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A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2019 Oct; Vol. 84 (4), pp. 899-907. Date of Electronic Publication: 2019 Aug 28. - Publication Year :
- 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.<br />Methods: Patients were treated with weekly MK-2206 (135 mg or 200 mg) plus HCQ (200 mg, 400 mg or 600 mg BID).<br />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.<br />Conclusion: The combination of MK-2206 and hydroxychloroquine was tolerable, but with substantial number of drug-related AEs and minimal evidence of antitumor activity.
- Subjects :
- Antineoplastic Combined Chemotherapy Protocols administration & dosage
Antineoplastic Combined Chemotherapy Protocols pharmacokinetics
Autophagy drug effects
Dose-Response Relationship, Drug
Drug Monitoring methods
Enzyme Inhibitors administration & dosage
Enzyme Inhibitors pharmacokinetics
Female
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasm Staging
Phosphatidylinositol 3-Kinases metabolism
Protein Serine-Threonine Kinases antagonists & inhibitors
Protein Serine-Threonine Kinases metabolism
Drug-Related Side Effects and Adverse Reactions diagnosis
Drug-Related Side Effects and Adverse Reactions etiology
Heterocyclic Compounds, 3-Ring administration & dosage
Heterocyclic Compounds, 3-Ring pharmacokinetics
Hydroxychloroquine administration & dosage
Hydroxychloroquine pharmacokinetics
Neoplasms blood
Neoplasms drug therapy
Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0843
- Volume :
- 84
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 31463691
- Full Text :
- https://doi.org/10.1007/s00280-019-03919-x