PURPOSE The purpose of our studies was to define the maximal-tolerated dose of liposomal doxorubicin (DOX-SL; Liposome Technology Inc, Menlo Park, CA), a doxorubicin formulation of polyethyleneglycol-coated liposomes, characterize the toxicities associated with this formulation, and evaluate any indication of antitumor activity within a phase I setting. PATIENTS AND METHODS Two separate phase I studies were conducted following the initial human pharmacokinetic testing at one of the sites (Hadassah). The starting dose of 20 mg/m2 at the University of Southern California was just below the dose without toxicity in the pharmacokinetic study. At Hadassah, the phase I starting dose was just above their earlier safe single doses, 60 mg/m2. Both studies involved cohorts of at least three patients and redosing every 3 to 4 weeks. To determine the recommended dose for phase II trials, an additional level of 50 mg/m2 every 3 weeks was explored, and the level of 60 mg/m2 every 4 weeks was expanded. RESULTS A total of 56 patients receiving 281 courses of DOX-SL was accrued and evaluated for toxicity. Hand-foot (H-F) syndrome and stomatitis are the two main dose-limiting factors of DOX-SL. Stomatitis was dose-limiting for high single doses of DOX-SL greater than 70 mg/m2. Skin toxicity manifested primarily as H-F syndrome was dose-limiting for repetitive dosing, but acceptable at either 50 mg/m2 every 3 weeks or 60 mg/m2 every 4 weeks. Attenuation of acute subjective symptoms and lack of alopecia were generally observed. Patients with carcinomas of the breast, ovary, prostate, and head and neck were among those showing objective antitumor responses or improvement based, in part, on blood levels of tumor markers. CONCLUSION 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 finding, as well as the antitumor activity observed, supports wide phase II testing of DOX-SL in solid tumors.