Reference Detail

Ref Type

Journal Article

PMID

(39002360)

Authors

Zhang X, Wen X, Peng R, Pan Q, Weng D, Ma Y, Zhang Y, Yang J, Men L, Wang H, Liang E, Wang C, Yang D, Zhang L, Zhai Y

Title

A first-in-human phase I study of a novel MDM2/p53 inhibitor alrizomadlin in advanced solid tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
ESMO open	9	8	2024 Aug	103636	ESMO Open

URL

Abstract Text

The mouse double minute 2 homolog (MDM2) oncogene exerts oncogenic activities in many cancers and represents a potential therapeutic target. This trial evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of alrizomadlin (APG-115), a novel MDM2/p53 inhibitor, in patients with advanced solid tumors.Patients with histologically confirmed advanced solid tumors who had progressed to standard treatment or lacked effective therapies were recruited. Alrizomadlin was administered once daily every other day for 21 days of a 28-day cycle until disease progression or intolerable toxicity.A total of 21 patients were enrolled and treated with alrizomadlin; 57.1% were male and the median age was 47 (25-60) years. The maximum tolerated dose of alrizomadlin was 150 mg and the recommended phase II dose was 100 mg. One patient in the 200-mg cohort experienced dose-limiting toxicity of thrombocytopenia and febrile neutropenia. The most common grade 3/4 treatment-related adverse events were thrombocytopenia (33.3%), lymphocytopenia (33.3%), neutropenia (23.8%), and anemia (23.8%). Alrizomadlin demonstrated approximately linear pharmacokinetics (dose range 100-200 mg) and was associated with increased plasma macrophage inhibitory cytokine-1, indicative of p53 pathway activation. Of the 20 assessable patients, 2 [10%, 95% confidence interval (CI) 1.2% to 31.7%] patients achieved partial response and 10 (50%, 95% CI 27.2% to 72.8%) showed stable disease. The median progression-free survival was 6.1 (95% CI 1.7-10.4) months, which was significantly longer in patients with wild-type versus mutant TP53 (7.9 versus 2.2 months, respectively; P < 0.001). Among patients with MDM2 amplification and wild-type TP53, the overall response rate was 25% (2/8) and the disease control rate was 100% (8/8).Alrizomadlin had an acceptable safety profile and demonstrated promising antitumor activity in MDM2-amplified and TP53 wild-type tumors. This study supports further exploration of alrizomadlin with recommended doses of 100 mg q.o.d. in 21 days on and 7 days off regimen.

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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

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

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
MDM2 amp TP53 wild-type	liposarcoma	predicted - sensitive	Alrizomadlin	Case Reports/Case Series	Actionable	In a Phase I trial, Alrizomadlin (APG-115) treatment demonstrated safety in patients with advanced solid tumors, with an overall response rate of 10% (2/20, partial responses) and stable disease in 50% (10/20) of evaluable patients and a median progression-free survival (PFS) of 6.1 months, with an overall response rate of 25% (2/8) and disease control rate of 100% (8/8) in liposarcoma patients with wild-type TP53 and MDM2 amplification (PMID: 39002360).	39002360