Comparison of darbepoetin alfa dosed weekly (QW) vs. extended dosing schedule (EDS) in the treatment of anemia in patients receiving multicycle chemotherapy in a randomized, phase 2, open-label trial

BACKGROUND: Chemotherapy-induced anemia (CIA) is responsive to treatment with erythropoiesis-stimulating agents (ESAs) such as darbepoetin alfa. Administration of ESAs on a synchronous schedule with chemotherapy administration could benefit patients by reducing clinic visits and potentially enhancing on-time chemotherapy delivery. METHODS: This phase 2, 25-week, open-label study evaluated the noninferiority of darbepoetin alfa administered weekly vs. as an extended dosing schedule (every 2 or 3 weeks) in patients with CIA. Patients were randomized 1:1 to an extended dosing schedule (EDS: darbepoetin alfa 300 μg Q2W if chemotherapy was QW, Q2W, or Q4W or darbepoetin alfa 500 μg Q3W if chemotherapy was Q3W) or weekly (150 μg QW regardless of chemotherapy schedule). Stratification factors included chemotherapy cycle length, screening hemoglobin (<10 g/dL vs. ≥10 g/dL), and tumor type (lung/gynecological vs. other nonmyeloid malignancies). The primary endpoint was change in hemoglobin from baseline to Week 13. RESULTS: Seven hundred fifty-two patients (374 QW patients; 378 EDS patients) received ≥1 dose of darbepoetin alfa and were included in the analysis. Demographics and disease state were similar between groups. Seventy-one percent of patients in the EDS group and 76% in the QW group achieved the target hemoglobin of ≥11.0 g/dL. There was a minimal difference in the primary endpoint of mean change in hemoglobin (baseline to Week 13) between the QW and the EDS groups (-0.04 g/dL; 95% confidence interval: -0.26, 0.17 g/dL). The upper limit of the 95% confidence interval was less than the prespecified limit of <0.75 g/dL, supporting noninferiority of the EDS dosing schedule. Reported adverse events were similar between groups. A slight increase in transfusions was reported in the QW group. CONCLUSION: Darbepoetin alfa, when administered synchronously with chemotherapy, on an EDS appears to be similarly efficacious to darbepoetin alfa weekly dosing with no unexpected adverse events. This study provides prospective data on how multiple dosing regimens available with darbepoetin alfa can be synchronized with chemotherapy administered across a range of dosing schedules. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00144131

Comparison of darbepoetin alfa dosed weekly (QW) vs. extended dosing schedule (EDS) in the treatment of anemia in patients receiving multicycle chemotherapy in a randomized, phase 2, open-label trial

Abstract Background Chemotherapy-induced anemia (CIA) is responsive to treatment with erythropoiesis-stimulating agents (ESAs) such as darbepoetin alfa. Administration of ESAs on a synchronous schedule with chemotherapy administration could benefit patients by reducing clinic visits and potentially enhancing on-time chemotherapy delivery. Methods This phase 2, 25-week, open-label study evaluated the noninferiority of darbepoetin alfa administered weekly vs. as an extended dosing schedule (every 2 or 3 weeks) in patients with CIA. Patients were randomized 1:1 to an extended dosing schedule (EDS: darbepoetin alfa 300 μg Q2W if chemotherapy was QW, Q2W, or Q4W or darbepoetin alfa 500 μg Q3W if chemotherapy was Q3W) or weekly (150 μg QW regardless of chemotherapy schedule). Stratification factors included chemotherapy cycle length, screening hemoglobin ( Results Seven hundred fifty-two patients (374 QW patients; 378 EDS patients) received ≥1 dose of darbepoetin alfa and were included in the analysis. Demographics and disease state were similar between groups. Seventy-one percent of patients in the EDS group and 76% in the QW group achieved the target hemoglobin of ≥11.0 g/dL. There was a minimal difference in the primary endpoint of mean change in hemoglobin (baseline to Week 13) between the QW and the EDS groups (-0.04 g/dL; 95% confidence interval: -0.26, 0.17 g/dL). The upper limit of the 95% confidence interval was less than the prespecified limit of Conclusion Darbepoetin alfa, when administered synchronously with chemotherapy, on an EDS appears to be similarly efficacious to darbepoetin alfa weekly dosing with no unexpected adverse events. This study provides prospective data on how multiple dosing regimens available with darbepoetin alfa can be synchronized with chemotherapy administered across a range of dosing schedules. Trial registration ClinicalTrials.gov Identifier NCT00144131.</p

Abstract #3594: A Phase 1 randomized crossover oral picoplatin bioavailability pharmacokinetics and pharmacodynamics study

Background:Picoplatin is a platinum analogue designed to overcome platinum resistance and have improved safety and efficacy compared to other platinums. It has been evaluated intravenously (IV) in \u3e750 patients and shown to have activity in lung, prostate, colorectal and ovarian cancer. IV picoplatin is being evaluated in a Phase 3 trial with patients who have platinum-refractory or resistant small cell lung cancer. Picoplatin has a low incidence of renal, ototoxicity, or neurotoxicity, established at Methods: Patients with advanced non-hematological malignancies were randomized in a two-period crossover, open label study. Single dose picoplatin (Cycle 1) was administered either IV or orally, and 4 weeks later followed by a second single picoplatin dose (Cycle 2) by the alternative route to Cycle 1. The IV dose was 120 mg/m2 administered over 1 hour and the oral doses were 50-400 mg (6 subjects per group). Blood samples were analyzed for platinum concentration in plasma (total platinum) and plasma ultrafiltrate (unbound platinum). Clinical and laboratory data were obtained to assess safety and pharmacodynamics. Results: Absolute plasma bioavailability of oral picoplatin (± SD) at doses of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg was respectively 79 ± 24%, 86 ± 18%, 39 ± 15% and 28 ± 16%, and 21 ± 6% measured as the AUC of total platinum and 110 ± 23%, 116 ± 28%, 44 ± 4%, 27 ± 10%, and 21 ± 5% as the AUC of unbound platinum. Both total and unbound platinum peak concentrations following picoplatin oral and IV dosing occurred at 3-5 hr and 1 hr (the end of the IV infusion), respectively. Four weeks after picoplatin dosing by either route, only background levels of circulating platinum could be detected, suggesting no drug accumulation between dosing cycles. Comparable prolonged total platinum terminal half-life was observed with mean values established at 125 ± 10 hr and 147 ± 43 hr (P=NS), respectively, after picoplatin dosing by IV and oral route. No differences were observed between pharmacokinetics of Cycle 1 and Cycle 2 oral dosing. All doses were well tolerated and no serious adverse events related to treatment were noted following the oral dose. Conclusion: Exposure to orally administered picoplatin was linear with dose at doses of 50, 100, and 200 mg per patient. Maximum exposure to orally administered picoplatin was achieved at doses \#8805;200 mg per patient. Orally administered picoplatin is sufficiently bioavailable to warrant further study. Modeling supports additional multi-dose clinical studies. Simulation based on the present results will guide design of the next oral picoplatin trial