Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA.
Winship Cancer Institute of Emory University, Atlanta, GA, USA.
Br J Cancer. 2020 Oct;123(8):1228-1234. doi: 10.1038/s41416-020-0988-2. Epub 2020 Jul 24.
Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes.
We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment.
The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit.
The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers.
NCT01218555.
目的：雷帕霉素靶蛋白抑制剂与来那度胺联合应用具有增强的临床前细胞毒性。我们在晚期实体瘤患者中进行了一项 1 期研究，以评估安全性、疗效和药效学（PD）结果。
我们采用 3+3 剂量递增设计，评估晚期实体瘤患者每日依维莫司和来那度胺的安全性和推荐的 2 期剂量（RP2D）。起始剂量分别为 5mg 和 10mg，如果没有剂量限制性毒性，则计划在无毒性的情况下将剂量递增至单药最大剂量 10mg 和 25mg。使用多参数流式细胞术和 LUMINEX 检测外周血中的淋巴细胞亚群和免疫细胞因子作为 PD 终点。每两个治疗周期后通过横断面成像评估疗效。
该研究共纳入 44 例患者，中位年龄为 58 岁，男性 28 例（63.6%）。确定了依维莫司和来那度胺的 RP2D 剂量分别为每日 10mg 和 25mg 连续给药。常见（>5%）≥3 级不良事件包括皮疹（19%）、中性粒细胞减少（19%）、低钾血症（11%）和疲劳（9%）。36 例可评估患者的最佳疗效结果为部分缓解 5 例（13.8%）、稳定疾病 24 例（55.8%）和进展性疾病 7 例（19.4%）。PD 评估显示细胞因子水平（白细胞介素-2（IL2）、IL21 和 IL17）、基线激活和总 CD8+淋巴细胞以及 B 细胞淋巴细胞和激活 NK 细胞的变化与临床获益显著相关。
该研究表明依维莫司和来那度胺联合应用具有安全性，在甲状腺和腺样囊性癌中具有有希望的疗效信号。
NCT01218555。
