Abstract #5651: Intermittent pan-HER inhibition with AC480 in combination with paclitaxel leads to robust synergistic reduction of tumor size in a preclinical model
Authors: Robert Armstrong, Barbara Belli, Ruwanthi Gunawardane, Ronald Nepomuceno, Joyce James, Michael Gardner, Jill Ricono, Wendell Wierenga, Shripad Bhagwat
Journal: Cancer Research (2009)

AC480 is a potent small molecule pan-HER inhibitor currently in Phase 2 of clinical development. Although continuous administration of the HER family inhibitors has been clinically efficacious, a significant percentage of non-responders and the appearance of acquired resistance have limited their therapeutic potential. In an effort to expand their therapeutic range, combination studies with other therapeutic agents have been initiated. Recent publications suggest that intermittent dosing of HER family inhibitors may improve combination efficacy relative to continuous dosing of the inhibitor (Solit et al 2005; Riely et al 2008). To determine whether AC480 might improve benefit in a combination regime we conducted studies in cell culture and in an in vivo xenograft model to assess potential for synergy between AC480 and paclitaxel. In cell culture, AC480 was tested with paclitaxel in BT474 breast cancer cells and their combined effect on cell viability was assessed using the median effect method of Chou and Talalay. Simultaneous treatment of cells with AC480 and paclitaxel led to synergy with a combination index of 0.62. To determine whether the observed in vitro synergy would translate to a tumor xenograft model we tested the combination in the HER2 over-expressing MX-1 breast tumor model. AC480 dosed as monotherapy either on a QDx21 day schedule at 180 mg/kg or on a QDx2 for each of three weeks (QDx2x3) at 300 mg/kg demonstrated no antitumor activity. Paclitaxel alone at 35mg/kg IP once per week for three weeks led to modest antitumor activity with no tumor regressions. For combination studies AC480 was tested at 180 and 300mg/kg on the QDx2x3 schedule with paclitaxel given on a Q7Dx3 schedule. AC480 was dosed on three distinct schedules that varied in their timing relative to paclitaxel. AC480 given for two days per cycle starting the day after paclitaxel administration demonstrated no additional benefit relative to paclitaxel alone at either dose tested. In contrast, when AC480 was given either the two days prior (-2, -1) to paclitaxel or the day before and the day of (-1, 0) paclitaxel treatment robust synergy was observed. The degree of synergy was dose- and schedule-dependent, with the -1, 0 schedule yielding the most significant antitumor effects. On the -2, -1 schedule no tumor regression was observed in the 180 mg/kg dosed animals, while 38% of the animals showed complete tumor regression at 300mg/kg. However, on the -1, 0 AC480 schedule complete tumor regression was observed in 50% and 100% of the animals treated with 180mg/kg and 300mg/kg of AC480, respectively. These studies demonstrate that intermittent dosing of AC480 in combination with paclitaxel leads to dose- and schedule-dependent synergy in a HER2 over-expressing human breast tumor model. Additional studies are underway to delineate the molecular mechanisms that may underlie this synergy.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5651.