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- Title
Oral MEK 1/2 Inhibitor Trametinib in Combination With AKT Inhibitor GSK2141795 in Patients With Acute Myeloid Leukemia With RAS Mutations: A Phase II Study.
- Authors
Ragon, Brittany Knick; Odenike, Olatoyosi; Baer, Maria R.; Stock, Wendy; Borthakur, Gautam; Patel, Keyur; Han, Lina; Chen, Helen; Ma, Helen; Joseph, Loren; Zhao, Yang; Baggerly, Keith; Konopleva, Marina; Jain, Nitin
- Abstract
<bold>Background: </bold>With proven single-agent activity and favorable toxicity profile of MEK-1/2 inhibition in advanced leukemia, investigation into combination strategies to overcome proposed resistance pathways is warranted. Resistance to MEK inhibition is secondary to upstream hyperactivation of RAS/RAF or activation of the PI3K/PTEN/AKT/mTOR pathway. This phase II multi-institution Cancer Therapy Evaluation Program-sponsored study was conducted to determine efficacy and safety of the combination of the ATP-competitive pan-AKT inhibitor GSK2141795, targeting the PI3K/AKT pathway, and the MEK inhibitor trametinib in RAS-mutated relapsed/refractory acute myeloid leukemia (AML).<bold>Patients and Methods: </bold>The primary objective was to determine the proportion of patients achieving a complete remission. Secondary objectives included assessment of toxicity profile and biologic effects of this combination. Twenty-three patients with RAS-mutated AML received the combination. Two dose levels were explored (dose level 1: 2 mg trametinib, 25 mg GSK2141795 and dose level 2: 1.5 mg trametinib, 50 mg GSK2141795).<bold>Results: </bold>Dose level 1 was identified as the recommended phase II dose. No complete remissions were identified in either cohort. Minor responses were recognized in 5 (22%) patients. The most common drug-related toxicities included rash and diarrhea, with dose-limiting toxicities of mucositis and colitis. Longitudinal correlative assessment of the modulation of MEK and AKT pathways using reverse phase protein array and phospho-flow analysis revealed significant and near significant down-modulation of pERK and pS6, respectively. Combined MEK and AKT inhibition had no clinical activity in patients with RAS-mutated AML.<bold>Conclusion: </bold>Further investigation is required to explore the discrepancy between the activity of this combination on leukemia cells and the lack of clinical efficacy.
- Subjects
ACUTE myeloid leukemia diagnosis; THERAPEUTIC use of antineoplastic agents; PYRIDINE; RESEARCH; GENETIC mutation; CLINICAL trials; ONCOGENES; HETEROCYCLIC compounds; ORAL drug administration; RESEARCH methodology; ACUTE myeloid leukemia; ANTINEOPLASTIC agents; EVALUATION research; MEDICAL cooperation; TREATMENT effectiveness; AMINES; COMPARATIVE studies; TRANSFERASES; RESEARCH funding
- Publication
Clinical Lymphoma, Myeloma & Leukemia, 2019, Vol 19, Issue 7, p431
- ISSN
2152-2650
- Publication type
journal article
- DOI
10.1016/j.clml.2019.03.015