Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma
| Autor: | Jennifer Gauvin, Kyriakos P. Papadopoulos, Cornfeld Mark J, Keith W. Orford, Amita Patnaik, Geraldine Ferron-Brady, Carlos Becerra, Alicia J. Allred, Gursel Aktan, Monica Motwani, Drew W. Rasco, Anthony W. Tolcher, Nageatte Ibrahim |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty Combination therapy Pyridones MAP Kinase Kinase 2 MAP Kinase Kinase 1 Antineoplastic Agents Pyrimidinones Thiophenes Toxicology Gastroenterology Cohort Studies Neoplasms Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Pharmacology (medical) Dosing Adverse effect Protein Kinase Inhibitors Aged Pharmacology Trametinib Dose-Response Relationship Drug business.industry Melanoma MEK inhibitor Middle Aged medicine.disease Rash Tumor Burden Oncology Tolerability Early Termination of Clinical Trials Pyrazoles Female medicine.symptom Multiple Myeloma business Proto-Oncogene Proteins c-akt |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 75:183-189 |
| ISSN: | 1432-0843 0344-5704 |
| Popis: | To identify the maximum tolerated dose (MTD) and recommended Phase II dose of MEK/AKT inhibitor combination of trametinib and afuresertib. 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. |
| Databáze: | OpenAIRE |
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