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

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 ¼ 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.

Tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology, and treatment

“…They lead to mutated enzymes with neomorphic activity, producing the oncometabolite 2-hydroxyglutarate (2-HG), which modulates cellular epigenetic programs, differentiation patterns, and metabolic profiles ( 4 – 6 ). Recent clinical trials in diffuse glioma have used the IDH1 mutation ( IDH1 -mut) as a therapeutic target ( 7 , 8 ). However, the therapeutic efficacy of these therapeutic approaches might critically depend on understanding metabolic alterations that occur in the context of IDH1 mutations.…”

Precision Oncology in Lower-Grade Gliomas: Promises and Pitfalls of Therapeutic Strategies Targeting IDH-Mutations

“…The study included a dose-escalation phase to determine MTD and recommended Phase II dose (RP2D), followed by dose-expansion cohorts to explore further the safety and clinical efficacy of BAY-1436032 in specific tumor types (LGG, GBM, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types). Overall, 55 glioma patients were treated in the trial, 17 (14 LGGs and 3 GBMs) into the dose-escalation phase, and 38 (25 LGGs and 13 GBMs) into the dose-expansion [43]. Of note, about 75% of LGG cases had anaplastic grade 3 tumors, and most of them (33 out of 35) had contrast-enhancing lesions, as this was an eligibility criterion to be enrolled in the dose-expansion [43].…”

“…Overall, 55 glioma patients were treated in the trial, 17 (14 LGGs and 3 GBMs) into the dose-escalation phase, and 38 (25 LGGs and 13 GBMs) into the dose-expansion [43]. Of note, about 75% of LGG cases had anaplastic grade 3 tumors, and most of them (33 out of 35) had contrast-enhancing lesions, as this was an eligibility criterion to be enrolled in the dose-expansion [43].…”

“…Therefore, the dosage of 1500 mg twice daily was selected for expansion cohorts based on PK data [43]. In the second part of the study, 6/52 patients (12%) experienced a grade ≥3 TEAE deemed to be related to the study drug, one of which was grade ≥4 (grade 4 lipase increase); 12/52 (31%) needed dose reductions, and 9/52 (24%) had to discontinue treatment because of TEAEs [43]. Overall, among the 35 LGGs evaluable patients for efficacy across all dose levels, 1 (3%) achieved CR, 3 (9%) PR, and 15 (43%) SD as the best response, with a PFS rate at three months of 0.31 (0.15-0.46) [43].…”

Optimal Management of Patients with Advanced or Metastatic Cholangiocarcinoma: An Evidence-Based Review

“…77 Additional agents are under development in this space including IDH305 (NCT02381886), FT-2012 (Olutasidenib) (NCT03684811), BAY-1436032 (NCT02746081), and LY3410738 (NCT04 521686). 79,80 These newer agents may offer treatment options for patients who have progressed on treatment with ivosidenib.…”