Abstract CT062: NCT02456857: A phase II trial of liposomal doxorubicin, bevacizumab and everolimus (DAE) in patients with localized triple-negative breast cancer (TNBC) with tumors predicted insensitive to standard neoadjuvant chemotherapy
Authors: Damodaran Senthil , Hess Ken , Rauch Maia , Astrada Beatrice , Santiago Lumarie , Litton Jennifer , Mittendorf Elizabeth , Lim Bora , Ueno Naoto , Tripathy Debu , Thompson Alastair , Gilcrease Mike , Yang Wei , Piwnica-Worms Helen , Symmans W. Fraser , Moulder Stacy L. 
Published: July 2017

Abstract
BACKGROUND: While targeted therapy has improved survival for ER+ and HER2+ breast cancers, no such therapy exists for TNBC. Nearly 50% of TNBC patients treated with neoadjuvant chemotherapy (taxane/anthracycline-based) will have insensitive disease manifested as extensive residual disease (RCB-II or III). This is associated with high chance of recurrence within 3 years of diagnosis. Through the Moon Shot program at MD Anderson, we have created a biomarker-driven drug development strategy (ARTEMIS: A Randomized, TNBC Enrolling trial to confirm Molecular profiling Improves Survival) to identify novel targeted therapies for chemo-insensitive disease in TNBC. In the ARTEMIS trial, patients with localized TNBC undergo biopsy for molecular profiling prior to the start of initial anthracycline-based chemotherapy. Results of molecular characterization along with diagnostic imaging is then used to identify patients with chemo-insensitive disease and inform second phase of neoadjuvant therapy to overcome intrinsic drug resistance. The mesenchymal subtype of TNBC is characterized by high incidence of PI3K pathway alterations. Consequently, preclinical models have demonstrated response to PI3K inhibitors in this subtype. Metaplastic breast cancers constitute approximately 30% of tumors characterized as ‘claudin-low/mesenchymal’ by gene expression profiling. A combination regimen consisting of liposomal doxorubicin, bevacizumab and mTOR inhibitors temsirolimus or everolimus (DAT or DAE) has demonstrated responses (including durable complete responses) in patients with advanced metaplastic breast cancers.
PRIMARY OBJECTIVE: Determine the rate of pathologic complete response (pCR/RCB-0) or minimal residual disease (RCB-I) after 4 cycles of DAE for treatment of mesenchymal TNBC deemed to be chemo-insensitive after first phase of neoadjuvant therapy in the ARTEMIS trial
TRIAL DESIGN AND STATISTICAL METHODS: Patients deemed to have chemo-insensitive mesenchymal TNBC identified through the ARTEMIS trial would be enrolled into this non-randomized phase II study. Considering that patients without response to initial chemotherapy have a very low chance (5%) of achieving pCR with additional cycles of chemotherapy, it would be clinically meaningful to see pCR improved to 20% in this population. Estimating pCR (RCB-0) or RCB-I as response, a two-stage Gehan-type design will be employed with 14 patients in the first stage. This design has a 49% chance of terminating after the first stage if the true response rate is 0.05, 23% chance if the true rate is 0.10, 10% chance if the true rate is 0.15 and 4% chance if the true rate is 0.20. If at least one patient responds, 23 more will be enrolled for a total of 37 patients. With 37 patients enrolled, the 95% confidence interval for a 0.20 response rate will extend from 0.10 to 0.35.
BRIEF ELIGIBILITY CRITERIA: Inclusion: early stage TNBC patients enrolled in the ARTEMIS trial with adequate organ, bone marrow and cardiac function Exclusion: patients with metastatic disease, medical illness that increases chance of moderate to severe toxicity, pregnant or lactating.
CORRELATIVE SCIENCE: correlate mesenchymal signatures and PI3K pathway aberrations and vimentin expression by IHC with response
Citation Format: Senthil Damodaran, Ken Hess, Maia Rauch, Beatrice Astrada, Lumarie Santiago, Jennifer Litton, Elizabeth Mittendorf, Bora Lim, Naoto Ueno, Debu Tripathy, Alastair Thompson, Mike Gilcrease, Wei Yang, Helen Piwnica-Worms, W. Fraser Symmans, Stacy L. Moulder. NCT02456857: A phase II trial of liposomal doxorubicin, bevacizumab and everolimus (DAE) in patients with localized triple-negative breast cancer (TNBC) with tumors predicted insensitive to standard neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT062. doi:10.1158/1538-7445.AM2017-CT062