Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced P53 wild-type solid tumors or multiple myeloma

• DOI: 10.1007/s10637-019-00840-1
• Publication Date: 2019-07-29T22:02:22Z
• Authors: W. Larry Gluck; Mrinal M. Gounder; Richard Frank; Ferry Eskens; Jean Yves Blay; Philippe A. Cassier; Jean-Charles Soria; Sant Chawla; Vincent de Weger; Andrew J. Wagner; David Siegel; Filip De Vos; Erik Rasmussen; Haby A. Henary
• Keywords: Pharmacodynamics

Summary 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), P53WT refractory enrolled to receive once-daily 232 (15, 30, 60, 120, 240, 480, and 960 mg) for seven days every 3 weeks (Q3W). expansion 68), -amplified (well-differentiated de-differentiated liposarcomas [WDLPS DDLPS], glioblastoma multiforme [GBM], other [OST]), MDM2-overexpressing ER+ breast cancer (BC), MM received at maximum tolerated (MTD). Safety, pharmacokinetics, pharmacodynamics, efficacy were assessed. Results had acceptable safety up 240 mg. Three dose-limiting toxicities of thrombocytopenia 2) neutropenia 1). Due these delayed cytopenias, mg Q3W was determined as highest tolerable assessed expansion. Adverse events typically mild/moderate included diarrhea, nausea, vomiting, fatigue, decreased appetite, anemia. plasma concentrations increased proportionally. Increases serum macrophage cytokine-1 from baseline generally dependent, indicating p53 pathway activation. Per local review, there no responses. Stable disease (durability months) observed WDLPS (3.9), OST (3.3), DDLPS (2.0), GBM (1.8), BC (1.4–2.0). Conclusions MM, showed dose-proportional stable observed.