PURPOSE: CXCR1, one of the receptors for CXCL8, has been identified as a druggable target on breast cancer cancer stem cells (CSC). Reparixin (R), an investigational oral inhibitor of CXCR1, was safely administered to metastatic breast cancer patients in combination with paclitaxel (P) and appeared to reduce CSC in a window-of-opportunity trial in operable breast cancer. The fRida trial (NCT02370238) evaluated the addition of R to weekly as first-line therapy for metastatic (m) TNBC. SUBJECTS AND METHODS: Subjects with untreated mTNBC were randomized 1:1 to R or placebo days 1-21 in combination with weekly P 80 mg/m2 on days 1, 8, 15 of 28-day cycles. The primary endpoint was PFS by central review. RESULTS: 123 subjects were randomized (62 to R + P and 61 to placebo + P). PFS was not different between the 2 groups (median 5.5 and 5.6 months for R + P and placebo + P, respectively; HR 1.13, p = 0.5996). ALDH+ and CD24-/CD44+ CSC centrally evaluated by IHC were found in 16 and 34 of the 54 subjects who provided a metastatic tissue biopsy at study entry. Serious adverse events (21.3 and 20% of subjects) and grade ≥ 3 adverse reactions (ADR) (9.1 and 6.3% of all ADRs) occurred at similar frequency in both groups. CONCLUSION: fRida is the first randomized, double-blind clinical trial of a CSC-targeting agent in combination with chemotherapy in breast cancer. The primary endpoint of prolonged PFS was not met. CLINICAL TRIAL REGISTRATION/DATE OF REGISTRATION: NCT01861054/February 24, 2015.

Azienda Ospedaliero Universitaria Santa Maria della Misericordia 33100 Udine Italy

Centrum Onkologii Ziemi Lubelskiej św Jana z Dukli Lublin Poland

CHU UCL Namur site Ste Elisabeth Namur Belgium

CLCC Francois Baclesse Caen France

Department of Medical Oncology Fox Chase Cancer Center 333 Cottman Ave Philadelphia PA 19111 USA

Fakultni nemocnice v Motole Onkologická klinika 2 LF UK a FN Motol Praha Czech Republic

Hospital Alvaro Cunqueiro 36204 Vigo Spain

IEO Istituto Europeo di Oncologia IRCCS 20141 Milano Italy

Research and Development Dompé farmaceutici s p a 20122 Milano Italy

Rogel Cancer Center University of Michigan Ann Arbor MI 48109 USA

The Methodist Hospital Research Institute Houston Tx 77030 USA

University of Milan Milano Italy

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