Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2-Negative Metastatic Breast Cancer.
Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2-Negative Metastatic Breast Cancer.
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DOI：
10.1158/1078-0432.ccr-16-2748
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发表时间：
2017-09-15
期刊：
影响因子：
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通讯作者：
Wicha M
中科院分区：
文献类型：
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作者：
Schott AF;Goldstein LJ;Cristofanilli M;Ruffini PA;McCanna S;Reuben JM;Perez RP;Kato G;Wicha M
CXCR 1被认为是乳腺癌干细胞（BCSC）选择性表达的可作用受体。Reparixin是一种研究性的趋化因子受体1和2（CXCR 1/2）变构抑制剂，并在人乳腺癌异种移植物中显示出对BCSC的活性。该Ib期临床试验检查了紫杉醇加瑞帕里辛治疗的剂量、安全性和药代动力学，并探索了瑞帕里辛对转移性乳腺癌（MBC）患者BCSC的影响（试验注册ID：NCT 02001974）。符合条件的患者患有MBC，并且是紫杉醇治疗的候选者。研究治疗包括每日3次（t.i.d.）的瑞帕里辛口服片剂的3天导入期，随后紫杉醇80 mg/m2/周（第1、8和15天，28天为一个周期）+瑞帕瑞辛片t.i.d. 21/28天;在3+3剂量递增方案中检查了三个剂量队列。以推荐的II期剂量招募额外的患者进入扩展队列，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。没有发生与研究治疗相关的G4-5不良事件或严重不良事件，并且瑞培新和紫杉醇之间没有相互作用来影响其各自的PK特征。记录了30%的反应率，2名患者的持久反应> 12个月。探索性生物标志物分析对BCSC的治疗效果不确定。每周一次紫杉醇加瑞帕新治疗MBC似乎是安全和可耐受的，在入组人群中显示了缓解。剂量水平3，1200 mg口服，每日3次，被选入一项随机II期试验进行进一步研究。（NCT02370238）
CXCR1 is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSC). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSC 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 metastatic breast cancer (MBC) patients (Trial registration ID: NCT02001974). Eligible patients had MBC and were candidates for paclitaxel therapy. Study treatment included a three-day run-in with reparixin oral tablets 3 times daily (t.i.d.), followed by paclitaxel 80 mg/m2/week (Days 1, 8, and 15 for 28-day cycle) + reparixin tablets t.i.d. 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 PK profiles. A 30% response rate was recorded, with durable responses > 12 months in two patients. Exploratory biomarker analysis was inconclusive for therapy effect on BCSC. 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 t.i.d., was selected for further study in a randomized Phase II trial. (NCT02370238)