Abstract OT1-4-04: A phase II randomized, open-label, neoadjuvant study of LCL161, an oral antagonist of inhibitor of apoptosis proteins, in combination with paclitaxel in patients with triple-negative breast cancer
Authors: Lluch-Hernández A , Ruiz Simon A , Huang C-S , Cortés Castán J , Ruiz-Borrego M , Telli M , Ismail-Khan R , Parton M , Tseng L-M , Chen S-C , Schmid P , Mayer I , Hurvitz S , García-Estévez L , Atienza R , Wu M , Cameron S , Beck JT , Bardia A 
Published: August 2014

Abstract
Background: Inhibitor of apoptosis proteins (IAPs) negatively regulate cell death through a variety of mechanisms. LCL161 is an oral small-molecule antagonist of IAPs that has demonstrated single-agent activity and synergy with paclitaxel in breast cancer tumor models. In preclinical studies, a gene expression signature has been shown to enrich for response to LCL161. The recommended dose of LCL161 1800 mg once weekly has demonstrated preliminary antitumor activity with paclitaxel in an ongoing Phase Ib study in patients with breast cancer.
Trial design: This is a Phase II, randomized, open-label study of neoadjuvant paclitaxel with or without LCL161 in women with operable, newly diagnosed triple-negative breast cancer (NCT01617668). Key inclusion criteria include women with histologically confirmed diagnosis of triple-negative breast cancer; clinical stages T2, N0–N2, M0; candidates for mastectomy or breast-conserving surgery; ECOG performance status ≤1; known status of the LCL161-predictive gene expression signature (positive and negative gene signature is a stratification factor); and adequate bone marrow and organ function. Key exclusion criteria are: bilateral or inflammatory breast cancer; locally recurrent breast cancer; patients currently receiving systemic therapy for any other malignancy, or having received systemic therapy for a malignancy in the preceding 3 months; impaired gastrointestinal function that may affect the absorption of LCL161; or uncontrolled cardiac disease.
Patients are randomized 1:1 to receive paclitaxel IV (80 mg/m2 weekly) with or without oral LCL161 (1800 mg once weekly) for 12 weeks (corresponding to 4 treatment cycles). Each treatment arm is stratified 1:1 based on gene expression signature status (positive or negative).
Endpoints: The primary endpoint is pathologic complete response (pCR), defined as the absence of invasive disease in the breast after 12 weeks of therapy, analyzed separately in the gene expression signature positive and negative groups. The key secondary endpoint is the pCR rate following treatment with LCL161 and paclitaxel in gene expression signature-positive or -negative tumors. Other secondary endpoints include: pCR rate in breast after 12 weeks of therapy in the full study population, and in patients with gene expression signature-positive and -negative tumors treated with paclitaxel alone; pCR rate in breast, regional nodes and axilla; biomarker evaluation including caspase 3 activation in tumor; safety; and pharmacokinetics of LCL161.
Statistical methods: pCR analysis will be performed according to treatment group and gene expression signature status. An absolute increase of at least 7.5% in pCR rate of the experimental arm over the control arm will be considered as evidence of clinically relevant efficacy.
Target accrual: Approximately 200 patients will be randomized into this study. Recruitment is ongoing across America, Europe, and Asia.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-4-04.