Abstract OT2-6-03: A single arm, preoperative, pilot study to evaluate the safety and biological effects of orally administered reparixin in early breast cancer patients who are candidates for surgery
Authors: Goldstein LJ , Sparano J , Perez RP , Vito C , Reuben JM , Landis MD , McCanna S , Ruffini PA , Cristofanilli M , Chang JC 
Published: August 2014

Abstract
Background: Breast cancer stem cells (BCSCs) have the ability to self renew and generate the full range of cells that make up a bulk tumor. Chemokine receptor 1 (CXCR1) is almost exclusively expressed in the aldehyde dehydrogenase-1 positive (ALDH-1+) BCSC population compared with its expression in bulk tumor cells. CXCR1 is a receptor for CXCL8 (previously IL8), a proinflammatory chemokine implicated in the metastasis and progression of multiple malignancies, including breast cancers. CXCL8 has also been shown to stimulate self-renewal of BCSCs in vitro. Reparixin, a low molecular weight blocker of CXCL8 biological activity, reduced ALDH-1+ cells in a human breast cancer xenograft when administered alone or in combination with taxane chemotherapy, and reduced metastases. Based on these findings, a phase 1b study of reparixin in combination with paclitaxel in metastatic breast cancer was initiated and is completing enrolment. This small, pilot, window of opportunity study aims at exploring the safety and effects of reparixin on BCSC markers in early breast cancer. Design and Treatment: Reparixin oral tablets 1000 mg will be given 3 times daily (tid) for 21 consecutive days in the interval prior to planned surgery. Main Eligibility Criteria: Patients must be female aged &gt; 18 years with ER-/PR-/HER-2 negative or ER+/PR+/HER-2 negative stage II and IIa operable breast cancer, with clinical tumor diameter of at least 2 cm, have had no prior surgery, radiotherapy, hormone therapy or chemotherapy, must be willing to undergo two mandatory tumor biopsies (pre- and post-therapy) that are not required for standard care. Objectives: Primary: 1) Evaluate the effects of orally administered reparixin on BCSCs in the primary tumor and the tumoral microenvironment by measuring: a) effects on BCSCs, in tissue samples by flow cytometry or RT-PCR and immunohistochemistry (IHC) b) pathway markers, Phosphatase and tensin homolog (PTEN) and CXCR1 levels in tissue samples by IHC c) Markers of inflammation in plasma samples and leukocyte subsets and study polymorphonuclear nuclear leukocyte [PMN] biology in peripheral blood samples d) Markers of angiogenesis, tumor infiltrating leukocytes, autophagy and EpCAM and EMT markers in tumor tissue samples 2) Evaluate the safety of oral reparixin administered three times daily (tid) for 21 consecutive days. Secondary: To define the pharmacokinetic (PK) profile of single agent orally administered reparixin. Statistical Methods: Comparative Analysis of pre- versus post-treatment biomarker results will be performed. In addition, exploratory correlative analyses may be carried out comparing changes in biomarker expression between selected biomarkers. Additional correlative analyses between biomarker results at specific timepoints may be investigated similarly. Safety and tolerability analysis will be applied on the safety population with descriptive statistics for the safety variables. Summary statistics will be performed for each PK parameter and correlative study parameter. Accrual status: To date, three subjects have been enrolled. Target accrual is 40 subjects. Contact for further Information: pieradelchi.ruffini@dompe.it.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-03.