Abstract P5-11-07: Pharmacokinetics of eflapegrastim in a phase 2 open-label dose-ranging study in breast cancer patients receiving TC regimen

Abstract

Abstract Background: Eflapegrastim (SPI-2012/HM10460A) is a novel, long acting recombinant human granulocyte colony-stimulating factor (rhG-CSF). Eflapegrastim consists of an rhG-CSF conjugated to the recombinant E coli derived Fc fragment of IgG4 via a polyethylene glycol linker. Eflapegrastim is in clinical development for the treatment of chemotherapy induced neutropenia in cancer patients. Methods: Pharmacokinetics (PK) of eflapegrastim was investigated in an open label, dose-ranging Phase 2 study in breast cancer patients receiving docetaxel + cyclophosphamide (TC) chemotherapy. The study consisted of 4 arms. Patients in Arms 1 through 3 received subcutaneous doses of 45, 135, or 270 µg /kg of eflapegrastim and patients in Arm 4 received 6 mg pegfilgrastim (Neulasta®) on Day 2 of each 21-day chemotherapy cycle. Serum samples were collected from a subset of eflapegrastim patients at pre-specified time-points and analyzed for eflapegrastim by a validated enzyme-linked immunosorption assay (ELISA). Pharmacokinetic analyses were conducted on serum concentration-time profiles after dosing in Cycle 1. The serum concentrations for samples collected in Cycle 3 were compared with the corresponding concentrations in Cycle 1. Pharmacokinetic analyses were not conducted for pegfilgrastim patients. Results: The PK profile of eflapegrastim was investigated in 11 patients, including 3 patients in the 45 µg/kg treatment arm, 4 patients in the 135 µg/kg treatment arm, and 4 patients in the 270 µg/kg treatment arm. Following single eflapegrastim doses of 45, 135, or 270 µg/kg, peak serum concentrations increased in a dose proportional manner. The summary of pharmacokinetics of eflapegrastim is presented in the Table below. Pharmacokinetic Parameters of Eflapegrastim in Patients Following Single Subcutaneous Doses in Cycle 1ParameterEflapegrastim 45 μg/kg/Eflapegrastim 135μg/kgEflapegrastim 270 μg/kgCmax, ng/mLN = 3; Mean = 7.00; SD = 6.08N = 4; Mean = 247; SD = 276N =3; Mean = 299; SD = 329Tmax, haN =2; Mean = 58.7; SD = 46.9 - 70.5N = 4; Mean =9.00; SD = 8 - 48.1N = 3; Mean = 24.00; SD = 24 - 24.1AUC0-312, ng•hr/mLN = 0; Mean = NC; SD = NCN = 2; Mean = 16000; SD = 5850N = 3; Mean = 22900; SD = 25100t1/2, hbN = 0; Mean = NC; SD = NCN = 2; Mean = 81.0; SD = 88.4N = 1; Mean = 31.5; SD = NCAUC = area under the concentration-time curve; Cmax = maximum serum concentration; h = hour; NC = not calculated; SD = standard deviation; t1/2 = half-life; Tmax = time to maximum serum concentration; a) Expressed as median and range; b) Expressed as harmonic mean and pseudo SD The maximum serum concentrations of eflapegrastim in Cycle 3 increased with the dose of eflapegrastim. The serum concentrations of eflapegrastim in Cycle 3 were generally lower than those in Cycle 1, but the profile was similar to Cycle 1. Conclusions: The Cmax and AUC(0-312) of eflapegrastim increased in a dose proportional manner following subcutaneous administration. The half-life of eflapegrastim ranged from 31.5 to 81.0 hours, which is consistent with the half-life of other long-acting myeloid growth factors. Citation Format: Vacirca JL, Papai Z, Horvath Z, Makharadze R, Reddy G, Song T, Koli P, Schwartzberg LS. Pharmacokinetics of eflapegrastim in a phase 2 open-label dose-ranging study in breast cancer patients receiving TC regimen [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-07.