| Autor: |
Gluck WL; Prisma Health - Upstate, Institute for Translational Oncology Research, 900 W. Faris Rd., 3rd Floor, Greenville, SC, 29605, USA. larry.gluck@prismahealth.org., Gounder MM; Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA., Frank R; Whittingham Cancer Center, Norwalk, CT, USA., Eskens F; Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands., Blay JY; Department of Medicine, Centre Léon Bérard, Lyon, France., Cassier PA; Department of Medicine, Centre Léon Bérard, Lyon, France., Soria JC; Department of Medicine, The Institute Gustave-Roussy, Paris, France.; Université Paris Sud, Orsay, France., Chawla S; Sarcoma Oncology Center, Cancer Center of Southern California, Santa Monica, CA, USA., de Weger V; Department of Internal Medicine, Netherlands Cancer Institute, Amsterdam, The Netherlands., Wagner AJ; Center for Sarcoma and Bone Oncology and Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Siegel D; Multiple Myeloma Division, John Theurer Cancer Center at the Hackensack University Medical Center, Hackensack, NJ, USA., De Vos F; Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Rasmussen E; Oncology Early Development, Amgen Inc., Thousand Oaks, CA, USA., Henary HA; Oncology Early Development, Amgen Inc., Thousand Oaks, CA, USA. |
| Abstrakt: |
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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