A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors
A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors
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DOI：
10.1007/s00280-019-03919-x
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发表时间：
2019-10-01
影响因子：
3
通讯作者：
Stein, Mark N.
中科院分区：
文献类型：
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作者：
Mehnert, Janice M.;Kaveney, Amanda D.;Stein, Mark N.
目的：鉴于协同抑制AKT诱导自噬的证据，我们研究了AKT抑制剂MK-2206与羟氯喹（HCQ）联合治疗晚期实体瘤患者的效果。方法采用MK-2206（135 mg或200 mg）每周1次联合HCQ（200 mg、400 mg或600 mg，BID）治疗。结果35例患者在5个剂量水平下入组。在剂量水平2（MK-2206 200 mg每周一次+HCQ 400 mg BID）下观察到2例3级斑丘疹DLT，在剂量水平2B（MK-2206 135 mg每周一次+HCQ 600 mg BID）下观察到1例3级疲乏DLT。最大耐受剂量（MTD）被宣布为剂量水平2B。MK-2206最常见的不良事件为高血糖（N = 18; 51%）、疲乏（N = 17; 49%）、斑丘疹（N = 16; 46%）、腹泻（N = 12; 34%）、厌食（N = 11; 31%）和恶心（N = 11; 31%）。发生归因于HCQ的不良事件的患者数量较少（N = 13），主要包括疲劳（N = 5; 14%）和斑丘疹（N = 3; 9%）。与HCQ联合给药时，观察到对MK-2206药代动力学特性的统计学显著性影响。此外，与MK-2206联合给药的HCQ血浆浓度显著高于既往研究中HCQ单药治疗的血浆水平。在5/34例（15%）患者中观察到疾病稳定的最佳总体缓解。结论MK-2206与羟氯喹联合用药可耐受，但与药物相关的AE数量较多，抗肿瘤活性证据很少。
Purpose Given the evidence that coordinate inhibition of AKT induces autophagy, we studied the combination of the AKT inhibitor, MK-2206 with hydroxychloroquine (HCQ) in patients with advanced solid tumors. Methods Patients were treated with weekly MK-2206 (135 mg or 200 mg) plus HCQ (200 mg, 400 mg or 600 mg BID). Results Thirty-five patients were enrolled across 5 dose levels. Two DLTs of grade 3 maculo-papular rash were observed at dose level 2 (MK-2206 200 mg weekly plus HCQ at 400 mg BID) and 1 DLT of grade 3 fatigue at dose level 2B (MK-2206 135 mg weekly plus HCQ 600 mg BID). The maximum tolerated dose (MTD) was declared as dose level 2B. The most common adverse events attributed to MK-2206 were hyperglycemia (N = 18; 51%), fatigue (N = 17; 49%), maculo-papular rash (N = 16; 46%), diarrhea (N = 12; 34%), anorexia (N = 11; 31%), and nausea (N = 11; 31%). Patients experiencing adverse events attributed to HCQ were small in number (N = 13) and primarily included fatigue (N = 5; 14%) and maculo-papular rashes (N = 3; 9%). Statistically significant effects on the pharmacokinetic properties of MK-2206 were observed in combination with HCQ. In addition, the plasma concentrations of HCQ in the combination with MK-2206 were significantly higher than the plasma levels of HCQ as monotherapy in prior studies. The best overall response of stable disease was observed in 5/34 (15%) patients. Conclusion The combination of MK-2206 and hydroxychloroquine was tolerable, but with substantial number of drug-related AEs and minimal evidence of antitumor activity.