A Phase I Trial of a Pegylated Liposomal Anthracycline (Doxil TM) and Lapatinib Combination in the Treatment of Metastatic Breast Cancer: Dose-Escalation Results of an Anthracycline and Lapatinib Combination Trial.
Authors: Cianfrocca M. , Kaklamani V. , Rosen S. , von Roenn J. , Rademaker A. , Rubin S. , Friedman R. , Uthe R. , Gradishar W. 
Published: December 2010

Abstract
Background: Liposomal formulations such as pegylated liposomal doxorubicin (PLD) were developed to improve the therapeutic index and overall benefit of the anthracyclines (A). Lapatinib (L) is a selective and highly competitive inhibitor of ErbB1 and ErbB2 tyrosine kinases. The combination of conventional doxorubicin and an ErbB2 targeting agent (trastuzumab) was effective but led to an unacceptable risk of cardiac toxicity. The combination of PLD and L however may be effective with less cardiac risk. Methods: This is an open-label, phase I, dose-escalation trial of PLD at 20, 30, 45 and 60 mg/m2 IV every 4 weeks (maximum of 8 doses) and L, 1500 mg po daily until progression in patients (pts) with metastatic breast cancer (MBC). EGFR and/or ErbB2 positivity was not required. Prior chemotherapy, endocrine therapy and trastuzumab were allowed however prior A use was limited to 240 mg/m2 of doxorubicin or 600 mg/m2 of epirubicin. Initially, prior EGFR targeting therapies were not allowed however the trial was subsequently amended to allow prior lapatinib. Concomitant CYP3A4 inducers/ inhibitors were not allowed. A left ventricular ejection fraction (LVEF) of ≥ 50% was required. The primary objective was to evaluate the safety, tolerability and feasibility of the combination of PLD and L, particularly with respect to cardiac safety. MUGAs were performed at entry and every 8 weeks thereafter. Results: 16 patients (PLD: 20 mg/m2 - 4 pts; 30 mg/m2 - 3 pts; 45 mg/m2 – 6 pts; 60 mg/m2- 3 pts) with a mean age of 53 yrs (range, 33-68) have been treated for a total of 30 treatment cycles. Dose-limiting toxicity (DLT) was not reached. One pt experienced an LVEF drop to &lt; 50% after 4 cycles however this was accompanied by a pericardial effusion felt to be secondary to progressive disease. Adverse events observed include: grade IV- mucus plugging and knee pain in 1 pt each; grade III- fatigue and hand-foot-syndrome (HFS) in 2 pts each and edema, diarrhea, dizziness, headache, stomatitis and skin toxicity in 1 pt each; grade I/II in ≥2 pts- anemia, leucopenia, fatigue, shortness of breath, pain, nausea, stomatitis, anorexia, diarrhea, increased alkaline phosphatase or transaminases, hypoalbuminemia and hyperglycemia. Preliminary response data in 11 evaluable pts reveals 1 PR, 3 SD, and 8 PD. Event-free and overall survival curves are as shown.Conclusions: In the first 16 pts treated, the combination of PLD and L has been well tolerated without treatment-related cardiac toxicity. One pt experienced an LVEF drop to &lt; 50%, however this was felt likely to be disease-related. DLT was not reached however grade 3 HFS occurred in 2 out of 3 pts in the 60 mg/m2 cohort. A pharmacokinetic interaction cohort at the 45 mg/m2 dose is planned.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3096.