A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors
Cancer Chemotherapy and Pharmacology(2019)
摘要
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.
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关键词
MK-2206, AKT, Phase I, Hydroxychloroquine, Autophagy
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