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01-10-2019 | Solid Tumor | Original Article

A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors

Authors: Janice M. Mehnert, Amanda D. Kaveney, Jyoti Malhotra, Kristen Spencer, Daniella Portal, Susan Goodin, Antoinette R. Tan, Joseph Aisner, Rebecca A. Moss, Hongxia Lin, Joseph R. Bertino, Darlene Gibbon, Laurence A. Doyle, Eileen P. White, Mark N. Stein

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2019

Abstract

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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Title: A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors
Authors: Janice M. Mehnert
Amanda D. Kaveney
Jyoti Malhotra
Kristen Spencer
Daniella Portal
Susan Goodin
Antoinette R. Tan
Joseph Aisner
Rebecca A. Moss
Hongxia Lin
Joseph R. Bertino
Darlene Gibbon
Laurence A. Doyle
Eileen P. White
Mark N. Stein
Publication date: 01-10-2019
Publisher: Springer Berlin Heidelberg
Keywords: Solid Tumor
Pharmacokinetics
Hydroxychloroquine
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03919-x

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