LIPOSOMAL DOXORUBICIN - ANTITUMOR-ACTIVITY AND UNIQUE TOXICITIES DURING 2 COMPLEMENTARY PHASE-I STUDIES

Purpose: The purpose of our studies was to define the maximal-tolerate d dose of liposomal doxorubicin (DOX-SL; Liposome Technology Inc, Menl o Park, CA), a doxorubicin formulation of polyethyleneglycol-coated li posomes, characterize the toxicities associated with this formulation, and evaluate any indication of antitumor activity within a phase I se tting. Patients and Methods: Two separate phase I studies were conduct ed following the initial human pharmacokinetic testing at one of the s ites (Hadassah). The starting dose of 20 mg/m(2) at the University of Southern California was just below the dose without toxicity in the ph armacokinetic study. At Hadassah, the phase I starting dose was just a bove their earlier safe single doses, 60 mg/m(2). Both studies involve d cohorts of at least three patients and redosing every 3 to 4 weeks, To determine the recommended dose for phase II trials, on additional l evel of 50 mg/m(2) every 3 weeks was explored, and the level of 60 mg/ m(2) every 4 weeks was expanded. Results: A total of 56 patients recei ving 281 courses of DOX-SL was accrued and evaluated for toxicity. Han d-foot (H-F) syndrome and stomatitis are the two main dose-limiting fa ctors of DOX-SL. Stomatitis was dose-limiting for high single doses of DOX-SL greater than 70 mg/m(2). Skin toxicity manifested primarily as H-F syndrome was dose-limiting for repetitive dosing, but acceptable at either 50 mg/m(2) every 3 weeks or 60 mg/m(2) every 4 weeks. Attenu ation of acute subjective symp toms and lack of alopecia were generall y observed. Patients with carcinomas of the breast, ovary, prostate, a nd head and neck were among those showing objective antitumor response s or improvement based, in part, on blood levels of tumor markers. Con clusion: The toxicity profile of DOX-SL differs prominently from that of the free drug administered by bolus or rapid infusion and with some differences, resembles that of prolonged continuous infusion. This fi nding, as well as the antitumor activity observed, supports wide phase II testing of DOX-SL in solid rumors.