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 enhanced by the addition of hydroxyurea. We developed a phase I trial to determine the maximum tolerated dose and pharmacokinetics of i.v. hydroxyurea (HU) in combination with i.p. 5-fluoro-2'-deoxyuridine (FUdR) and leucovorin (LV). Eligible patients had metastatic carcinoma confined mostly to the peritoneal cavity, and adequate hepatic, renal and bone marrow function. Patients 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 simultaneously 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 peritoneal 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 × 10 3 to 1.25 × 10 3 and the plasma HU clearance ranged from 4.63 to 5.81 l/h/m 2 . Peritoneal fluid AUC = 137 639 ′ 43 914 μg/ ml.min, t 1 /2 = 100.9 ′ 56.4 min and CI = 25.29 ′ 10.88 ml/min. Neutropenia represented the dose-limiting toxicity. We conclude that i.p. FUdR and LV in combination with i.v. HU is well tolerated. The addition of systemic HU increased the incidence of myelosuppression.