ABSTRACT: The objectives of this study were to assess the safety and efficacy of darbepoetin alfa (Aranesp) administered every 2 weeks in anemic patients with solid tumors receiving chemotherapy. This was an open-label, randomized, active-controlled, multicenter dose-finding study evaluating a range of every-2-week darbepoetin alfa doses. The active control arm received epoetin alfa (Epogen, Procrit) at 40,000 U weekly with a dose increase to 60,000 U weekly for subjects with an inadequate response. The lowest clinically effective doses of darbepoetin alfa in this study were 3.0 and 5.0 µg/kg every 2 weeks, with no additional benefit observed at higher doses. The percentage of patients who achieved a hematopoietic response in the 3.0- and 5.0-µg/kg groups was 66% (95% confidence interval [CI] = 46%-86%) and 84% (95% CI = 67%-100%), respectively, compared with 63% (95% CI = 46%-81%) in the epoetin alfa group. Darbepoetin alfa administered at a dose of 3.0 µg/kg every 2 weeks is safe and effective for treating anemia in patients with solid tumors on chemotherapy, and is comparable to epoetin alfa. A dose increase to 5.0 µg/kg of darbepoetin alfa administered every 2 weeks may be appropriate in patients with an inadequate initial response.
Anemia is a significant complication of cancer and of the myelosuppressive chemotherapy used to treat cancer patients. The etiology of cancer-associated anemia is multifactorial. Contributing factors to cancer-associated anemia include decreased endogenous erythropoietin levels, erythropoietin resistance, and decreased red blood cell survival. Anemia is associated with many symptoms, including weakness, dyspnea, lethargy, and fatigue. Cancer patients most often report fatigue as the symptom of their disease that has the most negative impact on their lives. Studies have shown that anemia contributes to the fatigue and subsequent poor quality of life in patients with cancer.[3-5]
Iron replacement is helpful in selected cases; in most patients, symptomatic anemia is managed with red blood cell transfusions and/or with erythropoietic agents (epoetin alfa [Epogen, Procrit] or the recently approved darbepoetin alfa [Aranesp]). Studies have shown that treatment with epoetin alfa is associated with an increase in hemoglobin, a decreased incidence of blood transfusions, and an improvement in quality of life.[5-8] However, response to treatment is defined differently in these studies and the statistical methodology applied also differs, making it difficult to compare results or apply a standard criterion for response.
Limitations of treatment with epoetin alfa include ambiguity about the optimal dose and schedule due to lack of published systematic dose-finding studies, and a lack of pharmacokinetic data in the cancer setting. In addition, the necessity of weekly or more frequent office visits and the number of required injections make this therapy impractical for some. Office visits for injections add to patient discomfort, and consume valuable time and resources for patients, caregivers, and health-care professionals.
Darbepoetin alfa is a unique erythropoiesis-stimulating protein that is the result of research on the structure/function relationship of erythropoietin. Although darbepoetin alfa stimulates erythropoiesis in the same manner as epoetin alfa, it is a glycoprotein that is biochemically distinct from epoetin alfa. Darbepoetin alfa contains two more N-glycosylation sites, permitting eight additional sialic acid residues relative to epoetin alfa. Increased sialic acid content correlates with a threefold increase in terminal half-life of the molecule with a consequential increase of in vivo potency. This prolonged half-life allows darbepoetin alfa to be administered less frequently while maintaining comparable efficacy to the more frequently administered epoetin alfa. The prolonged half-life has been confirmed in patients with chronic renal failure and in cancer patients undergoing multiple cycles of chemotherapy.[11,12] Darbepoetin alfa has been shown to be effective in treating chemotherapy-induced anemia when administered as infrequently as once every 3 or 4 weeks. These findings have important implications for the quality of life of patients with cancer, as well as potential implications for overall resource utilization.
This dose- and schedule-finding study of darbepoetin alfa was conducted in two parts in subjects with solid tumors receiving cyclic chemotherapy. The first part of this study (part A) evaluated a range of weekly doses of darbepoetin alfa with an epoetin alfa active control group administered as indicated in the product label (150 U/kg three times per week with a possible dose increase). The second part of this study (part B) evaluated a range of every-2-week doses of darbepoetin alfa with an epoetin alfa active control group administered at 40,000 U weekly with a possible dose increase.
As reported by Glaspy et al, in part A of this study, characterization of the relationship between darbepoetin alfa dose and effect showed increasing effect with higher doses in the dose range of 0.5 to 4.5 µg/kg weekly. The percentage of patients achieving a hemoglobin response (³ 2.0 g/dL increase in hemoglobin from baseline) ranged from 23% (95% confidence interval [CI] = 0%-46%) for the 0.5-µg/kg group to 76% (95% CI = 59%-94%) for the 4.5-µg/kg group over the 12-week treatment period. The mean change in hemoglobin and the incidence of transfusions were similar for the 1.5-µg/kg darbepoetin alfa dose group and the epoetin alfa group, with additional benefit observed at higher doses (Table 1). Subjects receiving higher doses of darbepoetin alfa appeared to have a faster time to hemoglobin response, such that the 4.5-µg/kg dose group had a median time to response of 7 weeks compared with 10 weeks for lower doses and epoetin alfa. Doses in excess of 4.5 µg/kg did not appear to confer any increase in efficacy.
