Abstract OT2-2-06: Phase II single arm study of liposomal doxorubicin (D), bevacizumab (A), and temsirolimus (T) for treatment of triple negative early breast cancer refractory to standard neoadjuvant chemotherapy
Authors: Murthy Rashmi K , Ueno Naoto T , Symmans William F , Litton Jennifer K , Arun Banu K , Ibrahim Nuhad K , Alvarez Ricardo H , Gilcrease Michael Z , Valero Vicente , Tripathy Debasish , Moulder Stacy L 
Published: May 2015

Abstract
Background: Historically, triple negative breast cancers (TNBCs) were categorized into an ill-defined group that lacked estrogen receptors, progesterone receptors, and overexpression of human epidermal growth factor receptor 2. When TNBCs are treated with standard neoadjuvant chemotherapy (NAC), a pathologic complete response (pCR) is achieved in only 30-50% of the time. In an effort to improve outcomes for chemotherapy - refractory disease, emerging subtypes of TNBC have been identified through advances in molecular profiling leading to the discovery of distinct molecular aberrations which may be targeted. For example, mesenchymal-like TNBCs are a subset with aberrations that activate the PI3K/AKT/mTOR axis. Similar to mesenchymal-like, metaplastic breast cancers are commonly triple negative, refractory to standard therapy, and also harbor a high rate of molecular aberrations that lead to activation of the PI3K pathway. As such, metaplastic tumors may act as a morphologically identified ‘surrogate of response’ to evaluate the activity of targeted therapy regimens in mesenchymal-like TNBC. Based upon favorable results noted in a phase I trial of liposomal doxorubicin, bevacizumab, and the mTOR inhibitor temsirolimus (DAT) in metastatic metaplastic tumors, we will conduct this single arm phase II trial with neoadjuvant DAT for chemotherapy-refractory mesenchymal-like TNBC.
Trial Design: At our institution, women with TNBC who are receiving NAC will be enrolled onto a triaging protocol, where they will be randomized in a 2:1 fashion to be evaluated by a microarray-based predictive signature to determine chemotherapy sensitivity and categorized as chemotherapy-sensitive (CS) or chemotherapy-insensitive (CI). Subsequently, patients will be treated with standard anthracycline-based chemotherapy (AC or FAC) for 4 cycles. Patients with CI tumors with &lt;80% decrease in tumor size and those with CS tumors with &lt;10% decrease in tumor size will be deemed non-responders. Mesenchymal-like non-responders will be recommended for this single arm phase II study of DAT. Eligible patients will receive D at a dose of 30mg/m2 IV on day 1, A at 15 mg/kg IV on Day 1, and T at 25mg IV on Days 1, 8, and 15 for 4 cycles.
Eligibility Criteria: Female; &gt; 18 years of age; newly diagnosed stage I-III triple negative breast cancer; refractory to standard NAC; LVEF &gt; 50% by Echocardiogram or MUGA; ECOG PS 0-1
Statistical Methods: The primary endpoint is pCR following therapy with DAT. Secondary objectives will include recurrence-free survival and overall survival. Using a Simon optimal two-stage design with alpha = beta = 10%, and then setting the threshold for an acceptable pCR rate at 20%, we would enroll 12 patients into the first stage. If we see 0 patients with pCR, we would stop the study after the first stage. If we see at least one patient with a pCR we will continue to enroll 25 more patients for a total of 37 patients. We would declare the treatment worthy of further study if we see at least 4 patients with pCR out of the 37 patients. This design has a 54% probability of early termination after the first stage if the true pCR probability is 5%.
Target Accrual: 37.
Citation Format: Rashmi K Murthy, Naoto T Ueno, William F Symmans, Jennifer K Litton, Banu K Arun, Nuhad K Ibrahim, Ricardo H Alvarez, Michael Z Gilcrease, Vicente Valero, Debasish Tripathy, Stacy L Moulder. Phase II single arm study of liposomal doxorubicin (D), bevacizumab (A), and temsirolimus (T) for treatment of triple negative early breast cancer refractory to standard neoadjuvant chemotherapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-2-06.