Background: Breast cancer stem cells (BCSC) have the ability to self renew and generate the full range of cells that make up a bulk tumor. Experimental models and retrospective clinical observations point to BCSC as responsible for tumor recurrence and metastasis. CXCR1, one of the receptors for CXCL8, has been identified on BCSC. Reparixin, an allosteric inhibitor of CXCR1, reduced BCSC in breast cancer xenografts (Ginestier C et al., JCI 2010) both as single agent and in combination with taxane chemotherapy. In a phase Ib trial in women with metastatic HER2-negative BC, the combination of escalating doses (400 to 1200 mg three times per day) of reparixin with weekly paclitaxel resulted in a low incidence and severity of adverse reactions, a sizeable response rate and time-to-progression, with some long-term responders (Schott AF et al., SABC 2014).

Trial Design: In this randomized, double-blind phase 2 trial patients will be randomized (1:1) to paclitaxel 80 mg/m2 on days 1, 8 and 15 of 28-day cycles in combination with reparixin or placebo oral tablets 1200 mg three times daily on days 1-21. Treatment continues until disease progression, unacceptable toxicity or withdrawal of consent. An independent Data Monitoring Committee has been appointed to oversee the trial. An independent Radiology Review will be performed for analysis of primary and secondary endpoints. Disease response will be assessed every 8 weeks. Patients will be followed up to 12 months after last enrolled patient completes treatment.

Eligibility Criteria: Patients must be female aged ≥18 years with untreated metastatic TNBC who have relapsed >12 and >6 months after the end of a taxane- or non taxane-based (neo)adjuvant chemotherapy regimen, respectively. They must have measurable disease, ECOG PS of 0-1, adequate organ function, and no history or evidence of brain metastases (brain CT or MRI required). Tumor tissue must be available from a metastatic site or from primary tumor for confirmation of diagnosis and correlative studies. Key exclusion criteria are pre-existing peripheral neuropathy G>1 and any disease significantly affecting gastrointestinal function.

Specific Aims: Primary: to evaluate progression-free survival (PFS) rate by independent assessment.

Secondary: to determine median PFS, overall survival (OS), objective response rates and safety of the combination treatment.

Exploratory: to determine median time to new tumor metastasis (TTM), proportion of patients progressing with new metastatic lesions, incidence and severity of peripheral neuropathy, and to evaluate BCSC in metastatic tissue

Statistical Methods: The trial design provides 80% power to detect an increase in 6 month PFS from 30% to 50% with a 2-sided 5% significance level (Chi-square test). Kaplan-Meier curves will be produced for median PFS, OS outcomes and exploratory median TTM. Appropriate descriptive statistics will be provided for safety variables.

Present Accrual and Target Accrual: Target accrual is 190 patients. Patients will be enrolled internationally in US and Europe.

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Citation Format: Chang JC, Schott AF, Wicha MS, Cristofanilli M, Ruffini PA, McCanna S, Goldstein LJ. A randomized, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for triple-negative breast cancer (fRida). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-07.