Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma

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• 作者：Anthony W. Tolcher ; Amita Patnaik…
• 关键词：Trametinib ; Afuresertib ; AKT Inhibitor ; MEK Inhibitor ; Combination therapy
• 刊名：Cancer Chemotherapy and Pharmacology
• 出版年：2015
• 出版时间：January 2015
• 年：2015
• 卷：75
• 期：1
• 页码：183-189
• 全文大小：180 KB
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• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Cancer Research
  Pharmacology and Toxicology
  Oncology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0843

文摘

Purpose To identify the maximum tolerated dose (MTD) and recommended Phase II dose of MEK/AKT inhibitor combination of trametinib and afuresertib. Patients and methods Eligibility criteria were advanced solid tumors, 18?years or older, Eastern Cooperative Oncology Group performance status 0?or?1, and adequate organ function. Exclusion criteria included Type 1 diabetes, active GI disease, leptomeningeal disease, or current evidence/risk of retinal venous occlusion/central serous retinopathy. Clinical safety parameters and response were evaluated and analyzed. Results Twenty patients were enrolled. Dose-limiting toxicities (Grade?2 esophagitis; Grade 3 aspartate aminotransferase increased, mucosal inflammation and hypokalemia) were reported at starting dose (1.5?mg?trametinib/50?mg afuresertib once daily continuously), exceeding the MTD. Subsequent de-escalation cohorts (1.5?mg/25 mg or 1.0?mg/50?mg?trametinib/afuresertib) were defined as MTDs for continuous dosing. Intermittent dosing schedule [1.5?mg trametinib (continuous)/50 mg afuresertib (Days?1-0 every 28?days)] was evaluated and considered tolerable. No patients were enrolled in Phase II. The most common adverse events reported (?0?% of all patients) included: diarrhea (60?%), dermatitis acneiform (55?%), maculo-papular rash (45?%), fatigue (30?%), dry skin (25?%), nausea (25?%), dyspnea (20?%), and vomiting?(20?%). One partial response (BRAF wild-type melanoma) was reported; four patients had stable disease as best response. Conclusion Continuous daily dosing of trametinib/afuresertib combination was poorly tolerated. Evaluation of intermittent dose schedule showed greater tolerability. Given the interest in combination treatment regimens of MAPK and PI3K/AKT pathway inhibitors, further study of intermittent dose schedule or combination of trametinib with more selective inhibitors may be warranted.