In the epoetin alfa group, patients with an inadequate initial response were allowed a dose increase at week 8 to 300 U/kg according to the US package insert for Procrit. Consequently, comparisons with darbepoetin alfa after this time point are confounded. In general, however, 1.5-µg/kg darbepoetin alfa weekly appeared to have a similar effect on hemoglobin variables compared with the epoetin alfa control arm up to week 8. Doses of darbepoetin alfa administered weekly at 2.25 µg/kg and above showed evidence of enhanced efficacy relative to the active control group. The differences between the darbepoetin alfa and active control groups observed earlier in the study were maintained at 12 weeks despite the epoetin alfa dose increase at week 8.
This paper reports findings from part B of the study for the purposes of identifying an appropriate dose of darbepoetin alfa administered every 2 weeks and of providing a preliminary comparison of every-2-week doses of darbepoetin alfa to weekly epoetin alfa.
The institutional review boards of participating medical centers approved the protocol, and all patients gave written informed consent before any study-related procedures were done. Inclusion criteria for patient eligibility were as follows: 18 years of age or older, diagnosed with a solid tumor, and scheduled to receive cyclic chemotherapy for at least 12 weeks after study enrollment. Patients also were required to be anemic (hemoglobin ≤ 11.0 g/dL), to have adequate serum folate and vitamin B12 concentrations, a life expectancy of at least 6 months, an Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate renal and liver function. Exclusion criteria included overt bleeding or hemolysis, receipt of more than two red blood cell transfusions within 4 weeks or any red blood cell transfusions within 16 days of randomization, receipt of epoetin alfa therapy within 8 weeks, known primary hematologic disorders that could cause anemia, and primary or metastatic disease of the central nervous system, or active cardiovascular diseases.
The data presented here were obtained from a phase I/II, multicenter, randomized, active-controlled, open-label study in anemic patients with solid tumors who were receiving multicycle chemotherapy. Patients were randomized to receive 12 weeks of subcutaneous therapy with darbepoetin alfa or epoetin alfa. Patients were randomized to receive one of four doses of darbepoetin alfa (3.0, 5.0, 7.0, and 9.0 µg/kg every 2 weeks) or epoetin alfa at 40,000 U weekly (Figure 1) in an equal allocation.
In keeping with common medical practice, subjects in the epoetin alfa group could have their dose increased to 60,000 U weekly at day 35 (study week 6) if they had an inadequate initial response. Day 35 was chosen for increasing the epoetin alfa dose based on data available at the time of initiation of the study with regard to common community practice with this agent. No patients receiving darbepoetin alfa were permitted to receive a dose increase at any time during the study; therefore, a direct comparison of the efficacy of an individual dose of darbepoetin alfa with epoetin alfa may be confounded for some end points. However, descriptive comparisons can be made between the two groups.
Safety End Points
All patients who received at least one dose of study drug were included in the safety analysis. Safety was assessed by screening for antibody formation to darbepoetin alfa, and by summarizing reports of adverse events. All adverse events were grouped according to the body system affected and by preferred term within body system according to a modified World Health Organization Adverse Reaction Term (WHOART) dictionary.
Efficacy End Points
The efficacy end points evaluated included hemoglobin response (³ 2.0 g/dL increase in hemoglobin over baseline in the absence of a red blood cell transfusion in the past 28 days), hemoglobin correction (hemoglobin ³ 12 g/dL in the absence of any red blood cell transfusion in the past 28 days), and hematopoietic response (hemoglobin value > 12.0 g/dL or a ³ 2.0-g/dL increase in hemoglobin over baseline in the absence of a red blood cell transfusion in the past 28 days) as defined in previous studies with epoetin alfa,[5,6] and mean change in hemoglobin from baseline. The incidence of red blood cell transfusions from week 5 to the end of the treatment phase was also evaluated.
Statistical analyses were conducted using the intent-to-treat analysis set (ie, all patients randomized to study drug who received at least one dose) with the last observation carried forward approach used to impute missing values. Baseline demographic and clinical characteristics were summarized by the mean (standard deviation) for continuous measures and number (percentage) for categorical measures. The proportion of patients achieving hematopoietic response was estimated by subtracting the Kaplan-Meier estimate of the survivor function at the time of the last observed hematopoietic response from 1, with 95% confidence limits calculated by using Greenwood’s estimate of the variance.
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