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.

Abstract

BACKGROUND:

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).

PATIENTS AND METHODS:

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).

RESULTS:

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.

CONCLUSION:

Further investigation is required to explore the discrepancy between the activity of this combination on leukemia cells and the lack of clinical efficacy.

• Authors: Brittany Knick Ragon, Olatoyosi Odenike, Maria R Baer, Wendy Stock, Gautam Borthakur, Keyur Patel, Lina Han, Helen Chen, Helen Ma, Loren Joseph, Yang Zhao, Keith Baggerly, Marina Konopleva, Nitin Jain
• Journal: Clinical lymphoma, myeloma & leukemia (Clin Lymphoma Myeloma Leuk) Vol. 19 Issue 7 Pg. 431-440.e13 (07 2019) ISSN: 2152-2669 [Electronic] United States
• PMID: 31056348 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Diamines
• GSK2141795
• Pyrazoles
• Pyridones
• Pyrimidinones
• trametinib
• MAP2K2 protein, human
• Proto-Oncogene Proteins c-akt
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Diamines (administration & dosage)
• Female
• Genes, ras
• Humans
• Leukemia, Myeloid, Acute (diagnosis, drug therapy, genetics)
• MAP Kinase Kinase 1 (antagonists & inhibitors)
• MAP Kinase Kinase 2 (antagonists & inhibitors)
• Male
• Middle Aged
• Mutation
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Pyrazoles (administration & dosage)
• Pyridones (administration & dosage)
• Pyrimidinones (administration & dosage)
• Treatment Outcome
• Young Adult