Phase I assessment of safety and therapeutic activity of BAY1436032 in patients with IDH1-mutant solid tumors

Mené sur 29 patients atteints d'un cancer, cet essai de phase I évalue la dose maximale tolérée de BAY1436032 (un inhibiteur de l'isocitrate déshydrogénase-1 de forme mutante) et analyse ses caractéristiques pharmacocinétiques et pharmacodynamiques

Résumé en anglais

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 (PK) of BAY1436032, and to evaluate its potential pharmacodynamic and antitumor effects.

Experimental Design: The study comprised dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily (BID) on a continuous basis in subjects with mIDH1 solid tumors.

Results: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across 5 doses (150-1500 mg BID). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2HG levels of 76%. BAY1436032 was well-tolerated and a maximum-tolerated dose was not identified. A dose of 1500 mg BID was selected for dose expansion, where 52 subjects were treated in cohorts representing 4 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% (1 CR, 3 PR) and stable disease in 43%. As of August 2020, 4 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.