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• W1489462465 abstract "Abstract Background. Experimental models and retrospective clinical observations point to cancer stem cells (CSCs) as the culprits for tumor recurrence and metastasis. CSCs account for a small proportion of tumor cells, suggesting that their elimination through pharmacological targeting would not necessarily translate in any sizeable tumor regression. Thus, an ideal CSCs targeting agent should be a nontoxic molecule that can be safely administered in combination with chemotherapy to reduce tumor burden and improve disease control. CXCR1, one of the receptors for CXCL8, has been identified on breast cancer (BC) CSCs (Ginestier C et al., JCI 2010). Reparixin, an allosteric inhibitor of CXCR1 with a large safety database in non-cancer patients, effectively targeted CSC in BC xenografts (Ginestier C et al., JCI 2010). Methods. Patients were female aged &gt; 18 years with HER-2 neg metastatic breast cancer (MBC), eligible for treatment with paclitaxel (not taxane-refractory), had received up to 3 prior CT lines for advanced BC (not including neo/adjuvant chemotherapy), had measurable disease according to RECIST 1.1, had ECOG PS of 0-1, had adequate organ function, and had no brain metastases. Patients received a 3-day run-in with reparixin oral tablets 3 times daily (tid) followed by paclitaxel 80 mg/m2/week (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. A further 17 subjects were enrolled at the highest tolerated dose (total 20 patients). Safety was assessed following one cycle. 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. Results. From 02/12 to 04/14, 33 patients entered the study. PK of reparixin at 400 mg tid, tmax = 0.5-1.5 hr, t1/2= 1.7 hr; at 800 mg tid, tmax = 0.5-3 hr, t1/2= 4.6 hr; at 1200 mg tid, tmax = 0.5-2 hr, t1/2 = 1.6 h. Co-administration of reparixin on days 1 and 8 had no effect on paclitaxel kinetics. Fifteen SAEs were recorded, none of which was related to Reparixin. Grade 3-4 adverse reactions were recorded in 30% (10/33) patients including haematological toxicity (5/10). Only one patient discontinued treatment for a reversible GI adverse reaction due to reparixin at the 1200 mg dose level. To date, 5 confirmed responses (2 CR, 3 PR) were recorded among 18 patients who underwent at least 1 tumor assessment (at 8 weeks). Response duration was 20m+ and 3m+(for CR) and 9m+, 6m+, 2m+ (for PR). Final data will be presented at the meeting. Conclusions. Combination treatment was safe and well tolerated at all dose levels without evidence of pharmacologic interactions and the recommended dose for subsequent studies is 1200 mg tid. Efficacy was demonstrated both in hormone receptor positive and triple receptor negative disease. A randomized phase II study of the combination versus single agent weekly paclitaxel in patients with MBC is warranted. Citation Format: Anne F Schott, Max S Wicha, Raymond P Perez, Giraldo Kato, Tiffany Avery, Massimo Cristofanilli, James M Reuben, R Katherine Alpaugh, Susan McCanna, Pier Adelchi Ruffini, Lori J Goldstein. A phase Ib study of the CXCR1/2 inhibitor reparixin in combination with weekly paclitaxel in metastatic HER2 negative breast cancer – First analysis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-03-01." @default.
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• W1489462465 title "Abstract P6-03-01: A phase Ib study of the CXCR1/2 inhibitor reparixin in combination with weekly paclitaxel in metastatic HER2 negative breast cancer – First analysis" @default.
• W1489462465 doi "https://doi.org/10.1158/1538-7445.sabcs14-p6-03-01" @default.
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