Phase I Study of Nonpegylated Liposomal Doxorubicin plus Trastuzumab in Patients with HER2-Positive Breast Cancer

Abstract

Background This was an open-label, nonrandomized, multicenter, 2-stage phase I trial of safety and preliminary efficacy of nonpegylated liposomal doxorubicin (NLD) in combination with trastuzumab in advanced breast cancer, with emphasis on cardiac toxicity. Patients and Methods Forty patients (median age, 48 years; range, 30–74 years) with HER2/ neu 2+ or 3+ tumors (by immunohistochemistry) were recruited December 1999 to November 2002. Patients were eligible if they received ≤ 1 previous trastuzumab regimen, ≤ 2 cytotoxic regimens for advanced breast cancer, and lifetime cumulative anthracycline doses ≤ 240 mg/m 2. The study regimen comprised NLD 60 mg/m 2 every 3 weeks and trastuzumab loading dose 4 mg/kg followed by 2 mg/kg weekly. Treatment cycles lasted 21 days. Clinical cardiac assessments were performed with multigated acquisition scans every 2 cycles. Patients were evaluated for cardiac toxicity after receiving ≥ 1 cycle. Cardiac safety was assessed after completing ≥ 4 full treatment cycles. Results Thirty out of 40 patients (75%) received ≥ 4 treatment cycles and were evaluable for cardiac safety. Five patients (13%), 4 who were doxorubicin pretreated, developed left ventricular ejection fraction reductions to < 50%, and 2 (5%) of these patients experienced clinical cardiac toxicity. Fifty percent of the patients had objective tumor responses; median progression-free survival was approximately 21 weeks. Twenty-six patients (65%) had grade 3/4 neutropenia; 2 patients experienced febrile neutropenia. Conclusion Nonpegylated liposomal doxorubicin plus trastuzumab is active in HER2-positive patients with advanced breast cancer and is associated with a lower risk of cardiac toxicity than conventional doxorubicin plus trastuzumab.