Autophagy Inhibition to Augment mTOR Inhibition: a Phase I/II Trial of Everolimus and Hydroxychloroquine in Patients with Previously Treated Renal Cell Carcinoma.
Autophagy Inhibition to Augment mTOR Inhibition: a Phase I/II Trial of Everolimus and Hydroxychloroquine in Patients with Previously Treated Renal Cell Carcinoma.
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DOI：
10.1158/1078-0432.ccr-18-2204
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发表时间：
2019-04-01
期刊：
影响因子：
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通讯作者：
Amaravadi RK
中科院分区：
文献类型：
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作者：
Haas NB;Appleman LJ;Stein M;Redlinger M;Wilks M;Xu X;Onorati A;Kalavacharla A;Kim T;Zhen CJ;Kadri S;Segal JP;Gimotty PA;Davis LE;Amaravadi RK
依维莫司抑制雷帕霉素（mTOR）的机制靶点，激活细胞保护性自噬。羟氯喹（HCQ）抑制自噬。基于mTOR抑制剂与自噬抑制剂组合时显示协同细胞毒性的临床前数据，我们启动了依维莫司和HCQ组合的临床试验，以确定其在透明细胞肾癌（ccRCC）患者中的安全性和活性。三个中心在晚期ccRCC患者中进行了依维莫司每日10 mg和HCQ的I/II期试验。目的是确定HCQ与每日依维莫司的最大耐受剂量，并估计在1-3种先前治疗方案后接受依维莫司/HCQ的ccRCC患者的6个月无进展生存期（PFS）率。相关的研究，以确定患者亚群，实现了最大的好处，包括群体药代动力学，测量自噬体的电子显微镜和下一代肿瘤测序。在I期试验中未观察到DLT。确定了HCQ 600 mg bid联合依维莫司的推荐II期剂量。22/33例（67%）可评价患者的疾病控制（疾病稳定（SD）+部分缓解（PR））。在2/33例患者（6%）中观察到部分缓解。15/33例（45%）实现疾病控制的患者实现了PFS ≥6个月。HCQ 600 mg每日2次与依维莫司10 mg每日联合用药可耐受。达到了>40%的6个月PFS率的主要终点。HCQ在未来的RCC或其他试验中是一种可耐受的自噬抑制剂。
Everolimus inhibits the mechanistic target of rapamycin (mTOR), activating cytoprotective autophagy. Hydroxychloroquine (HCQ) inhibits autophagy. Based on preclinical data demonstrating synergistic cytotoxicity when mTOR inhibitors are combined with an autophagy inhibitor, we launched a clinical trial of combined everolimus and HCQ, to determine its safety and activity in patients with clear cell renal carcinoma (ccRCC). Three centers conducted a phase I/II trial of everolimus 10 mg daily and HCQ in patients with advanced ccRCC. The objectives were to determine the maximum tolerated dose of HCQ with daily everolimus, and to estimate the rate of 6 month progression-free survival (PFS) in ccRCC patients receiving everolimus/HCQ after 1–3 prior treatment regimens. Correlative studies to identify patient subpopulations that achieved the most benefit included population pharmacokinetics, measurement of autophagosomes by electron microscopy and next generation tumor sequencing. No DLT was observed in the phase I trial. The recommended phase II dose of HCQ 600 mg bid with everolimus was identified. Disease control (Stable disease (SD) + partial response (PR)) occurred in 22/33 (67%) evaluable patients. Partial response was observed in 2/33 patients (6%). PFS ≥6 months was achieved in 15/33 (45%) of patients who achieved disease control. Combined HCQ 600mg twice daily with 10 mg daily everolimus was tolerable. The primary endpoint of >40% 6 month PFS rate was met. HCQ is a tolerable autophagy inhibitor in future RCC or other trials.