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Ref Type Journal Article
PMID (31359240)
Authors Gluck WL, Gounder MM, Frank R, Eskens F, Blay JY, Cassier PA, Soria JC, Chawla S, de Weger V, Wagner AJ, Siegel D, De Vos F, Rasmussen E, Henary HA
Title Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced P53 wild-type solid tumors or multiple myeloma.
Journal Investigational new drugs
Vol
Issue
Date 2019 Jul 29
URL
Abstract Text Background This open-label, first-in-human, phase 1 study evaluated AMG 232, an oral selective MDM2 inhibitor in patients with TP53 wild-type (P53WT), advanced solid tumors or multiple myeloma (MM). Methods In the dose escalation (n = 39), patients with P53WT refractory solid tumors enrolled to receive once-daily AMG 232 (15, 30, 60, 120, 240, 480, and 960 mg) for seven days every 3 weeks (Q3W). In the dose expansion (n = 68), patients with MDM2-amplified (well-differentiated and de-differentiated liposarcomas [WDLPS and DDLPS], glioblastoma multiforme [GBM], or other solid tumors [OST]), MDM2-overexpressing ER+ breast cancer (BC), or MM received AMG 232 at the maximum tolerated dose (MTD). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. Results AMG 232 had acceptable safety up to up to 240 mg. Three patients had dose-limiting toxicities of thrombocytopenia (n = 2) and neutropenia (n = 1). Due to these and other delayed cytopenias, AMG 232 240 mg Q3W was determined as the highest tolerable dose assessed in the dose expansion. Adverse events were typically mild/moderate and included diarrhea, nausea, vomiting, fatigue, decreased appetite, and anemia. AMG 232 plasma concentrations increased dose proportionally. Increases in serum macrophage inhibitor cytokine-1 from baseline were generally dose dependent, indicating p53 pathway activation. Per local review, there were no responses. Stable disease (durability in months) was observed in patients with WDLPS (3.9), OST (3.3), DDLPS (2.0), GBM (1.8), and BC (1.4-2.0). Conclusions In patients with P53WT advanced solid tumors or MM, AMG 232 showed acceptable safety and dose-proportional pharmacokinetics, and stable disease was observed.

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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
TP53 wild-type Advanced Solid Tumor sensitive KRT-232 Phase I Actionable In a Phase I trial, KRT-232 (AMG 232) demonstrated acceptable safety, and resulted in stable disease in 80% (31/39) of patients with TP53 wild-type advanced solid tumors, with a median duration of 3.1 months (PMID: 31359240; NCT01723020). 31359240
TP53 wild-type estrogen-receptor positive breast cancer predicted - sensitive KRT-232 Phase I Actionable In a Phase I trial, KRT-232 (AMG 232) demonstrated acceptable safety, and resulted in stable disease in 83.3% (10/12) of patients with TP53 wild-type ER-positive breast cancer (BC), with a median duration of 2.0 months in ER-positive, PR-positive BC, 1.4 months in ER-positive, PR-negative BC, and one patient achieved unconfirmed partial response per central evaluation (PMID: 31359240; NCT01723020). 31359240
TP53 wild-type multiple myeloma predicted - sensitive KRT-232 Phase I Actionable In a Phase I trial, KRT-232 (AMG 232) demonstrated acceptable safety, and resulted in stable disease in 50% (5/10) of patients with TP53 wild-type multiple myeloma (PMID: 31359240; NCT01723020). 31359240
TP53 wild-type liposarcoma predicted - sensitive KRT-232 Phase I Actionable In a Phase I trial, KRT-232 (AMG 232) demonstrated acceptable safety, and resulted in stable disease in 100% (10/10) of patients with TP53 wild-type well-differentiated liposarcomas (WDLPS) and 70% (7/10) of patients with TP53 wild-type de-differentiated liposarcomas, with median duration of 3.9 and 2.0 months respectively, and one patient with WDLPS achieved unconfirmed partial response per central evaluation (PMID: 31359240; NCT01723020). 31359240