Abstract OT2-08-02: Capivasertib and paclitaxel in first-line treatment of patients with metastatic triple-negative breast cancer: A phase III trial (CAPItello-290)
Authors: Schmid Peter , Cortes Javier , Robson Mark , Iwata Hiroji , Hegg Roberto , Verma Sunil , Nechaeva Marina , Xu Binghe , Haddad Vincent , Imedio Esteban Rodrigo , Schiavon Gaia , Foxley Andrew , Park Yeon Hee 
Published: March 2020

Abstract
Background: Triple-negative breast cancer (TNBC) generally has an aggressive clinical course, including distant metastases and increased likelihood of death within 5 years of diagnosis compared with non-TNBCs. Therapeutic options for metastatic TNBC patients are limited to sequential chemotherapy, although recent advances with novel agents have been made for specific subgroups (PD-L1 inhibitor atezolizumab in combination with nab-paclitaxel in patients with PD-L1-positive tumors and PARP inhibitors in germline BRCA-mutant patients). However, improvements in progression-free survival (PFS) derived from immune-oncology and PARP inhibitors are still insufficient in terms of informing patient selection and overall magnitude of benefit. Developing novel treatments in both early and advanced TNBC settings remains a significant unmet need in the management of advanced breast cancer. The PI3K/AKT/PTEN signaling pathway is often activated in TNBC, mainly through activating mutations in PIK3CA or AKT1 and/or inactivating alterations in PTEN. The Phase II PAKT study (NCT02423603) demonstrated that addition of the oral AKT inhibitor capivasertib to first-line paclitaxel resulted in significantly longer PFS and overall survival (OS) in patients with advanced TNBC, especially in patients with PIK3CA/AKT1/PTEN-altered tumors (Schmid, 2018). The Phase III trial we report (NCT03997123) will further evaluate the efficacy and safety of capivasertib in combination with paclitaxel in first-line treatment of patients with metastatic TNBC in an unselected population and will also explore potential predictive markers of sensitivity to the combination of paclitaxel and capivasertib. Methods: Eligible patients for this double-blind, randomized, placebo-controlled trial must have metastatic TNBC or locally advanced disease not amenable to resection with curative intent. Patients must be candidates for single-agent taxane therapy and have received no prior systemic therapy for locally advanced inoperable or metastatic disease. Prior chemotherapy in the (neo)adjuvant setting must be completed ≥12 months prior to enrollment. Patients will be randomized 1:1 to paclitaxel 80 mg/m2 (days 1, 8 and 15) with either capivasertib 400 mg twice daily or placebo (days 2-5, 9-12, 16-19) every 28 days until objective radiologic disease progression as defined by RECIST 1.1, unacceptable toxicity, or death. Stratification factors will be prior adjuvant chemotherapy, visceral vs non-visceral disease, and geographic region. Post-randomization central testing of tumor tissue (collected prior to enrollment) will be carried out to identify predictive markers of sensitivity to treatment. The primary endpoints of this study are PFS and OS. Secondary endpoints include safety and tolerability, time to second progression or death, objective response rate, duration of response, and clinical benefit rate. Enrollment for this study opened in May 2019.
Citation Format: Peter Schmid, Javier Cortes, Mark Robson, Hiroji Iwata, Roberto Hegg, Sunil Verma, Marina Nechaeva, Binghe Xu, Vincent Haddad, Esteban Rodrigo Imedio, Gaia Schiavon, Andrew Foxley, Yeon Hee Park. Capivasertib and paclitaxel in first-line treatment of patients with metastatic triple-negative breast cancer: A phase III trial (CAPItello-290) [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 OT2-08-02.