[3119] RAD001 (everolimus) in combination with weekly paclitaxel and trastuzumab in patients with HER-2-overexpressing metastatic breast cancer with prior resistance to trastuzumab: a multicenter phase I clinical trial.

O'Regan R, Andre F, Campone M, Naughton M, Manlius C, Pylvaenaeinen I, Sahmoud T, Hurvitz S Emory University School of Medicine, Atlanta; Institut Gustave Roussy, Villejuif, France; Centre Regional Rene Gauducheau, Nantes, France; Washington University School of Medicine, St Louis; Novartis Pharmaceuticals, Basel, Switzerland; UCLA, Los Angeles

Background: Resistance to trastuzumab (H) is associated with loss of PTEN and AKT/mTOR activation. Preclinical models demonstrate that RAD001, an oral inhibitor of mTOR (a downstream component of the PI3K/AKT signaling pathway), enhances the efficacy of trastuzumab and suggest that RAD001 could reverse resistance to trastuzumab.
Methods: Paclitaxel (T, 80 mg/m²) IV was administered over 60 min on D 1, 8 and 15 q4w. Trastuzumab 4 mg/kg loading dose was administered IV over 90 min on Day 1 (if patient (pt) was not already receiving H), followed by weekly 2 mg/kg IV over 30 min. RAD001 was administered as either a daily (5 and 10 mg) or weekly (30, 50 and 70mg) cohorts. Treatment continues until progression or unacceptable toxicity.
Results: As of June 9 2007, 22 heavily pretreated pts were enrolled; 6 to the 5mg daily, 6 to the 10mg daily and 10 to the 30mg weekly cohorts. All pts were resistant to H and all patients, except one, received prior taxane. Median number of prior regimens was 6 (range: 1-26). Two DLTs were observed during the first cycle; febrile neutropenia on the daily 5mg arm and confusional state on the weekly 30mg arm. To date, 17 pts were evaluable for efficacy (Table 1). Among the 7 pts who were resistant to both T and H, 5 had PR (4/5 pts and 1/2 on the 5mg daily and 30mg weekly cohorts, respectively) and 2 had SD >16 weeks. Fifteen pts remain on treatment. The most commonly reported AEs are neutropenia and stomatitis. Recruitment continues.
Conclusions: RAD001 is well tolerated in combination with weekly TH regimen. Preliminary efficacy shows a high rate of tumor responses in heavily pre-treated pts, including pts resistant to both T and H. Mature results and biomarkers data will be presented.

Table 1. Efficacy

Response	5mg/d (n=5)	10mg/d (n=3)	30mg/w (n=9)
PR	5	0	2
SD	0	3	6
Progression	0	0	1

Friday, December 12, 2008 5:00 PM

Poster Session III: Treatment: Advanced Therapy - Targeted (5:00 PM-7:00 PM)