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 Lévy, Jenny C. Chang, Stéphanie Henry, I. Fernández-Pérez, Jana Prausová, Elżbieta Starosławska, Giuseppe Viale, Beth Butler, Susan McCanna, Pier Adelchi Ruffini, Max S. Wicha, Anne F. Schott, for the fRida Trial Investigators, Ricardo H. Álvarez, Anne F. Schott, Maysa Abu‐Khalaf, Nuhad Ibrahim, Brooke Daniel, Michael W. Meshad, David E. Kanamori, Amelia Zelnak, Mark S. Graham, Jason E. Comer, Manon Huizing, François Duhoux, Vincent R. Richard, Didier Verhoeven, Martin Šmakal, Marta Krásenská, Milan Kohoutek, Martina Zimovjanová, Eugen Kubala, Mario Campone, Jean-Marc Ferrero, Anthony Gonçalvès, Laurence Venat‐Bouvet, Jacques Médioni, Laura Biganzoli, Héctor Soto Parrà, Paolo Pedrazzoli, Marco Colleoni, Mauro Moroni, Dino Amadori, Paolo Morandi, Saverio Cinieri, Piotr Tomczak, Tomasz Sarosiek, Marek Z. Wojtukiewicz, Andrzej Mruk, Bożena Kukiełka-Budny, Silvia Antolin Novoa, Estela Vega Alonso, M. Martín Jiménez
Abstract
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/m 2 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.