Phase I Assessment of Safety and Therapeutic Activity of BAY1436032 in Patients with IDH1-Mutant Solid Tumors

Wick, Antje; Baehr, Oliver; Schuler, Martin; Rohrberg, Kristoffer; Chawla, Sant P.; Janku, Filip; Schiff, David; Heinemann, Volker; Narita, Yoshitaka; Lenz, Heinz-Josef; Ikeda, Masafumi; Ando, Yuichi; Wick, Wolfgang; Steinbach, Joachim P.; Burger, Michael C.; Wenger, Katharina; Lassen, Ulrik; Sankhala, Kamalesh K.; Roggia, Cristiana; Genvresse, Isabelle; Munhoz, Catya; Rentzsch, Christine; Reschke, Susanne; Langer, Simon; Wagner, Markus; Kaulfuss, Stefan; Cai, Charles; Lagkadinou, Eleni; Jeffers, Michael; Pena, Carol und Tabatabai, Ghazaleh (2021): Phase I Assessment of Safety and Therapeutic Activity of BAY1436032 in Patients with IDH1-Mutant Solid Tumors. In: Clinical Cancer Research, Bd. 27, Nr. 10: S. 2723-2733

Abstract

Purpose: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects. Patients and Methods: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors. Results: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150-1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG. Conclusions: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1078-0432
• Sprache: Englisch