Phase I and pharmacologic study of i.v. hydroxyurea infusion given with i.p. 5-fluoro-2 '-deoxyuridine and leucovorin

Preclinical data suggests that the action of fluoropyrimidines may be enhan ced by the addition of hydroxyurea. We developed a phase I trial to determi ne the maximum tolerated dose and pharmacokinetics of i.v, hydroxyurea (HU) in combination with i.p. 5-fluoro-2'-deoxyuridine (FUdR) and leucovorin (L V). Eligible patients had metastatic carcinoma confined mostly to the perit oneal cavity, and adequate hepatic, renal and bone marrow function. Patient s were treated with a fixed dose of FUdR (3 g) and LV (640 mg) administered on days 1-3. HU was administered as a 72-h infusion starting simultaneousl y with i.p. therapy on day 1, The following dose levels were studied: 2.0, 2.5, 3.0 and 3.6 g/m(2)/day. Pharmacokinetics were studied in blood and per itoneal fluid, Twenty-eight patients were accrued. Steady-state plasma and peritoneal fluid HU levels increased with increasing dose, and steady state was achieved within 12 h of continuous dosing, The steady-state HU plasma: peritoneal fluid concentration ratio ranged from 1.06 x 10(3) to 1.2 5x 10( 3) and the plasma HU clearance ranged from 4.63 to 5.81 l/h/m(2). Peritonea l fluid AUC = 137 639+/-43 914 mug/ ml min, t(1/2) = 100.9+/-56.4 min and C I = 25.29+/-10.88 ml/min. Neutropenia represented the dose-limiting toxicit y. We conclude that i.p. FUdR and LV in combination with i.v. HU is well to lerated, The addition of systemic HU increased the incidence of myelosuppre ssion. [(C) 2001 Lippincott Williams & Wilkins.].