CI) of patients maintaining hemoglobin (i.e. average decrease ≤0.5 g/dl) during the maintenance phase was similar between the i.v. (82%; 95% CI 66% to 92%) and s.c. (80%; 95% CI 66% to 90%) groups. Thirty-five per cent (95% CI 20% to 50%) of patients in the i.v. group and 32% of patients in the s.c. group (95% CI 18% to 45%) received red blood cell transfusions during week 5 to the end of the treatment period. Darbepoetin alfa was well tolerated in both groups. No significant difference (P=0.36) in weekly darbepoetin alfa serum concentrations was observed between groups.

Conclusions: Darbepoetin alfa can be administered i.v. or s.c. at equal doses for the treatment of anemia in this setting.

Key words: anemia, darbepoetin alfa, drug administration schedule, erythropoietin, hemoglobin


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Anemia is a frequent complication in patients with cancer, either as a consequence of the cancer itself or as a direct result of the damaging effects of cytotoxic chemotherapy or radiotherapy on erythroid progenitor cells in the bone marrow. Anemia can have a profound effect on patient quality of life through its clinical manifestations of dyspnea, weakness and fatigue [1Go–3Go]. Erythropoietic agents have provided an effective treatment option for patients with chemotherapy-induced anemia, resulting in increased hemoglobin, reduced red blood cell transfusion requirements and improved quality of life [4Go–6Go].

Darbepoetin alfa (Aranesp®), which has a longer serum half-life than recombinant human erythropoietin (rHuEPO) [7Go–9Go], has been shown to effectively correct anemia in patients with cancer undergoing chemotherapy when given once weekly, every 2 weeks or every 3 weeks [5Go, 6Go, 10Go, 11Go]. Data from these studies suggested that a darbepoetin alfa dose of 4.5 µg/kg once weekly resulted in higher hemoglobin response rates than lower doses of darbepoetin alfa once weekly or rHuEPO three times weekly. The results also indicated that a darbepoetin alfa dose of 4.5 µg/kg administered once every 3 weeks effectively maintained hemoglobin concentrations in most patients. The ability to dose darbepoetin alfa every 3 weeks represents an important advance in the treatment of chemotherapy-induced anemia, as it results in improved patient convenience and resource utilization.

Although darbepoetin alfa is most frequently administered subcutaneously (s.c.) in the oncology setting, with once-per-cycle administration, intravenous (i.v.) darbepoetin alfa could be given at the same time as chemotherapy, reducing the need for additional patient visits and s.c. injections. Concerns regarding the efficiency of i.v. dosing have been raised by studies in patients with chronic kidney disease, which indicated that i.v. administration of rHuEPO required a ≥47% dose increase to achieve the same efficacy as s.c. administration [12Go, 13Go]. No such loss of dose efficiency has been noted in studies of darbepoetin alfa in the nephrology setting [14Go–16Go]. The use of i.v. darbepoetin alfa would result in added convenience for oncology patients with central venous catheters. In the oncology setting, however, no information is available regarding the comparability of i.v. versus s.c. administration of darbepoetin alfa.

The current study was designed to evaluate the relative efficacy of i.v. and s.c. dosing of darbepoetin alfa in the oncology setting. In both the i.v. and s.c. groups, darbepoetin alfa was administered using a correction dose of 4.5 µg/kg once weekly for 6 weeks followed by a maintenance dose of 4.5 µg/kg once every 3 weeks for the remainder of the 18-week treatment period.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study population
The institutional review boards for each of the 10 study centers in the USA approved the protocol, and all patients provided written informed consent before any study-specific procedures were carried out. Patients ≥18 years of age with non-myeloid malignancies and at least 12 additional, planned weeks of chemotherapy (regardless of schedule) were eligible for participation. Patients were required to have anemia (hemoglobin concentration ≤11 g/dl) primarily due to cancer or chemotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and adequate liver and renal function (serum creatinine and serum bilirubin <2x the central laboratory normal range). Patients were excluded from the study if they had received more than two red blood cell transfusions within 4 weeks before study day 1 (the first day of study drug administration), any red blood cell transfusion within 14 days before study day 1, or rHuEPO or darbepoetin alfa therapy within 4 weeks before study day 1. Other exclusion criteria included known primary hematological disorders that could cause anemia, a known history of any seizure disorder, and cardiac or chronic inflammatory diseases.

