Phase 1 study of the MDM2 antagonist RO6839921 in patients with acute myeloid leukemia
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PHASE I STUDIES
Phase 1 study of the MDM2 antagonist RO6839921 in patients with acute myeloid leukemia Geoffrey L. Uy 1 & Sarit Assouline 2 & Anne-Marie Young 3 & Steven Blotner 4 & Brian Higgins 4 & Lin-Chi Chen 4 & Karen Yee 5 Received: 2 January 2020 / Accepted: 15 January 2020 # The Author(s) 2020
Abstract In acute myeloid leukemia (AML), TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients received 120–300 mg AP of idasanutlin. The MTD was 200 mg, with DLTs at 250 (2/8 patients) and 300 mg (2/5). Treatment–related adverse events in >20% of patients were diarrhea, nausea, vomiting, decreased appetite, and fatigue. Six deaths (23.1%) occurred, all unrelated to treatment. Pharmacokinetics showed rapid and near-complete conversion of the prodrug to AP and dose-proportional exposure across doses. Variability ranged from 30%–47% (22%–54% for idasanutlin). TP53 was 21 (87.5%) wild-type and 3 mutant (12.5%). The composite response rate (complete remission [CR], CR with incomplete hematologic recovery/ morphological leukemia-free state [CRi/MLFS], or CR without platelet recovery [CRp]) was 7.7%. Antileukemic activity (CR, CRi/MLFS, partial response, hematologic improvement/stable disease) was observed in 11 patients (disease control rate, 42%): 10/11 were TP53 wild-type; 1 had no sample. p53 activation was demonstrated by MIC-1 induction and was associated with AP exposure. There was not sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development of RO6839921. NCT02098967. Keywords Acute myeloid leukemia . MDM2 . Idasanutlin . Safety
Introduction
Support for third-party writing assistance for this manuscript, furnished by writer Denise Kenski, PhD, CMPP, of Health Interactions, Inc, was provided by F. Hoffmann-La Roche Ltd. and Genentech, Inc. * Geoffrey L. Uy [email protected] 1
Division of Oncology, Washington University School of Medicine, St Louis, MO, USA
2
Jewish General Hospital, Montreal, QC, Canada
3
Pharma Research and Early Development, Roche Innovation Center, Welwyn Garden City, UK
4
Pharma Research and Early Development, Roche Innovation Center, New York, NY, USA
5
Princess Margaret Cancer Centre, Toronto, ON, Canada
The p53 protein is a growth-suppressive and pro-apoptotic protein that plays a central role in the protection of cells from tumor development. [1, 2] In normal cells, a close relationship exists between p53 and its primary regulator, murine double minute 2 (MDM2), which controls bot
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