Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Clin Cancer Res. 2017 Sep 15;23(18):5358-5365. doi: 10.1158/1078-0432.CCR-16-2748. Epub 2017 May 24.
Chemokine receptor 1 (CXCR1) is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSCs). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSCs in human breast cancer xenografts. This phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in patients with metastatic breast cancer (MBC) (trial registration ID: NCT02001974). Eligible patients had MBC and were candidates for paclitaxel therapy. Study treatment included a 3-day run-in with reparixin oral tablets three times a day, followed by paclitaxel 80 mg/m/week (days 1, 8, and 15 for 28-day cycle) + reparixin tablets three times a day for 21/28 days; three dose cohorts were examined in a 3+3 dose escalation schema. Additional patients were recruited into an expansion cohort at the recommended phase II dose to further explore pharmacokinetics, safety, and biological effects of the combination therapy. There were neither G4-5 adverse events nor serious adverse events related to study therapy and no interactions between reparixin and paclitaxel to influence their respective pharmacokinetic profiles. A 30% response rate was recorded, with durable responses >12 months in two patients. Exploratory biomarker analysis was inconclusive for therapy effect on BCSCs. Weekly paclitaxel plus reparixin in MBC appeared to be safe and tolerable, with demonstrated responses in the enrolled population. Dose level 3, 1200 mg orally three times a day, was selected for further study in a randomized phase II trial (NCT02370238). .
趋化因子受体 1（CXCR1）被认为是一种可作用的受体，选择性地表达于乳腺癌干细胞（BCSCs）。Reparixin 是一种研究性的趋化因子受体 1 和 2（CXCR1/2）的变构抑制剂，在人乳腺癌异种移植中对 BCSCs 具有活性。这项 Ib 期临床试验研究了紫杉醇联合 Reparixin 治疗的剂量、安全性和药代动力学，并探索了 Reparixin 对转移性乳腺癌（MBC）患者 BCSCs 的影响（试验注册 ID：NCT02001974）。符合条件的患者患有 MBC，并且是紫杉醇治疗的候选者。研究治疗包括 Reparixin 口服片剂每日三次的 3 天导入期，随后是紫杉醇 80mg/m/周（第 1、8 和 15 天为 28 天周期）+Reparixin 片剂每日三次，持续 21/28 天；在 3+3 剂量递增方案中检查了三个剂量组。在推荐的 II 期剂量下，招募了更多的扩展队列患者，以进一步探索联合治疗的药代动力学、安全性和生物学效应。没有出现 G4-5 级不良事件或与研究治疗相关的严重不良事件，Reparixin 和紫杉醇之间也没有相互作用影响各自的药代动力学特征。记录了 30%的缓解率，两名患者的缓解持续时间超过 12 个月。探索性生物标志物分析对于 BCSCs 的治疗效果没有结论。每周紫杉醇联合 Reparixin 在 MBC 中似乎是安全且可耐受的，在入组人群中显示出了疗效。选择 1200mg 口服每日三次的 3 级剂量进行进一步的随机 II 期试验研究（NCT02370238）。