Study design
This was a multicenter, randomized, open-label, two-arm study of s.c. and i.v. darbepoetin alfa in patients with non-myeloid malignancies receiving multicycle chemotherapy. After a screening period, eligible patients were randomly assigned in a 1:1 allocation to receive darbepoetin alfa (Aranesp; Amgen, Inc., Thousand Oaks, CA, USA) administered i.v. or s.c. for 18 weeks. The 18-week treatment period included a correction phase and a maintenance phase. During the correction phase (weeks 1–6), patients in each treatment group received darbepoetin alfa at a dose of 4.5 µg/kg once weekly. During the maintenance phase, patients received darbepoetin alfa at a less-frequent dose of 4.5 µg/kg once every 3 weeks (at weeks 9, 12 and 15). All patients were evaluated for 4 weeks after the last dose of darbepoetin alfa.

No dose increases were permitted during the study. Darbepoetin alfa was withheld for patients with hemoglobin concentrations >14 g/dl (for women) or >15 g/dl (for men), and was reinstated at a dose of 4.5 µg/kg once every 3 weeks (only at weeks 3, 6, 9, 12 or 15) once the hemoglobin concentration decreased to ≤13 g/dl. Iron supplementation was at the discretion of the investigator and study center. Red blood cell transfusions were recommended for patients with hemoglobin concentrations ≤8 g/dl or for patients with hemoglobin concentrations >8 g/dl if symptoms of anemia were present. Blood samples for hematological and pharmacokinetic assessments were drawn weekly, and safety was evaluated throughout the study.

The primary objective of this study was to evaluate the relative efficacy of i.v. versus s.c. darbepoetin alfa administration, based on the change in hemoglobin concentration from baseline. In addition, the percentage of patients achieving hemoglobin maintenance (defined as an average reduction in hemoglobin of ≤0.5 g/dl during the maintenance phase) was evaluated. The efficacy of darbepoetin alfa was also evaluated by assessing the percentage of patients achieving a hematopoietic response (a hemoglobin concentration ≥12 g/dl or an increase of ≥2 g/dl over baseline in the absence of red blood cell transfusions during the preceding 28 days) and the percentage of patients achieving the hemoglobin target (a hemoglobin concentration ≥11 in the absence of red blood cell transfusions within the preceding 28 days), which is consistent with National Comprehensive Cancer Network practice guidelines [17Go]. In addition, the percentage of patients receiving a red blood cell transfusion was evaluated from week 5 to the end of the treatment period, consistent with previous studies of erythropoietic agents [4Go, 5Go, 18Go].

Safety was evaluated by analyzing the incidence of adverse events and the potential formation of antibodies to darbepoetin alfa.

Pharmacokinetic assessments
The weekly serum concentrations of darbepoetin alfa were summarized by route of administration (i.v. and s.c.) over time. All patients were scheduled to have pharmacokinetic samples collected; the pharmacokinetic analysis included all patients who had at least one sample collected after initiation of dosing. Darbepoetin alfa serum concentrations were determined by a validated enzyme-linked immunosorbent assay [8Go]. All concentrations less than the limit of quantitation were given a value of zero. The concentrations were not corrected for endogenous erythropoietin, which cross-reacts in the assay.

Antibody assessments
Potential antibody formation was first evaluated using a radioimmunoprecipitation (RIP) screening assay to detect seroreactivity. Any RIP-reactive samples were to be further evaluated using a cell-based bioassay to detect neutralizing or inhibiting effects on the activity of darbepoetin alfa and a Biacore assay (Biacore International, AB, Uppsala, Sweden) to confirm the presence of antibodies and to characterize the nature of the binding and the antibody classes observed.

