Abstract P3-11-07: A randomized phase II trial of reparixin, a CXCR1 inhibitor, in combination with paclitaxel in the treatment of mTNBC
Authors: Goldstein Lori J , Mansutti Mauro , Levy Christelle , Chang Jenny C , Henry Stephanie , Fernandez-Perez Isaura , Viale Giuseppe , Viale Guiseppe , Butler Beth , McCanna Susan , Ruffini Pier A , Wicha Max , Schott Anne F 
Published: March 2020

Abstract
Background: CXCR1, one of the receptors for CXCL8, has been identified as a druggable target on breast cancer Cancer Stem Cells (CSC): In a phase 1b study, the combination of reparixin (R), an investigational oral inhibitor of CXCR1, and weekly paclitaxel (P) was well tolerated with a sizeable ORR and TTP in metastatic HER-2-ve breast cancer, with some long-term responders (Schott AF et al., CCR 2017). fRida (NCT02370238) is a phase 2, randomized, double-blind study evaluating the safety and efficacy of R+P vs placebo +P in untreated metastatic (m) TNBC.
Trial Design: Patients with untreated mTNBC were stratified by prior (neo)adjuvant chemotherapy and randomized 1:1 to R 1200 mg or placebo three times per day dd1-21 and weekly P 80 mg/m2 dd 1, 8, 15 q28dd. Response was assessed per RECIST 1.1 (by central review). The primary endpoint was PFS. Secondary endpoints were OS, ORR and safety. This is the final analysis for PFS (data cut off 2/20/2019).
Results: A total of 123 patients were randomized (62 to R+P and 61 to placebo + P). Patient characteristics (safety population) are summarized in Table 1. Median follow-up was 14.5 months. 74 PFS events (R+P 40, placebo+P 34), were observed in the ITT population. Median PFS was not significantly different between the 2 groups [median 5.5 and 5.7 months, HR 1.14 (95% C.I. 0.71-1.81), p=.589]. OS is not expected to reach statistical significance based on the results at the data cut off after 71 events (37 in R+P and 34 in placebo+P groups, respectively) [HR 1.03 (95% C.I. .64-1.56), p=.897). Findings were consistent across de novo stage IV and relapsed patients. BOR was similar between the two groups (R+P 28.1% vs placebo+P 25.9%). Median duration of response was longer in R+P than placebo+P group (median 293 vs 172 days, p=0.767). Among exploratory endpoints, a lower proportion of patients in the R+P group vs the placebo+P group had new metastatic lesions at disease progression (17/39 vs 23/34, respectively, p=.172). In patients where metastatic tissue was available at baseline (n=55), ALDH+ and CD24−/CD44+ CSC centrally evaluated by IHC were found in 17 and 29 patients respectively, with 9 patients displaying both CSC populations. G≥3 ADRs, which occurred in 21.3% and 10% of patients in R+P and placebo+P group, respectively, represented 6% of all ADRs in both groups.
Conclusions: fRida is the first randomized, double-blind placebo-controlled clinical trial of a CSC-targeting agent in combination with chemotherapy in breast cancer. The primary endpoint of prolonged PFS was not met. Sensitivity analyses are ongoing. The safety profile was consistent with that previously reported for this combination. ALDH+ and CD24−/CD44+ appeared to be largely non-overlapping CSC populations in metastatic tissue, similar to primary breast cancer (Goldstein LJ et al., AACR 2016).
Table 1.R+Pplacebo+Page, median (range)57 (29, 79)57.5 (36, 77)PS 0/1 (n)37/2441/19de novo stage IV (n)148relapsed after (neo)adjuvant chemotherapy (n)4752prior taxane (n)4045Liver mets (n)1411Lung mets (n)1224≥3 metastatic sites(n)39
Citation Format: Lori J Goldstein, Mauro Mansutti, Christelle Levy, Jenny C Chang, Stephanie Henry, Isaura Fernandez-Perez, Giuseppe Viale, Guiseppe Viale, Beth Butler, Susan McCanna, Pier A Ruffini, Max Wicha, Anne F Schott. A randomized phase II trial of reparixin, a CXCR1 inhibitor, in combination with paclitaxel in the treatment of mTNBC [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-07.