Pharmacokinetics of fractionated cyclophosphamide (CY) in children with recurrent malignancies

Abstract

8533 Background: CY is an inactive pro-drug that requires hepatic biotransformation into its primary cytotoxic metabolite, 4-hydroxycyclophosphamide (HCY). The fractionated CY (FCY) schedule described is clinically relevant with a reported 59% response rate in advanced or refractory solid tumors. Because of proposed CY metabolic auto-induction it was hypothesized that the sum of the areas-under-the-curve (AUCs) of HCY for the FCY schedule would exceed the AUC of the standard (SCY) schedule, and that the sum of the 24-hour urinary CY recovery would be less with FCY than SCY. Methods: Patients received FCY x 1 [CY 500 mg/m2/day x 5 days plus etoposide 100 mg/m2/day x 5 days] and SCY x 1 [CY 2.5 g/m2/day x 1 plus etoposide 100 mg/m2/day x 5 days], each given 3 weeks apart. Patients were randomized to receive FCY as the first or second course. Courses were followed by G-CSF (5 micorgrams/kg/day). Serum samples drawn at hours 0, 0.5, 1, 3, 6, 8 and 24 after CY administration, were analyzed for HCY by HPLC with detection by UV-vis. Urine samples were analyzed for CY by HPLC with detection by electrospray ionization mass spectrometry. Results: 19 patients, 1–21 years of age, with recurrent solid tumors and leukemia were enrolled. Samples for one patient were misplaced, two patients did not complete the second cycle of therapy, one due to progressive disease and one who had an amputation for local tumor control of an epithelioid sarcoma and one patient did not have complete CY analysis. No effect was noted for the randomization of courses. Mean FCY urinary CY concentrations were lower than mean SCY (0.35±0.06 vs. 0.68±0.16 microM/ml; p = .03; n=15). Mean FCY HCY AUC was higher than mean SCY AUC (88±31 vs. 31.2±6 microM; p = .07; n=16). Patients received G-CSF after 32 courses (89%). Bone marrow suppression was notable with 81% grade 3 or 4 leucopenia (84% SCY, 77% FCY) and 28% grade 3 or 4 thrombocytopenia (37% SCY, 18% SCY). Hospitalization for fever and neutropenia occurred after 11 courses (7 SCY/4 FCY). No other significant toxicity occurred. Conclusions: We conclude that fractionated cyclophosphamide allows greater exposure to its active metabolite and this regimen should be evaluated in frontline therapies for pediatric cancers responsive to CY. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen