Abstract OT2-3-01: Phase Ib pilot study to evaluate reparixin in combination with chemotherapy with weekly paclitaxel in patients with HER-2 negative metastatic breast cancer (MBC)
Authors: Schott AF , Wicha M , Cristofanilli M , Ruffini P , McCanna S , Reuben JM , Goldstein LJ 
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 positive (ALDH+) 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. Tissue damage induced by chemotherapeutic agents may induce CXCL8 as part of the injury response. This suggests that strategies aimed at interfering with the CXCL8/CXCR1 axis, activated by conventional chemotherapy (CT), may be able to target BCSCs and increase the efficacy of current therapies. 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 Ib study to determine the safety of paclitaxel plus reparixin therapy, and to explore the effects of reparixin on BCSCs and the tumor microenvironment, was initiated.
Design and Treatment: Patients will receive a three-day run-in with reparixin oral tablets 3 times/day (tid) followed by paclitaxel 80 mg/m2/week (Days 1, 8, and 15 for 28-day cycle) + reparixin oral tablets tid for 21 days. Three dose levels of 3–6 subjects will be explored in total: Dose level 1 = 400 mg oral reparixin tid; Dose level 2 = 800 mg reparixin tid; and Dose level 3 = 1200 mg reparixin tid. An additional 6 subjects will be enrolled at the highest tolerated dose. Safety will be assessed following one cycle. Treatment continues as long as clinical benefit is observed.
Main Eligibility Criteria: Patients must be female aged &gt; 18 years with HER-2 negative MBC, eligible for treatment with paclitaxel (not taxane-refractory), have had up to 3 prior CT lines for advanced breast cancer (not including neo/adjuvant chemotherapy), must have measurable disease according to RECIST criteria version 1.1, have ECOG PS of 0–1, have adequate organ function, and have no brain metastases.
Objectives: Primary: To evaluate the safety and pharmacokinetic (PK) profile of the combination treatment. Secondary: 1) To evaluate tumor biopsies for the effects of reparixin on BCSC markers and tumoral microenvironment; 2) To evaluate blood samples for a) enumeration and molecular characterization of circulating tumor cells (CTCs), biomarker profiling for BCSC and epithelial-mesenchymal transition (EMT), and b) inflammatory cytokines; 3) To assess disease response for indication of efficacy.
Statistical Methods: All tumor data collected will be reviewed and listed. No formal statistical analysis of this data is planned. 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, four subjects have been enrolled at the first dose level. Target accrual is 15–24 subjects.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-01.