Multicenter phase I clinical trial of daily and weekly RAD001 in combination with vinorelbine and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with prior resistance to trastuzumab

Abstract

1057 Background: RAD001 (everolimus) is an oral inhibitor of the mTOR serine-threonine kinase, a downstream component of the PI3K/AKT signaling pathway playing a critical role in regulation of protein synthesis and ultimately cell growth, proliferation, and angiogenesis. RAD001 shows activity in breast cancer patients (pts) as both monotherapy and in combination with letrozole. Preclinical models demonstrate that RAD001 enhances the efficacy of trastuzumab. Loss of PTEN and AKT/mTOR activation have been reported to mediate resistance to trastuzumab. Methods: Vinorelbine was administered at a dose of 25 mg/m2, IV over 10–15 min on days 1 and 8 q3w. Trastuzumab 4 mg/kg loading dose administered IV over 90 min on day 1 (if pt was not already receiving trastuzumab), followed by weekly trastuzumab 2 mg/kg IV over 30 min. In the daily RAD001 arm, 2 cohorts were planned (5 and 10mg) and in the weekly RAD001 arm, 4 cohorts were planned (20, 30, 50 and 70mg). Treatment continues until progression or unacceptable toxicity. Results: As of Jan 8, 2008, 19 heavily pretreated pts were enrolled: nine to the 5mg daily, six to 20mg weekly and four to the 30mg weekly cohorts. All pts received prior taxane. Median number of prior chemotherapy regimens was 3 (range: 1–5). In the 5mg daily arm, the main safety concern was grade 2 and 3 stomatitis which led to dose reduction in three patients and dose interruption in three more. Neutropenia was also reported. Preliminary efficacy: eight pts have been evaluated; 2 pts had PR (22+, 26+ weeks) and four pts SD (12, 13+, 28, 42+ weeks). Among the 10 pts recruited to the weekly arm, grade 4 neutropenia was reported in 4 and 3 pts in the 20 and 30mg cohorts, respectively. No other serious adverse reactions were observed to date. Preliminary efficacy: Nine pts were evaluated; 1 pt had PR (23+ weeks) and seven pts SD (11+, 14+, 19, 26+, 26+, 37+, 43+ weeks). Recruitment continues. Conclusions: Initial findings show that RAD001 is generally well tolerated in combination with vinorelbine and trastuzumab and shows promising activity in heavily pretreated pts with HER2-overexpressing metastatic breast cancer. We aim to present updated results at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Pharmaceuticals Novartis, Roche, Genentech Novartis Novartis, Roche, Genentech Novartis