在转移性三阴性乳腺癌患者中联合使用艾瑞布林和依维莫司的 I 期临床试验。
Phase I clinical trial of the combination of eribulin and everolimus in patients with metastatic triple-negative breast cancer.
机构信息
Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center and Beckman Research Institute, 1500 E. Duarte Road, Duarte, CA, 91010, USA.
Department of Biostatistics, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA.
出版信息
Breast Cancer Res. 2019 Nov 8;21(1):119. doi: 10.1186/s13058-019-1202-4.
BACKGROUND
Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC.
METHODS
The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m, days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m days 1 and 8 every 3 weeks).
RESULTS
Twenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0-8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]).
CONCLUSION
Eribulin 1.1 mg/m days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT02120469. Registered 18 April 2014.
背景
PI3K/AKT/mTOR 通路的改变是三阴性乳腺癌（TNBC）中常见的基因组异常。依维莫司与埃博霉素在 TNBC 细胞系和异种移植模型中具有协同作用。这项 I 期试验旨在测试在转移性 TNBC 患者中联合使用埃博霉素和依维莫司的安全性和耐受性。
方法
本研究的主要目的是评估联合用药的安全性和毒性。入组了最多接受过四线化疗的转移性 TNBC 患者。埃博霉素和依维莫司联合使用三种剂量水平进行测试：A1（依维莫司 5mg 每日；埃博霉素 1.4mg/m2，第 1 和第 8 天每 3 周一次）、A2（依维莫司 7.5mg 每日；埃博霉素 1.4mg/m2，第 1 和第 8 天每 3 周一次）和 B1（依维莫司 5mg 每日；埃博霉素 1.1mg/m2，第 1 和第 8 天每 3 周一次）。
结果
入组了 27 名中位年龄为 55 岁的患者。在 8 名接受 A1 剂量水平治疗的可评估患者中，有 4 名出现剂量限制性毒性（DLT）。在 3 名接受 A2 剂量水平治疗的可评估患者中，有 2 名出现 DLT。在 12 名接受 B1 剂量水平治疗的可评估患者中，有 4 名出现 DLT。DLTs 为中性粒细胞减少症、口腔炎和高血糖症。在研究期间，59%的患者出现了≥3 级毒性，44%的患者出现了≥3 级血液学毒性，22%的患者出现了 4 级血液学毒性。最常见的血液学毒性为中性粒细胞减少症、白细胞减少症和淋巴细胞减少症。33%的患者出现了≥3 级非血液学毒性。最常见的非血液学毒性为口腔炎、高血糖症和疲劳。中位完成的周期数为 4 个（范围 0-8）。在 25 名合格患者中，9 名患者（36%）获得最佳反应为部分缓解，9 名（36%）病情稳定，7 名（28%）病情进展。中位无进展生存期为 2.6 个月（95%CI [2.1, 4.0]），中位总生存期（OS）为 8.3 个月（95%CI [5.5, 未定义]）。
结论
埃博霉素 1.1mg/m2，第 1 和第 8 天每 3 周一次，联合依维莫司 5mg 每日，被定义为具有可接受毒性的最高剂量（RP2D）。该联合用药安全，疗效适度。一项事后分析表明，使用地塞米松漱口液的参与者额外增加了一个周期的治疗。
试验注册
ClinicalTrials.gov，NCT02120469。于 2014 年 4 月 18 日注册。
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