LAUSR

Background:While TNBC patients with pathologic complete response (pCR) or residual cancer burden (RCB-I) have good survival rates, those with extensive residual disease (RCB-II or RCB-III) after neoadjuvant chemotherapy (NACT) have poor prognosis. Patients without response to their first chemotherapeutic regimen have very low chance (5%) of achieving pCR. 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 focusing on chemo-insensitive disease. The PI3K/Akt/mTOR pathway is a critical regulator of cell growth, apoptosis, metabolism in cancer cells and its activation is known to play an important role in resistance to chemotherapy. Clinical studies have shown that the combination of PI3K pathway inhibitors with taxanes are associated with improvement in response rates and survival. Alpelisib is approved for hormone receptor positive, HER2 negative, metastatic breast cancer patients with activating PIK3CA mutations. This study hypothesizes combination of alpelisib with nab-paclitaxel will improve PCR/RCB-1 in treatment-resistant early stage TNBC patients with activating PIK3CA or PTEN loss of function alterations. Trial Design: This will be a non-randomized, two- arm, open label, phase II study to evaluate the clinical activity of alpelisib and nab-paclitaxel in high-risk TNBC patients with PIK3CA or PTEN alterations with refractory or suboptimal response to anthracycline-based NACT. Eligibility criteria Stage 1-3 TNBC defined as ER Activating alterations in PIK3CA, or PTEN loss Residual primary tumor size of at least 1.0 cm or evidence of lymph node involvement by imaging (ultrasound or MRI) after anthracycline-based NACT ECOG performance status ≤1 Normal organ and marrow function Received at least one dose of an anthracycline-based NACT (eligible if therapy was discontinued due to disease progression or therapy intolerance) Specific aims To determine if alpelisib in combination with nab-paclitaxel will improve rates of pathologic response (pCR/RCB-0 or RCB-I) from 5% to 20% in patients with chemotherapy insensitive TNBC with activating PIK3CA alterations (Arm-1) or PTEN loss of function alterations (Arm-2) To determine the radiographic response rate for alpelisib in combination with nab-paclitaxel in chemotherapy insensitive TNBC with PIK3CA (Arm-1) or PTEN (Arm-2) alterations Determine toxicity of alpelisib in combination with nab-paclitaxel given in the neoadjuvant setting Determine progression free survival (PFS) at 3 years for patients treated with alpelisib in combination with nab-paclitaxel given in the neoadjuvant setting Statistical methods Primary objective is to determine if alpelisib in combination with nab-paclitaxel in the neoadjuvant setting will improve rates of pathologic response (counting pCR/RCB-0 or RCB-I as response) from 5% (control) to 20% (experimental arms). A Simon two-stage design will be employed with 12 patients in the first stage. If at least one patient has pCR/RCB-1, 25 more patients will be added for a total of 37 patients (alpha = beta = 10%). This design has a 54% probability of early termination after the first stage if the true pCR or RCB-I probability is 5%. Contact information for people with a specific interest in the trial [email protected] Citation Format: Senthil Damodaran, Jennifer K Litton, Kenneth R. Hess, Colleen T. Eppig, Krzysztof J. Grzegorzewski, Funda Meric-Bernstam, Ignacio I. Wistuba, Jason B White, Gaiane M. Rauch, Rosalind P. Candelaria, Beatriz E. Adrada, Bora Lim, Stacy L. Moulder, Debu Tripathy. A phase-2 trial of neoadjuvant alpelisib and nab-paclitaxel in anthracycline refractory triple negative breast cancers with PIK3CA or PTEN alterations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-06-01.