TY - JOUR
T1 - Oral MEK 1/2 Inhibitor Trametinib in Combination With AKT Inhibitor GSK2141795 in Patients With Acute Myeloid Leukemia With RAS Mutations
T2 - A Phase II Study
AU - Ragon, Brittany Knick
AU - Odenike, Olatoyosi
AU - Baer, Maria R.
AU - Stock, Wendy
AU - Borthakur, Gautam
AU - Patel, Keyur
AU - Han, Lina
AU - Chen, Helen
AU - Ma, Helen
AU - Joseph, Loren
AU - Zhao, Yang
AU - Baggerly, Keith
AU - Konopleva, Marina
AU - Jain, Nitin
N1 - Funding Information:
This trial was supported by the National Cancer Institute Cancer Therapy and Evaluation Program (CTEP). N. Jain has received research funding from the MDACC High-Impact Clinical Research Support Program (HI-CRSP). The remaining authors have stated that they have no conflicts of interest.
Funding Information:
This trial was supported by the National Cancer Institute Cancer Therapy and Evaluation Program (CTEP). N. Jain has received research funding from the MDACC High-Impact Clinical Research Support Program (HI-CRSP). The remaining authors have stated that they have no conflicts of interest.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/7
Y1 - 2019/7
N2 - 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.
AB - 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.
KW - AML
KW - Developmental therapeutics
KW - Drug resistance
KW - Neoplasia-myeloid leukemias and dysplasias
KW - Phase II clinical trials
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U2 - 10.1016/j.clml.2019.03.015
DO - 10.1016/j.clml.2019.03.015
M3 - Article
C2 - 31056348
AN - SCOPUS:85064911009
SN - 2152-2650
VL - 19
SP - 431-440.e13
JO - Clinical Lymphoma, Myeloma and Leukemia
JF - Clinical Lymphoma, Myeloma and Leukemia
IS - 7
ER -