Reference Detail

Ref Type

Journal Article

PMID

(32020437)

Authors

Uy GL, Assouline S, Young AM, Blotner S, Higgins B, Chen LC, Yee K

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Investigational new drugs			2020 Feb 04	1430-1441	Invest New Drugs

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Idasanutlin	Idasanutlin	0	6
RO6839921	RO6839921	1	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Idasanutlin		RO-5503781\|RO 5503781\|RO5503781\|RG7388\|RG-7388	MDM2 Inhibitor 22	Idasanutlin (RG7388) binds to MDM2 to block subsequent interaction with p53, which prevents degradation of p53, thereby resulting in restoration of wild-type p53 activity and potentially promoting apoptosis of tumor cells (PMID: 23808545, PMID: 32338053, PMID: 32020437).
RO6839921		RO-6839921	MDM2 Inhibitor 22	RO6839921 is a pegylated prodrug of idasanutlin that binds to MDM2 and inhibits its interaction with p53, preventing degradation of p53, thereby potentially resulting in restoration of wild-type p53 activity and apoptosis of tumor cells (PMID: 31734832, PMID: 32020437).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References