Phase I and Pharmacokinetic Study of E7070, a Novel Chloroindolyl Sulfonamide Cell-Cycle Inhibitor, Administered as a One-Hour Infusion Every Three Weeks in Patients With Advanced Cancer

Abstract

PURPOSE: The objectives were to determine the maximum-tolerated dose, the recommended dose, the dose-limiting toxicity, the pharmacokinetics, and the activity of E7070, a novel cell-cycle inhibitor. PATIENTS AND METHODS: E7070 was given as a 1-hour intravenous infusion every 3 weeks in two groups of patients with advanced solid tumors who met prespecified eligibility criteria (group A) or who met the same eligibility criteria but in addition were less heavily pretreated and had more favorable liver functions (group B). RESULTS: Forty patients (31 patients in group A and nine patients in group B) were entered. Dose escalation proceeded through eight levels (range, 50 to 1,000 mg/m2). In group A, neutropenia and thrombocytopenia were dose-limiting toxicities occurring during the first cycle in two of seven patients treated at the doses of 700 mg/m2 and two of four patients treated at 800 mg/m2. Identical dose-limiting toxicities were observed in zero of six and two of three patients from group B at doses of 800 and 1,000 mg/m2, respectively. Other toxicities included acne-like skin eruption, mucositis, conjunctivitis, nausea, fatigue, and alopecia. At doses greater than 400 mg/m2, the area under the concentration-time curve increased disproportionately to the administered dose. Tumor stabilization lasting ≥ 6 months was observed in six assessable patients. CONCLUSION: The recommended doses of E7070 in this schedule were 700 mg/m2 (group A) and 800 mg/m2 in patients who were less heavily pretreated (group B) with a moderate tumor burden. Prolonged disease stabilization observed in this study might warrant further investigation of E7070 in selected tumor types.