Statistical analysis
The efficacy analysis included all randomized patients who received at least one dose of darbepoetin alfa. Point estimates and 95% confidence intervals (CIs) were calculated for the mean change in hemoglobin concentration from baseline to the end of the treatment period. The mean change in hemoglobin was also estimated for the correction phase (weeks 1–6). Two methods were used for the analysis of change in hemoglobin: the intention-to-treat method used the last available value (last value carried forward) that was not within 28 days of red blood cell transfusion to calculate the change from baseline, and the available data analysis included only patients with hemoglobin values at the specified time point (week 18 for the end of the treatment period or week 6 for the correction phase) but not within 28 days after red blood cell transfusion. The percentage of patients achieving a hematopoietic response or hemoglobin target and the percentage of patients receiving a red blood cell transfusion from week 5 to the end of the treatment period were estimated using the Kaplan–Meier method. The crude percentage of patients achieving hemoglobin maintenance was also calculated. Descriptive statistics were calculated for all other end points.

The sample size of 60 patients per treatment group had 85% power to detect a 50% difference in the mean change in hemoglobin between treatment groups, assuming the mean change in hemoglobin concentration in the s.c. group was 1.7 g/dl [standard deviation (SD) ~1.7] and the mean change in hemoglobin concentration in the i.v. group was 0.85 g/dl, using a one-sided t-test at a significance level of 0.05.

Weekly darbepoetin alfa serum concentrations were summarized by treatment group and compared longitudinally using SAS Proc Mixed, version 8.2 (SAS Institute Inc., Cary, NC, USA). Only samples that were determined to be collected within an acceptable window of the nominal timepoints (±2 days) were included in the analysis.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient demographics and disposition
A total of 120 patients were randomly assigned to receive darbepoetin alfa i.v. (60 patients) or s.c. (60 patients) (Figure 1). Two patients (one in each treatment group) did not receive darbepoetin alfa; thus, 118 patients were included in the analyses of efficacy and safety (59 in each treatment group).



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Figure 1. Patient disposition. IV, intravenous; SC, subcutaneous.

 
Baseline demographic and clinical characteristics are provided in Table 1. The most common primary tumor type in both treatment groups was lung cancer (39% i.v. group, 27% s.c. group). A higher percentage of patients had lung cancer or gastrointestinal cancer in the i.v. group than in the s.c. group. Most patients had an ECOG performance status of 0 or 1. The mean hemoglobin concentration at baseline was similar between the i.v. (9.51 g/dl) and s.c. (9.61 g/dl) groups. Thirty-six per cent of patients in the i.v. group and 29% of patients in the s.c. group received platinum-containing chemotherapy during the study.


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Table 1. Patient characteristics

 
The percentage of patients completing darbepoetin alfa treatment was 43% in the i.v. group and 62% in the s.c. group. Most patients who withdrew in the i.v. group did so before week 12, whereas most patients who withdrew in the s.c. group completed at least 12 weeks of treatment. In the i.v. group, the most frequent reason for discontinuing darbepoetin alfa treatment was discontinuation or delay of chemotherapy (22% i.v. group, 5% s.c. group). In the s.c. group, determination of ineligibility for the study (2% i.v. group, 7% s.c. group) and protocol violations (3% i.v. group, 7% s.c. group) were the most frequent reasons for discontinuing darbepoetin alfa.

Efficacy
Change in hemoglobin from baseline. Mean hemoglobin concentrations over time are shown in Figure 2. The mean change in hemoglobin from baseline was similar between the i.v. and s.c. treatment groups during the correction phase of the study (weeks 1–6) (Table 2). Using an intention-to-treat analysis, a difference between treatment groups was observed for the hemoglobin change during the entire study period in favor of s.c. administration; however, this difference was not statistically significant. The percentage of patients achieving hemoglobin maintenance (i.e. average decrease in hemoglobin of ≤0.5 g/dl during the maintenance phase) was similar for the i.v. (82%; 95% CI 66% to 92%) and s.c. (80%; 95% CI 66% to 90%) treatment groups.



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Figure 2. Mean hemoglobin (Hgb) concentrations during the treatment period. Hemoglobin values within 28 days of a transfusion were excluded. Error bars represent the confidence intervals around the mean (alpha=0.05). IV, intravenous; SC, subcutaneous.

