A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors
| العنوان: | A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors |
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| المؤلفون: | 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 |
| المصدر: | Cancer Chemotherapy and Pharmacology. 84:899-907 |
| بيانات النشر: | Springer Science and Business Media LLC, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| تدمد: | 1432-0843 0344-5704 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9d375949b8c2f06e9abb273aacfa71f9 https://doi.org/10.1007/s00280-019-03919-x |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....9d375949b8c2f06e9abb273aacfa71f9 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14320843 03445704 |
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