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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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.
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 1–10 every 28 days)] was evaluated and considered tolerable. No patients were enrolled in Phase II. The most common adverse events reported (≥10 % 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.
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.
KeywordsTrametinib Afuresertib AKT Inhibitor MEK Inhibitor Combination therapy
We thank the patients who participated in this study and all of the personnel who contributed to the patient care and data collection for this study. This study was sponsored by GlaxoSmithKline (GSK) and is registered on the US National Institutes of Health website ClinicalTrials.gov (NCT01476137). All listed authors meet the criteria for authorship set forth by the International Committee for Journal Medical Editors (ICJME). The authors wish to acknowledge the following individuals for their contribution and critical review during development of this manuscript: Mary Richardson, Shannon Morris, Laurie Rosenstein and Jen Beyer (GSK). Editorial support with this manuscript was provided by Kristofer Klein at Modoc Research Services, Inc. (Wilmington, NC, USA) and was funded by GSK.
Conflict of interest
Anthony W. Tolcher, Amita Patnaik, Kyriakos Papadopoulos, Carlos R. Becerra, and Drew Rasco received research funding from GSK. Geraldine Ferron-Brady, Jennifer Gauvin, Keith Orford, Mark Cornfeld, and Monica Motwani are employed by GSK. Alicia Allred, Nageatte Ibrahim, and Gursel Aktan were employed by GSK at the time the research was conducted.
The study was conducted in accordance with International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) good clinical practice (GCP) and all applicable patient privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008. The protocol and informed consent were reviewed and approved by a national, regional, or investigational center institutional review board (IRB) for each participating institution in accordance with ICH GCP and applicable country-specific requirements, including US FDA Title 21 Code of Federal Regulations (CFR) 312.3(b) for constitution of IRBs.
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