 

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Table 2. Mean change in hemoglobin during the correction and maintenance phases of the study

 
Hematopoietic response and hemoglobin target. The percentage (95% CI) of patients achieving hematopoietic response during the treatment period was 68% (52% to 83%) in the i.v. group and 80% (67% to 92%) in the s.c. group. Similar results were observed for achieving the hemoglobin target, with 73% (95% CI 59% to 87%) of patients in the i.v. group and 80% (95% CI 68% to 92%) of patients in the s.c. group achieving this end point.

Red blood cell transfusions. A similar percentage of patients received a red blood cell transfusion during weeks 5 to the end of the treatment period in the i.v. group (35%; 95% CI 20% to 50%) and the s.c. group (32%; 95% CI 18% to 45%). The mean number of units of red blood cells transfused was also similar between the i.v. [0.6 units; standard error (SE) 0.1 units] and s.c. (1 unit; SE 0.3 units) groups.

Pharmacokinetics
Pharmacokinetic samples (1638 total) were available from 59 patients in each treatment group, of which 1362 (83%) were adequate for inclusion in the summary statistics; these samples were representative of the prespecified sampling times. During the correction phase of once-weekly dosing, trough darbepoetin alfa serum concentrations (i.e. those measured immediately before the next dose) were ~5 ng/ml in both cohorts, with no evidence of accumulation (Figure 3). For example, 1 week after the first and sixth doses, mean (SD) darbepoetin alfa serum concentrations were 6.44 (5.69) ng/ml (n=46) and 5.00 (4.16) ng/ml (n=41) for i.v. dosing, and 5.40 (4.54) ng/ml (n=53) and 5.02 (4.22) ng/ml (n=49), for s.c. dosing, respectively. Mean concentrations tended to be slightly higher in the s.c. group than the i.v. group, although the difference was not statistically significant (P=0.41). During the maintenance phase, when dosing was extended to once every 3 weeks, the trough concentrations were similar to baseline values (<1 ng/ml) for each cohort. At 1 week after each dose, the concentration in each group was again ~5 ng/ml. For example, at week 10, mean (SD) darbepoetin alfa serum concentrations were 4.54 (3.49) ng/ml (n=32) and 4.60 (4.11) ng/ml (n=47) for i.v. and s.c. dosing, respectively. No significant difference (P=0.36) in weekly darbepoetin alfa serum concentrations was observed between treatment groups over the entire 18-week evaluation period.



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Figure 3. Mean (standard error) darbepoetin alfa serum concentrations as measured weekly (note: the week 1 value represents baseline due to endogenous erythropoietin). IV, intravenous; SC, subcutaneous.

 
Safety
The adverse event profile of darbepoetin alfa was similar between the i.v. and s.c. groups and was consistent with that previously observed in clinical trials of darbepoetin alfa. The most common adverse events in both treatment groups were fatigue and nausea. Seven patients (12%) in the i.v. group and five (8%) in the s.c. group died during the study or within 30 days after the last dose of darbepoetin alfa. Deaths were generally attributed to progressive disease. No antibody formation to darbepoetin alfa was observed.


    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Darbepoetin alfa is generally administered s.c. in the oncology setting, although the advent of less-frequent dose schedules (e.g. once every 3 weeks) has raised the possibility of i.v. administration at the same time as chemotherapy. As noted in the ASH/ASCO treatment guidelines for the use of erythropoietic agents in patients with cancer, few studies have evaluated the i.v. administration of erythropoietic therapies in the oncology setting, and no study included in the guidelines directly compared i.v. with s.c. administration in this population [19Go]. Previous studies of i.v. rHuEPO in patients with cancer have typically evaluated dose schedules of two to five times per week and total doses higher than those approved for use in this setting [20Go–23Go]. Other evidence has indicated that substantially higher doses (≥47%) of rHuEPO are needed with i.v. administration relative to s.c. administration in patients with chronic kidney disease [12Go, 13Go].

