ancer Receiving Myelosuppressive Chemotherapy
The pharmacokinetics and safety of pegfilgrastim were studied in 37 pediatric patients with sarcoma in Study 4 [see
Clinical Studies 14.1]. The mean (± standard deviation [SD]) systemic exposure (AUC 0-inf) of pegfilgrastim after
subcutaneous administration at 100 mcg/kg was 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n
= 11), 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), and 29.3 (± 23.2) mcg·hr/mL in the 12 to 21
years age group (n = 13). The terminal elimination half-lives of the corresponding age groups were 30.1 (± 38.2)
hours, 20.2 (± 11.3) hours, and 21.2 (± 16.0) hours, respectively.
13 NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenesis studies have been performed with pegfilgrastim products.
Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative weekly dosesapproximately 6 to 9 times higher than the recommended human dose (based on body surface area).
14 CLINICAL STUDIES
Patients with Cancer Receiving Myelosuppressive Chemotherapy Pegfilgrastim was eva luated in three randomized, double-blind, controlled studies. Studies 1 and 2 were activecontrolledstudies that employed doxorubicin 60 mg/m2 and docetaxel 75 mg/m2 administered every 21 days for upto 4 cycles for the treatment of metastatic breast cancer. Study 1 investigated the utility of a fixed dose ofpegfilgrastim. Study 2 employed a weight-adjusted dose. In the absence of growth factor support, similar
chemotherapy regimens have been reported to result in a 100% incidence of severe neutropenia (ANC < 0.5 x 109/L)with a mean duration of 5 to 7 days and a 30% to 40% incidence of febrile neutropenia. Based on the correlationbetween the duration of severe neutropenia and theincidence of febrile neutropenia found in studies with filgrastim,duration of severe neutropenia was chosen as theprimary endpoint in both studies, and the efficacy of pegfilgrastimwas demonstrated by establishing comparability to filgrastim-treated patients in the mean days of severeneutropenia.
In Study 1, 157 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) on day2 of each chemotherapy cycle or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of eachchemotherapy cycle. In Study 2, 310 patients were randomized to receive a single subcutaneous injection of
pegfilgrastim (100 mcg/kg) on day 2 or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of eachchemotherapy cycle.
Both studies met the major efficacy outcome measure of demonstrating that the mean days of severe neutropenia ofpegfilgrastim-treated patients did not exceed that of filgrastim-treated patients by more than 1 day in cycle 1 of duration of severe neutropenia as a predictor of efficacy. Selection of the dosing regimen of UDENYCA is based onreducing the duration of severe neutropenia.
chemotherapy. The mean days of cycle 1 severe neutropenia in Study 1 were 1.8 days in the pegfilgrastim armcompared to 1.6 days in the filgrastim arm [difference in means 0.2 (95% CI -0.2, 0.6)] and in Study 2 were 1.7 daysin the pegfilgrastim arm compared to 1.6 days in the Filgrastim arm [difference in means 0.1 (95% CI -0.2, 0.4)].
A secondary endpoint in both studies was days of severe neutropenia in cycles 2 through 4 |
