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

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

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)431-440.e13
JournalClinical Lymphoma, Myeloma and Leukemia
Volume19
Issue number7
DOIs
StatePublished - Jul 2019

Keywords

  • AML
  • Developmental therapeutics
  • Drug resistance
  • Neoplasia-myeloid leukemias and dysplasias
  • Phase II clinical trials

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Bioinformatics Shared Resource
  • Functional Proteomics Reverse Phase Protein Array Core
  • Tissue Biospecimen and Pathology Resource
  • Clinical Trials Office

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this