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

Autor: Jyoti Malhotra, Eileen White, Daniella E Portal, Joseph Aisner, Hongxia Lin, Mark N. Stein, Rebecca A. Moss, Susan Goodin, Kristen Spencer, Laurence A Doyle, Amanda Kaveney, Darlene Gibbon, Janice M. Mehnert, Joseph R. Bertino, Antoinette R. Tan
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Cancer Research
medicine.medical_specialty
Drug-Related Side Effects and Adverse Reactions
Maximum Tolerated Dose
Nausea
Anorexia
Protein Serine-Threonine Kinases
Toxicology
Gastroenterology
Phosphatidylinositol 3-Kinases
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Pharmacokinetics
Neoplasms
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
Autophagy
medicine
Humans
Pharmacology (medical)
Enzyme Inhibitors
Adverse effect
Neoplasm Staging
Pharmacology
Dose-Response Relationship
Drug
business.industry
Hydroxychloroquine
Middle Aged
Rash
Diarrhea
030104 developmental biology
Oncology
chemistry
030220 oncology & carcinogenesis
MK-2206
Female
Drug Monitoring
medicine.symptom
business
Heterocyclic Compounds
3-Ring
medicine.drug
Zdroj: Cancer Chemotherapy and Pharmacology. 84:899-907
ISSN: 1432-0843
0344-5704
DOI: 10.1007/s00280-019-03919-x
Popis: 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. Patients were treated with weekly MK-2206 (135 mg or 200 mg) plus HCQ (200 mg, 400 mg or 600 mg BID). 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. The combination of MK-2206 and hydroxychloroquine was tolerable, but with substantial number of drug-related AEs and minimal evidence of antitumor activity.
Databáze: OpenAIRE
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