Abstract OT2-3-11: Tivozanib in combination with paclitaxel vs placebo with paclitaxel in patients with locally advanced or metastatic triple-negative breast cancer
Authors: Mayer EL , Miller K , O'Shaughnessy J , Dickler M , Vogel C , Leyland-Jones B , Steelman L , Robinson M , Kuriyama N , Agarwal S 
Published: August 2014

Abstract
Background: Triple-negative breast cancer (TNBC) is an aggressive cancer with inferior survival outcomes. Although weekly paclitaxel (WP) is effective in the treatment (tx) of metastatic breast cancer (MBC), optimization of therapies for patients (pts) with TNBC is essential. Angiogenesis is a hallmark of advanced cancer, with subset analyses suggesting activity of angiogenesis inhibitors in TNBC. Tivozanib (TIVO) is a potent and selective inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 with a promising role in metastatic renal cell carcinoma, and established safety in Phase I combination with WP in MBC.
Purpose: This Phase II trial will assess the efficacy and safety of TIVO + WP in the first-line setting for pts with advanced or metastatic TNBC and evaluate the performance of candidate angiogenesis biomarkers.
Objectives: The primary objective of this study is to compare progression-free survival (PFS) of pts treated with TIVO + WP vs pts treated with placebo (PB) + WP. Secondary objectives include objective response rate (ORR), overall survival (OS), safety and tolerability, quality of life, and correlative candidate biomarker endpoints. The pharmacokinetics of TIVO + WP also will be characterized.
Study Design and Methods: This multicenter, randomized, PB-controlled, two-arm study will enroll pts with metastatic or unresectable TNBC (evaluable per RECIST) and no prior systemic therapy. Pts must have confirmed available archival tumor tissue. Pts will be stratified by ECOG performance score and number of metastatic sites, then randomized to receive either oral TIVO 1.5 mg once daily for 3 weeks (wks) on/1 wk off and intravenous WP 90 mg/m2 for 3 wks on/1 wk off, or PB + WP. One cycle will be 4 wks; tx will continue until disease progression or unacceptable toxicity. Archival tumor tissue and blood samples will be evaluated for response biomarkers, including a hypoxia sensitivity gene signature, a myeloid resistance gene signature, and angiogenic ligands. All pts will be followed for survival until death. Adverse events will be monitored throughout the study. Pharmacokinetic samples will be collected during cycles 1 and 2. PAM-50–defined intrinsic molecular subtype populations also will be evaluated retrospectively.
Recruitment of 130 patients is planned, with an interim analysis after 80 pts to measure ORR (130 pts with a total of 82 investigator-assessed PFS events provides 80% power to detect statistically significant PFS differences between tx arms). Endpoint analyses will use the intent-to-treat population. The primary efficacy analysis will use investigator assessments of response and a two-sided 95% confidence interval for the hazard ratio produced using Cox proportional hazards regression models. OS will be compared using the log-rank test. Analyses of candidate biomarkers and determination of an optimal predictive cutoff for response also are planned. Trial enrollment will commence in fall 2012.
Conclusion: This study will determine whether TIVO, a selective and potent VEGFR inhibitor, combined with WP improves clinical outcomes in pts with TNBC, and whether clinical activity is associated with candidate angiogenesis biomarkers.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-11.