No differences in dose requirements for i.v. versus s.c. administration have been observed for darbepoetin alfa in the nephrology setting [14Go, 15Go]. This observation may be a result of the longer circulating half-life of darbepoetin alfa relative to rHuEPO. The terminal half-life of darbepoetin alfa in patients with chronic renal failure previously has been reported to be 25.3 h after i.v. administration and 48.8 h after s.c. administration, whereas that of rHuEPO has been reported to be 8.5 h by the i.v. route and 16–24 h (historically) by the s.c. route [9Go]. A recent study in patients with chemotherapy-induced anemia determined that the mean (SD) terminal half-life of darbepoetin alfa after s.c. administration was 73.7 (27.3) h [24Go]. It has been hypothesized that effective erythropoiesis requires maintenance of a minimum threshold concentration of an erythropoietic agent for a significant portion of the dosing interval [25Go]. Thus, the longer half-life of darbepoetin alfa results in maintenance of erythropoiesis for a longer period relative to rHuEPO by both the i.v. and s.c. routes.

In the current study, both i.v. and s.c. darbepoetin alfa administration effectively increased hemoglobin concentrations in patients with non-myeloid malignancies at the same dose and schedule. The dosing schedule in this study included a correction phase and a less-frequent maintenance phase. The goal of this dosing strategy was to improve the efficiency of treatment. In both the i.v. and s.c. treatment groups, correction of hemoglobin was achieved with the initial once-weekly darbepoetin alfa dose of 4.5 µg/kg, and maintenance of hemoglobin concentrations was achieved with a dose of 4.5 µg/kg once every 3 weeks. Similar hemoglobin results were observed for the i.v. and s.c. groups during the maintenance phase with once every 3 weeks dosing of 4.5 µg/kg. This indicates comparable efficacy between i.v. and s.c. routes even at a lower average weekly dose than that commonly used in clinical practice (2.25 µg/kg/week). In addition, the similar hemoglobin results for the correction phase indicate comparability between routes with the higher weekly dose used during the first 6 weeks of therapy.

This phase II study had limited power to detect small differences between treatment groups for the change in hemoglobin from baseline. Greater increases in hemoglobin were observed with s.c. administration over the course of the entire treatment period. The higher percentage of patients who withdrew from the study in the i.v. group (primarily owing to delays/discontinuation of chemotherapy) may have contributed to the differences observed between the treatment groups for this particular end point. These differences, however, did not translate into significant differences with regard to more clinically relevant end points, such as the ability to maintain hemoglobin at the recommended target range of 11–12 g/dl [17Go, 19Go] or transfusion rates. The safety profile of darbepoetin alfa was similar with i.v. or s.c. administration and was consistent with that previously observed in this patient population.

The pharmacokinetic data collected provide a rationale for the route-independent efficacy observed in this study. The weekly concentrations of darbepoetin alfa were similar after either i.v. or s.c. dosing throughout the course of the study. Higher concentrations were sustained with once-weekly dosing than with once every 3 weeks dosing, as was expected based on the known pharmacokinetic properties of darbepoetin alfa in chemotherapy-induced anemia [8Go]. However, even at 4.5 µg/kg once weekly, no accumulation was observed. Although endogenous erythropoietin cross-reacts in the assay used, and it is known that its concentration fluctuates in the presence of chemotherapy [24Go], the percentage of patients that received darbepoetin alfa 2–4 days after chemotherapy (corresponding to the time of maximal chemotherapy effects on endogenous erythropoietin levels) was comparable for the i.v. and s.c. dose groups (data not shown). Thus, the potential confounding effect of endogenous erythropoietin levels on the current comparison of i.v. and s.c. exposures is probably minimal.

The results of this randomized, controlled study indicate that darbepoetin alfa can be administered i.v. or s.c. using a weekly followed by a once every 3 weeks schedule for the treatment of anemia in patients with non-myeloid malignancies receiving chemotherapy.


    Acknowledgements
 
The authors thank the study coordinators and patients at each of the participating centers. Susan Armstrong managed the study. Livia Sutjandra and Sameer Doshi assisted with the pharmacokinetic analyses, and Jose Rodriguez was responsible for the bioanalysis. Erik Poulsen assisted with the statistical analysis. Kathy Jelaca-Maxwell managed the safety data. This study was supported by Amgen Inc., Thousand Oaks, CA, USA.

Received for publication August 11, 2004. Revision received December 1, 2004. Accepted for publication February 8, 2005.


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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