Background. Experimental models and retrospective clinical observations point to Cancer Stem Cells (CSC) as responsible for tumor initiation, treatment resistance, disease recurrence and metastasis. CXCR1, one of the receptors for CXCL8, was identified on breast cancer (BC) CSC. Reparixin, an investigational allosteric inhibitor of CXCR1, administered as monotherapy reduced the metastatic spread of human BC cells and the CSC content of human BC xenograft in mice (Ginestier C et al., JCI 2010).Methods. In this single arm, monotherapy trial (NCT01861054) patients were female aged ? 18 years with HER-2 negative operable BC with a clinical diameter of >1 cm not eligible for neoadjuvant treatment. It was planned to enrol 20 patients with ER+ and/or PgR+ and 20 patients with ER-/PgR- BC (i.e., Triple-Negative BC, TNBC). Patients received reparixin oral tablets 1000 mg 3 times daily (t.i.d.) for 21 days prior to surgery. Patients underwent core biopsies at baseline and at the completion of therapy. Primary objectives were evaluation of the effects of reparixin on CSC and tumor microenvironment and the safety of reparixin. The secondary objective was to define the pharmacokinetic (PK) profile of orally administered reparixin. Signal of Activity (SoA) was defined as a reduction by at least 20% in ALDH-1+ or CD24-/CD44+ CSC by flow cytometry (FC), with consistent reduction by immunohistochemistry (IHC).Results. 18 patients with ER+ and/or PgR+ BC and 2 with TNBC were enrolled. The trial was terminated due to slow enrolment in TNBC cohort. Safety: adverse reaction of grade ?2 (none serious) were experienced by 10/20 patients. All patients completed study treatment. PK: reparixin was rapidly absorbed (median Tmax 1h) and metabolized with median t1/2 of about 1.5 hr on both day 1 and 21. Efficacy: 12/18 and 2/2 patients in the ER+ and/or PgR+ BC group and TNBC group, respectively, had a sizeable ALDH+ and/or CD24-/CD44+ cell population at baseline and a second biopsy evaluated by FC. 11 evaluable patients achieved SoA (9/12 ER+ and/or PgR+ and 2/2 TNBC). The possibility to confirm FC results in tissue sections was hindered by very low numbers of CSC. A reduction in total CXCR1+ cells was found by FC in 7/13 evaluable patients and a reduction in p62 by IHC in 8/13 evaluable patients, suggesting target engagement and induction of autophagy.Conclusions. Enrolment of patients with TNBC in preoperative trials with single non cytotoxic agents is limited by the widespread use of neoadjuvant treatment. Reparixin 1000 mg t.i.d. for 21 consecutive days appeared to be well tolerated. SoA was achieved in 11/14 evaluable patients. The clinical relevance of a ?20% reduction of CSC following a single 21-day course of reparixin in this patient population is unknown. A randomized phase 2 study of reparixin plus paclitaxel versus paclitaxel in frontline treatment of metastatic TNBC is ongoing (NCT02370238).

Citation Format: Lori J. Goldstein, Raymond P. Perez, Denise A. Yardley, Linda K. Han, James M. Reuben, Susan McCanna, Beth Butler, Pier Adelchi Ruffini, Jenny C. Chang. 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. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT057.