Purpose MDM2 is a negative regulator of the tumor suppressor p53. RO6839921 is 
an inactive pegylated prodrug of idasanutlin, an MDM2 antagonist, developed for 
intravenous administration. On cleavage by plasma esterases, the active 
principle (AP = idasanutlin) is released. This phase 1 study investigated the 
safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with 
advanced solid tumors (NCT02098967). Methods Patients were evaluated on a 5-day 
dosing schedule every 28 days. Dose escalation used the Bayesian new continual 
reassessment model. Accelerated dose titration was permitted until grade ≥2 
drug-related AEs were observed. The target DLT rate to define the MTD was 
16-25%. p53 activation was assessed by measuring macrophage inhibitory 
cytokine-1 (MIC-1). Results Forty-one patients received 14-120 mg AP; 39 were 
DLT evaluable. The MTD was 110-mg AP (8% DLT rate), whereas 120-mg AP had a 44% 
DLT rate. DLTs were neutropenia, thrombocytopenia, and stridor. The most common 
treatment-related AEs (≥30%) were nausea, fatigue, vomiting, and 
thrombocytopenia. Pharmacokinetic analyses indicated rapid conversion of prodrug 
to AP and an approximately linear and dose-proportional dose-exposure 
relationship, with a 2-fold increase in exposure between Days 1 and 5 of AP. 
MIC-1 increases were exposure dependent. Stable disease was observed in 14 
patients (34%). Conclusions RO6839921 showed reduced pharmacokinetic exposure 
variability and a safety profile comparable with that of oral idasanutlin. 
Although this study indicated that RO6839921 could be administered to patients, 
the results did not provide sufficient differentiation or improvement in the 
biologic or safety profile compared with oral idasanutlin to support continued 
development.