BAY1436032 / Bayer - LARVOL DELTA

Characterizing Secondary-Site Mutations in Isocitrate-Dehydrogenase-1 (IDH1) (ASH 2024) - "The inhibitors investigated include ivosidenib (AG120), IDH889, IDH305, DS-1001b, GSK864, BAY1436032, olutasidenib (FT-2102), and vorasidenib (AG881), some of which either are in clinical trials or are FDA-approved. Conclusion Second-site mutants of mIDH1 exhibit different leukemogenic properties and differentiation potential in vivo, and show distinct patterns of resistance and sensitivity to ivosidenib, olutasidenib and other mIDH1 inhibitors. Our study provides a rationale to choose an IDH1 inhibitor in patients with secondary site IDH1 mutations."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • HOXA9 • IDH1 • ITGAM

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=81 | Completed | Sponsor: Bayer | Active, not recruiting ➔ Completed

Metastases • Trial completion • Brain Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • IDH1

Monitoring response to a clinically relevant IDH inhibitor in glioma-Hyperpolarized C magnetic resonance spectroscopy approaches. (PubMed, Neurooncol Adv) - "We studied IDHmut-expressing normal human astrocyte (NHAIDH1mut) cells and rats with BT257 tumors, and assessed response to the IDHmut inhibitor BAY-1436032 (n ≥ 4)...Using HP [5-C,1-C]αKG we detected metabolism with an signal-to-noise ratio of 23 for 2HG and 17 for glutamate. Our findings point to the clinical potential of HP αKG, which recently received FDA investigational new drug approval for research, for noninvasive localized imaging of IDHmut status."

Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=81 | Active, not recruiting | Sponsor: Bayer | Trial completion date: Dec 2023 ➔ Dec 2024

Metastases • Trial completion date • Brain Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

Efficacy and Safety of IDH Inhibitors in AML: A Systematic Review of Clinical Trials (ASH 2022) - "In two clinical trials (N=192) on ND mIDH-2 AML patients, ORR was 74%-89%, CR was 54%-55%, and MLFS was 4%-11% with enasidenib + chemotherapy/azacytidine as compared to ORR of 36%, CR of 12%, and MLFS of 0% with azacytidine alone...In two clinical trials, ORR with BAY1436032 (N=27) and olutasidenib (N=123) were 15% and 46% respectively...Olutasidenib was also effective in patients with R/R mIDH-1 AML. More randomized double-blind multicenter clinical trials are needed to confirm these results."

Clinical • Review • Acute Myelogenous Leukemia • Anemia • Brain Cancer • CNS Tumor • Glioma • Hematological Disorders • Hematological Malignancies • Hepatology • Leukemia • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • IDH1

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=81 | Active, not recruiting | Sponsor: Bayer | Trial completion date: Dec 2022 ➔ Dec 2023

Trial completion date • Brain Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

Targeting TCA cycle metabolites by small molecule inhibitors ameliorate LPS induced immune tolerance in Macrophages through epigenetic mechanisms (IMMUNOLOGY 2022) - "Intracellular signaling, DNA methylation, and nuclear localization were measured using RPPA, Illumina EPIC, and confocal microscopy, respectively.  Metabolic inhibitors of glycolysis (metformin), the TCA cycle (BAY 1436032), and mTOR (rapamycin and everolimus) blocked LPS-induced immune tolerance. Previous studies demonstrated that LPS induces epigenetic-mediated immune tolerance. Here we show this can be mitigated by inhibiting glycolysis, mTOR pathway and TCA cycle.  This could have clinical implications in treatment of sepsis and Tuberculosis among other diseases."

Immunology • Infectious Disease • Inflammation • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • Septic Shock • Tuberculosis • IDH1 • LDHA • MAP1LC3A

MRS based biomarkers of IDH1 mutant glioma response to the IDH inhibitor BAY-1436032 (SNO 2021) - "Gliomas are the most prevalent type of brain tumor in the central nervous system. These findings are consistent with our previous study, which investigated the MRS-detectable consequences of two other mutant IDH inhibitors: AG120 and AG881. Collectively, our work identifies translatable MRS-based metabolic biomarkers of mutant IDH1 inhibition."

Biomarker • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • IDH1

[VIRTUAL] SAFETY AND EFFICACY OF MUTANT IDH1 INHIBITOR BAY1436032 IN SUBJECTS WITH IDH1-MUTATED AML (EHA 2020) - "Conclusion BAY1436032 showed a favorable safety profile and was effective in a subset of patients. Most patients did not achieve complete and sustained target inhibition as indicated by plasma R-2HG levels."

