A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

Abstract

The aims of this phase I study were to establish the maximum tolerated dose, safety profile and activity of liposomal daunorubicin, DaunoXome (NeXstar Pharmaceuticals), in the treatment of metastatic breast cancer. DaunoXome was administered intravenously over 2 h in 21 day cycles and doses were increased from 80 to 100, 120 and 150 mg m 2 . Sixteen patients were enrolled. A total of 70 cycles of DaunoXome were administered. The maximum tolerated dose was 120 mg m 2 , the dose-limiting toxicity being prolonged grade 4 neutropenia or neutropenic pyrexia necessitating dose reductions at 120 and 150 mg m 2 . Asymptomatic cardiotoxicity was observed in three patients: grade 1 in one treated with a cumulative dose of 800 mg m 2 and grade 2 in two, one who received a cumulative dose of 960 mg m 2 and the other a cumulative dose of 600 mg m 2 with a previous neoadjuvant doxorubicin chemotherapy of 300 mg m 2 . Tumour response was evaluable in 15 patients, of whom two had objective responses, six had stable disease and seven had progressive disease. In conclusion, DaunoXome is associated with mild, manageable toxicities and has anti-tumour activity in metastatic breast cancer. The findings support further phase II evaluation of DaunoXome alone and in combination with other standard nonanthracycline cytotoxic or novel targeted agents. Although the dose-limiting toxicity for DaunoXome was febrile neutropenia at 120 mg m 2 , we would recommend this dose for further evaluation, as the febrile neutropenia occurred after four or more cycles in three of the four episodes seen, was short lived and uncomplicated.

Cardiac Safety of Liposomal Anthracyclines

“…Early clinical studies indicated that liposomal daunorubicin may have a more favorable cardiac safety profile than the conventional formulation [15][16][17]. However, evidence of cardiotoxicity has been observed at higher cumulative doses of liposomal daunorubicin (600-900 mg/m 2 ) [18,19].…”

“…O'Byrne and colleagues conducted a phase I dose-escalation study to determine the maximum tolerated dose, safety profile, and activity of liposomal daunorubicin in the treatment of metastatic breast cancer (MBC) [18]. Sixteen anthracycline-naïve patients received 2-hour infusions of liposomal daunorubicin given every 21 days.…”

“…All patients had normal cardiac function at baseline, with LVEFs >50%. The maximum tolerated dose in that study was 120 mg/m 2 , 18 Cardiac Safety of Liposomal Anthracyclines with dose-limiting toxicities of prolonged grade 4 neutropenia or neutropenic pyrexia. Significant asymptomatic cardiotoxicity was reported in three patients.…”

Clinical development of liposome based drugs: formulation, characterization, and therapeutic efficacy

“…81 Daunorubicin has also been incorporated into liposomes for the formulation of liposomal anticancer chemotherapy drugs. DaunoXome ® (Gilead Sciences, Inc) is a commercial liposomal formulation of daunorubicin in which the drug is entrapped into small unilamellar vesicles (45 nm) composed of DSPC and cholesterol in 2:1 molar ratio.…”

Cardiac profiles of liposomal anthracyclines

“…41 Sixteen anthracycline-naïve patients received a 2-hour infusion of liposomal daunorubicin at an initial dose of 80 mg/m 2 every 21 days, which was increased to 100 mg/m 2 , 120 mg/m 2 , 150 mg/m 2 , and 180 mg/m 2 thereafter. All patients had normal cardiac function at baseline, defined as LVEF Ͼ 50%.…”