A randomized, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for metastatic triple-negative breast cancer (fRida)

Lori J Goldstein, Mauro Mansutti, Christelle Levy, Jenny C Chang, Stephanie Henry, Isaura Fernandez-Perez, Jana Prausovà, Elzbieta Staroslawska, Giuseppe Viale, Beth Butler, Susan McCanna, Pier Adelchi Ruffini, Max S Wicha, Anne F Schott, fRida Trial Investigators, Ricardo H Alvarez, Anne F Schott, Maysa Abu-Khalaf, Nuhad Ibrahim, Brooke Daniel, Michael Meshad, David Kanamori, Amelia Zelnak, Mark Graham, Jason Comer, Manon Huizing, Francois Duhoux, Vincent Richard, Didier Verhoeven, Martin Smakal, Marta Krasenska, Milan Kohoutek, Martina Zimovjanova, Eugen Kubala, Mario Campone, Jean-Marc Ferrero, Anthony Goncalves, Laurence Venat-Bouvet, Jacques Medioni, Laura Biganzoli, Hector Soto Parra, Paolo Pedrazzoli, Marco Colleoni, Mauro Moroni, Dino Amadori, Paolo Morandi, Saverio Cinieri, Piotr Tomczak, Tomasz Sarosiek, Marek Wojtukiewicz, Andrzej Mruk, Bożena Kukielka-Budny, Silvia Antolin Novoa, Estela Vega Alonso, Miguel Martin Jimenez, Lori J Goldstein, Mauro Mansutti, Christelle Levy, Jenny C Chang, Stephanie Henry, Isaura Fernandez-Perez, Jana Prausovà, Elzbieta Staroslawska, Giuseppe Viale, Beth Butler, Susan McCanna, Pier Adelchi Ruffini, Max S Wicha, Anne F Schott, fRida Trial Investigators, Ricardo H Alvarez, Anne F Schott, Maysa Abu-Khalaf, Nuhad Ibrahim, Brooke Daniel, Michael Meshad, David Kanamori, Amelia Zelnak, Mark Graham, Jason Comer, Manon Huizing, Francois Duhoux, Vincent Richard, Didier Verhoeven, Martin Smakal, Marta Krasenska, Milan Kohoutek, Martina Zimovjanova, Eugen Kubala, Mario Campone, Jean-Marc Ferrero, Anthony Goncalves, Laurence Venat-Bouvet, Jacques Medioni, Laura Biganzoli, Hector Soto Parra, Paolo Pedrazzoli, Marco Colleoni, Mauro Moroni, Dino Amadori, Paolo Morandi, Saverio Cinieri, Piotr Tomczak, Tomasz Sarosiek, Marek Wojtukiewicz, Andrzej Mruk, Bożena Kukielka-Budny, Silvia Antolin Novoa, Estela Vega Alonso, Miguel Martin Jimenez

Abstract

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.

Keywords: CXCR1; Cancer stem cells; Reparixin; TNBC.

Conflict of interest statement

PAR, SMC, and BB are full-time employees of Dompé farmaceutici s.p.a. All other authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Patient disposition: Randomization, trial populations, and follow-up are shown, and so are the numbers of subjects who were receiving study treatment on the data cutoff date (February 20, 2019)
Fig. 2
Fig. 2
Progression-free survival in the ITT population: Kaplan–Meier estimates of PFS, according to the Response Evaluation Criteria in Solid Tumors, version 1.1, as assessed by the independent radiology review, among subjects in the ITT population. Stratified hazard ratios for disease progression or death are reported along with p values. Tick marks indicate censored data
Fig. 3
Fig. 3
Overall survival in the ITT population: Kaplan–Meier estimates of OS among subjects in the ITT population. Stratified hazard ratios for death are reported along with p values. Tick marks indicate censored data. 6 subjects (4 in reparixin + paclitaxel and 2 in placebo + paclitaxel) did not re-sign ICF to protocol amendment 2 or later and were censored at 1 year after the off treatment visit

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