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

Publication date: Available online 26 March 2019Source: Clinical Lymphoma Myeloma and LeukemiaAuthor(s): 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 JainAbstractWith 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 CTEP-sponsored study was conducted to determine efficacy and safety of the combination of ATP-competitive pan-AKT inhibitor GSK2141795, targeting the PI3K/AKT pathway, and MEK inhibitor trametinib in RAS-mutated relapsed/refractory acute myeloid leukemia (AML). The primary objective was to determine the proportion of patients achieving a complete remission (CR). 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). Dose level 1 was identified as the recommended phase II dose. No CRs were identified in either cohort. Minor responses were recognized in 5 patien...
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research