Clinical • Acute Myelogenous Leukemia • Fatigue • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • IDH1

Safety, efficacy, PK and PD biomarker results of the first-in-human study of mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor BAY 1436032 in patients (pts) with mIDH1 advanced solid tumours (ESMO 2019) - P1; "BAY is well tolerated as anticipated due to specificity for mIDH1. BAY inhibited mIDH1-R132X activity as evidenced by a PD effect in pts with measurable 2-HG, with objective response in 3 pts (all gliomas). Clinical trial identification: NCT02746081."

Biomarker • Clinical • P1 data

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors (clinicaltrials.gov) - P1; N=81; Active, not recruiting; Sponsor: Bayer; Trial completion date: Dec 2021 ➔ Dec 2022

Clinical • Trial completion date • Brain Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors (clinicaltrials.gov) - P1; N=100; Recruiting; Sponsor: Bayer; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Brain Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors (clinicaltrials.gov) - P1; N=100; Not yet recruiting; Sponsor: Bayer

Clinical • New P1 trial • Brain Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors (clinicaltrials.gov) - P1; N=81; Active, not recruiting; Sponsor: Bayer; Trial completion date: Dec 2019 ➔ Jun 2020

Clinical • Trial completion date • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors (clinicaltrials.gov) - P1; N=81; Active, not recruiting; Sponsor: Bayer; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors (clinicaltrials.gov) - P1; N=81; Active, not recruiting; Sponsor: Bayer; Trial primary completion date: Mar 2019 ➔ Nov 2018

Clinical • Trial primary completion date • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors (clinicaltrials.gov) - P1; N=81; Active, not recruiting; Sponsor: Bayer; Trial completion date: Jun 2020 ➔ Dec 2020

Clinical • Trial completion date • Brain Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors (clinicaltrials.gov) - P1; N=81; Active, not recruiting; Sponsor: Bayer; Trial completion date: Jun 2019 ➔ Dec 2019

Clinical • Trial completion date • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors (clinicaltrials.gov) - P1; N=100; Recruiting; Sponsor: Bayer; Trial primary completion date: Jul 2018 ➔ Dec 2018

Clinical • Trial primary completion date • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors (clinicaltrials.gov) - P1; N=81; Active, not recruiting; Sponsor: Bayer; Trial completion date: Mar 2021 ➔ Dec 2021

Clinical • Trial completion date • Brain Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors (clinicaltrials.gov) - P1; N=100; Recruiting; Sponsor: Bayer; Trial primary completion date: Dec 2018 ➔ Mar 2019; Trial completion date: Feb 2019 ➔ Jun 2019

Clinical • Trial completion date • Trial primary completion date • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

Phase I Study of BAY1436032 in IDH1-mutant Advanced Solid Tumors (clinicaltrials.gov) - P1; N=81; Active, not recruiting; Sponsor: Bayer; Trial completion date: Dec 2020 ➔ Mar 2021

Clinical • Trial completion date • Brain Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

Early Noninvasive Metabolic Biomarkers of Mutant IDH Inhibition in Glioma. (PubMed, Metabolites) - "Several mutant IDH inhibitors are currently in clinical trials, including AG-881 and BAY-1436032. Importantly, all models demonstrated enhanced animal survival following both treatments and the metabolic alterations were observed prior to any detectable differences in tumor volume between control and treated tumors. Our study therefore identifies potential translatable early metabolic biomarkers of drug delivery, mutant IDH inhibition and glioma response to treatment with emerging clinically relevant therapies."

Biomarker • Journal • Glioma • Oncology • Solid Tumor • IDH1 • IDH2

Phase I assessment of safety and therapeutic activity of BAY1436032 in patients with IDH1-mutant solid tumors. (PubMed, Clin Cancer Res) - "BAY1436032 was well-tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG."

Clinical • Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor

[VIRTUAL] Interplay between IDH1 and ATRX mutations govern innate immune responses in gliomas (SNO 2020) - "On the other hand, presence of IDH1R132H led to a suppression in baseline expression of key innate immune players, which could be rescued by the mutant IDH1 inhibitor, BAY-1436032...Our data indicates the presence of an interplay between IDH1 and ATRX mutations that may regulate innate signaling in gliomas. Understanding the mechanisms governing this interplay may aid in designing therapies that exploit this interplay."

IO Biomarker • Glioma • Oncology • Solid Tumor • ATRX • IDH1