A Phase Ib Trial of RAD001, an mTOR Inhibitor, with Weekly Cisplatin and Paclitaxel in Patients with HER2-Negative Metastatic Breast Cancer.
Authors: Mayer I. , Burris H. , Bendell J. , Means-Powell J. , Arteaga C. , Shyr Y. , Pietenpol J. 
Published: December 2010

Abstract
Background: Pre-clinical data suggests that in basal-like breast cancers (triple-negative and some luminal B), drugs that either negatively modulate p63 and/or activate p73, such as cisplatin and paclitaxel, promote p73-dependent apoptosis. This is enhanced upon concomitant inhibition of mTOR with RAD001 (Everolimus). We conducted a phase Ib trial in patients with HER2-negative metastatic breast cancer to explore the safety, tolerability and anti-tumor activity of the combination of paclitaxel, cisplatin and RAD001.Materials and Methods: This was an open-label, phase Ib dose-escalation study. RAD001 was started at 20 mg/week on a 28-day treatment cycle, and was escalated over 3 dose levels (20, 25 and 30 mg/week). Cisplatin (25 mg/m2) and paclitaxel (80 mg/m2) doses were fixed, and were administered once a week for 3 weeks on a 28-day treatment cycle. Treatment was continued until dose-limiting toxicity (DLT) was observed or until progression of disease. All toxicities were documented using the NCI CTC v.3. Disease assessment was done every 2 months after initiation of therapy.Results: A total of 16 patients were enrolled. Median age was 55 years and the median number of previous chemotherapy regimens in the metastatic setting was 3. Seventy percent of the patients had triple-negative disease, all patients had metastatic visceral disease, and 25% of those had concomitant bone metastasis. Three patients are still on study, but have not had their first assessment of disease. Of the 13 patients that are currently evaluable for best response, 1 had a complete response (CR), 2 had partial response (PR), 7 had stable disease (SD), and 3 had disease progression (PD) at their first disease assessment. All patients with CR or PR received the higher dose level (RAD001 30 mg/week). Twelve patients have discontinued study drugs at this time; 7 due to disease progression, 3 due to toxicity and 2 due to maximum benefit. Overall median time to progression (TTP) was 5 months. The most common toxicities were alopecia (100%), neutropenia (28%), anemia (10%) and fatigue (5%). Grade 3 and 4 toxicities were overall uncommon (8.5%) and consisted of neutropenia which lasted for less than 5 days. No DLTs were seen at any of the dose levels.Discussion: The combination of weekly RAD001, cisplatin and paclitaxel was overall very well tolerated, despite neutropenia (non-dose limiting and without serious sequelae). Significant antitumor activity in this heavily pre-treated patient population was seen at all dose levels and appeared to be higher in the group treated with RAD001 30 mg/week. The recommended phase II doses for this combination are cisplatin 25 mg/m2, paclitaxel 80 mg/m2 given weekly for 3 weeks, and RAD 30 mg/week, on a 28-day treatment cycle. A phase Ib-II study of cisplatin, paclitaxel, and daily doses of RAD001 is ongoing.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3093.