A randomized, open-label, single-dose, self-controlled, dose-escalation phase I study of Y-pegylated recombinant human granulocyte-colony stimulating factor

Objective: To assess the safety and efficacy of single-dose Y-pegylated recombinant human granulocyte-colony stimulating factor (YPEG-rHuG-CSF) in the prophylaxis of chemotherapy-induced neutropenia, and to explore the dose-response relationships between YPEG-rHuG-CSF and recombinant human granulocyte-colony stimulating factor (rHuG-CSF, Topneuter^®). Methods: Cancer patients who were chemotherapy and radiotherapy naive received chemotherapy with three cycles of the same regimen with paclitaxel and carboplatin or epirubicin and cyclophosphamide. Firstly, patients were treated just with chemotherapy in cycle 1 defined as the screening or blank control cycle. Subsequently, patients were treated with chemotherapy and 48 hours after chemotherapy a single subcutaneous injection of YPEG-rHuG-CSF in cycle 2 or daily rHuG-CSF in cycle 3. The dose-escalation study enrolled five successive cohorts of patients (3 to 9 per cohort) treated with YPEG-filgrastim at 10, 20, 30, 45 or 60 μg·kg^-1. The five successive cohorts of patients were randomized to receive daily rHuG-CSF at 150 μg or 300 μg in the control arms. Results: Thirty patients were enrolled into the trial and assessed the safety and efficacy. There were 3, 6, 6, 9, and 6 patients to be enrolled in five successive cohorts treated with single-dose YPEG-rHuG-CSF at 10, 20, 30, 45 or 60 μg·kg^-1, fifteen patients with daily rHuG-CSF at 150 μg or 300 μg in the control arms, respectively. The tolerability study revealed that the adverse events observed during the three cycles were most attributable to complications associated with cancer chemotherapies and YPEG-rHuG-CSF was well tolerated. The most frequently reported YPEG-rHuG-CSF-related adverse event was mild to moderate musculoskeletal pain (14/30, 46.67%), the same as rHuG-CSF (Topneuter^®). The pharmacodynamics research revealed that YPEG-rHuG-CSF could decrease the incidence of Grade 3~4 neutropenia and resulted in an ANC dynamic profile with double peaks, which was the same as rHuG-CSF. There were some dose-response relationships for YPEG-rHuG-CSF according to the ANC dynamic change. Conclusion: YPEG-rHuG-CSF revealed good tolerability and efficacy in this trial. Neither dose-limiting toxicities (DLT) nor maximum-tolerated dose (MTD) were observed. The recommended dose of YPEG-rHuG-CSF in Phase II is 45 μg·kg^-1 per chemotherapeutic cycle.