PHASE-I EVALUATION OF A WATER-SOLUBLE ETOPOSIDE PRODRUG, ETOPOSIDE PHOSPHATE, GIVEN AS A 5-MINUTE INFUSION ON DAY-1, DAY-3, AND DAY-5 IN PATIENTS WITH SOLID TUMORS

Purpose: To determine the toxicities, maximum-tolerated dose (MTD), an d pharmacology of etoposide phosphate, a water-soluble etoposide deriv ative, administered as a 5-minute intravenous infusion on a schedule o f days 1, 3, and 5 repeated every 21 days. Patients and Methods: Thirt y-six solid tumor patients with a mean age of 63 years, performance st atus of 0 to 1, WBC count greater than or equal to 4,000/mu L, and pla telet count greater than or equal to 100,000/mu L, with normal hepatic and renal function were studied. Doses evaluated in etoposide equival ents were 50, 75, 100, 125, 150, 175, and 200 mg/m(2)/d. Etoposide in plasma and urine and etoposide phosphate in plasma were measured by hi gh-performance liquid chromatography (HPLC). Eleven of 36 patients wer e treated with concentrated etoposide phosphate at 150 mg/m(2)/d. Resu lts: Grade I/II nausea, vomiting, alopecia, and fatigue were common. L eukopenia (mainly neutropenia) occurred at doses greater than 75 mg/m( 2), with the nadir occurring between days 15 and 19 posttreatment. All effects were reversible. Hypotension, bronchospasm, and allergic reac tions were not observed in the first 25 patients. The MTD due to leuko penia was determined to be between 175 and 200 mg/m(2)/d. In 11 patien ts treated with concentrated etoposide phosphate, no local phlebitis w as noted, bur two patients did develop allergic phenomena. The convers ion of etoposide phosphate to etoposide was not saturated in the dosag es studied. Etoposide phosphate had peek plasma concentrations at 5 mi nutes, with a terminal half-life (t(1/2)) of 7 minutes. Etoposide reac hed peek concentrations at 7 to 8 minutes, with a t(1/2) of 6 to 9 hou rs. Both etoposide phosphate and etoposide demonstrated dose-related l inear increases in maximum plasma concentration (C-max) and area under the curve (AUC). Conclusion: Etoposide phosphate displays excellent p atient tolerance in conventional dosages when administered as a 5-minu te intravenous bolus. The suggested phase II dose is 150 mg/m(2) on da ys 1, 3, and 5. The ability to administer etoposide phosphate as a con centrated, rapid infusion may prove of value both in the outpatient cl inic and in high-dose regimens. (C) 1994 by American Society of Clinic al Oncology.