Phase 1 study of the MDM2 antagonist RO6839921 in patients with acute myeloid leukemia

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.

Phase I dose-escalation study of milademetan in patients with relapsed or refractory acute myeloid leukemia

“…Gastrointestinal symptoms (e.g., decreased appetite, nausea, and vomiting) are common TEAEs with milademetan as well as other MDM2 inhibitors. In addition, the drug's safety profile observed in this study is comparable with that of other MDM2 inhibitors [16].…”

“…Furthermore, a multicenter, randomized, double-blind phase III trial using cytarabine with or without idasantulin, another MDM2 inhibitor, in R/R AML is ongoing [ 20 ]. Geoffrey and Sarit, in a phase I monotherapy study in the USA and Canada, demonstrated the favorable safety and antileukemic efficacy of an intravenous administration of MDM2 antagonist RO6839921 in patients with AML [ 16 ].…”

Emerging agents and regimens for AML

“…Data from early phase trials demonstrated clinical response with monotherapy with idasanutlin (RG7388) or in combination with other agents [68]. In general, monotherapy with MDM2 inhibitors revealed very modest anti-leukemia effect in R/R AML, including RG7112 [70], RO6839921 (an inactive pegylated prodrug of idasanutlin) [71], and AMG-232 [72]. Other MDM2 inhibitors under investigation preclinically or in early phase clinical trials were reviewed [73].…”

Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials

“…Intravenous injection of RO6839921 at a safe dose showed good anti-tumor activity in osteosarcoma and AML xenograft models [ 33 ]. Although phase I studies demonstrated improved pharmacokinetic parameters of RG7388 for advanced solid tumors and AML, its safety was comparable to that of RG7388 and did not show sufficient advantages [ 34 , 35 ].…”