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.