Abstract C22: A phase Ib study of the CXCR1/2 inhibitor Reparixin in combination with weekly paclitaxel in metastatic HER2 negative breast cancer - final analysis
Authors: Schott Anne F. , Wicha Max S. , Perez Raymond P. , Kato Giraldo , Avery Tiffany , Cristofanilli Massimo , Reuben James M. , Alpaugh R. Katherine , Ruffini Pier Adelchi , Mccanna Susan , Goldstein Lori J. 
Published: May 2016

Abstract
Background. Cancer Stem Cells (CSC) 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 CSC as responsible for tumor recurrence and metastasis. An ideal CSC targeting agent should be a non toxic molecule that can be safely administered also in combination with chemotherapy to improve disease control. CXCR1, one of the receptors for CXCL8, has been identified on breast cancer CSC. Reparixin, an allosteric inhibitor of CXCR1, reduced CSC in breast cancer (BC) xenografts (Ginestier C et al., JCI 2010) both as single agent and in combination with taxane chemotherapy.
Methods. Patients were female aged ≥ 18 years with HER-2 negative metastatic BC, non taxane-refractory, who had received up to 3 prior chemotherapy (CT) lines for advanced BC (not including neo/adjuvant CT), had measurable disease according to RECIST 1.1, ECOG PS of 0-1, adequate organ function, and no brain metastases. Patients received a 3-day run-in with reparixin oral tablets 3 times daily (tid) followed by paclitaxel 80 mg/m2 (days 1, 8, and 15 for 28-day cycle) + reparixin oral tablets tid for 21 days. Three dose levels of 3-6 subjects were explored: 400 mg, 800 mg and 1200 mg oral reparixin tid. The highest safe dose level was expanded twice to gain additional safety and activity data. Treatment continued until disease progression, unacceptable toxicity or withdrawal of consent. Primary endpoints were safety and tolerability, and pharmacokinetic (PK) profile of the combination treatment. Among secondary endpoints, assessment of disease response every 2 cycles for indication of efficacy and correlative evaluations on peripheral blood samples were conducted. First analysis (i.e., 60 days post last patient in, LPI) of the results from this trial was reported earlier (Schott AF et al., SABC 2014).
Results. Herein we report data at 6 months post LPI. From 02/2012 to 04/2014, 33 patients entered the study (4 in cohort 1, 3 in cohort 2 and 26 in cohort 3). 30 patients were evaluable for safety. Neither grade 4 adverse events (AE) nor Serious AE related to reparixin were reported. 9/23 patients at the highest dose level reported Grade 3 AE among which granulocytopenia (3 patients) and peripheral neuropathy (2 patients) that are commonly seen with paclitaxel alone. Overall, 8 confirmed responses (2 CR, 6 PR) were observed among 26 patients who underwent at least 1 tumor assessment (every 8 weeks). Response duration (days) was 645+, 466+ (for CR) and 280+, 169, 141, 113, 113+, 47 (for PR). Two additional patients experienced SD &gt; 6 months (318 and 288 days, respectively). Of responding patients, all but one was from cohort 3. Median TTP (days) in the safety population was 58, 67 and 170 in cohorts 1, 2 and 3, respectively.
Conclusions. Combination treatment demonstrated good tolerability with low incidence and severity of adverse reactions. The recommended dose of reparixin for the combination was established at 1200 mg tid. A sizeable response rate and mTTP was recorded, with some interesting long term responders. A randomized phase II study of the combination versus single agent weekly paclitaxel in frontline treatment of patients with metastatic triple-negative BC is ongoing (NCT02370238).
Citation Format: Anne F. Schott, Max S. Wicha, Raymond P. Perez, Giraldo Kato, Tiffany Avery, Massimo Cristofanilli, James M. Reuben, R. Katherine Alpaugh, Pier Adelchi Ruffini, Susan Mccanna, Lori J. Goldstein. A phase Ib study of the CXCR1/2 inhibitor Reparixin in combination with weekly paclitaxel in metastatic HER2 negative breast cancer - final analysis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C22.