Abstract LB-293: Phase II study of the oral AKT inhibitor, MK-2206, for acute myeloid leukemia (AML) in second relapse.
Authors: Konopleva Marina Y. , Walter Roland B. , Faderl Stefan , Jabbour Elias , Zeng Zhihong , Borthakur Gautam , Ruvolo Peter , Huang Xuelin , Kadia Tapan , Feliu Jennie , Burger Jan A. , Andreeff Michael , Liu Wenbin , Kornblau Steven M. , Baggerly Keith , Estey Elihu , Kantarjian Hagop 
Published: August 2014

Abstract
Outcomes of adults with AML remain unsatisfactory. To explore the role of the AKT signaling pathway in AML, we examined samples from AML patients (pts) utilizing reverse phase protein arrays (RPPAs). High levels of the phosphorylated Ser473 form of AKT were associated with shorter remission (p=0.03) and shorter overall survival (p=0.09) in 92 newly diagnosed AML pats with intermediate-risk cytogenetics undergoing induction chemotherapy, identifying AKT as rational drug target. We studied the effects of MK-2206, an investigative oral, highly specific allosteric inhibitor of the 3 isoforms of human AKT, in human AML. MK-2206 dephosphorylated AKT and inhibited growth of AML cell lines and primary AML blasts at low-micromolar concentrations. We then conducted a phase 2 trial of MK-2206 (200 mg once weekly) in adult pats who had failed 1 other therapy for persistent AML or relapsed after a prior CR &lt;12 months, a population with expected CR rates of &lt;5%. Nineteen pats (18 evaluable) with median age 70 (31-86) years were enrolled, one of whom had isolated extramedullary relapse. Nine pats had prior MDS; 5 had normal cytogenetics, 5 had complex cytogenetics or del7, 3 trisomy 8, and 6 had other cytogenetic changes; no patients had FLT3 mutations. Median number of cycles was 2; 4 pats completed ≥ 3 cycles. One response (a CRp) was observed (95% CI: 0-17%). This pat was a 77-yo man with a normal karyotype AML and prior history of CMML, who failed 2 prior regimens including high-dose cytarabine, and continued on MK-2206 for a total of 11 cycles after which he progressed. The most common grade 3/4 adverse event (AE) related to MK-2206 was pruritic rash occurring in 6/18 pats (30%). Other frequent MK-2206-related AEs were rash (n=6; grade 1/2), hyperglycemia (n=12; all grade 1/2 except for one grade 4), QTC prolongation (n=3; all grade 1). We used RPPAs to assess target inhibition in peripheral blood (PB) in 8 pats prior to and 24 hours after the first MK-2206 dose, and in bone marrow (BM) prior to and after 28 days in 5 pats. We examined (a) the direct target, (b) immediate downstream targets (20 total), and (c) all 157 proteins assayed. Considered alone, the decrease in Ser473 AKT was significant (t-test p=0.018). The larger sets show no significant changes after adjusting for multiple testing. Decrease in Ser473 AKT (median 28%; range, 12-45%) was seen in 5/8 PB and 3/5 BM samples; and in Thr308 pAKT in 5/8 PB and 4/5 BM samples. In turn, changes in AKT targets were less prevalent (downregulation of pFOX3A in 3/5, pPRAS40 in 2/5, pS6K in 4/5 and p4EBP1 in 2/5 PB samples), possibly due to incomplete AKT inhibition. Our results indicate single-agent MK-2206 has limited activity in this pat population, with rash being the dose-limiting toxicity precluding further dose escalation. The modest inhibitory effects on AKT and its downstream targets in our RPPA studies suggest that other approaches to block this pathway should be explored in the AML setting.
Citation Format: Marina Y. Konopleva, Roland B. Walter, Stefan Faderl, Elias Jabbour, Zhihong Zeng, Gautam Borthakur, Peter Ruvolo, Xuelin Huang, Tapan Kadia, Jennie Feliu, Jan A. Burger, Michael Andreeff, Wenbin Liu, Steven M. Kornblau, Keith Baggerly, Elihu Estey, Hagop Kantarjian. Phase II study of the oral AKT inhibitor, MK-2206, for acute myeloid leukemia (AML) in second relapse. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-293. doi:10.1158/1538-7445.AM2013-LB-293