Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors

Conclusions Ivosidenib demonstrated good oral exposure and a long half-life. Robust, persistent plasma 2-HG inhibition was observed in IDH1-mutant cholangiocarcinoma and chondrosarcoma. Ivosidenib 500  mg QD is an appropriate dose irrespective of various intrinsic and extrinsic factors.Trial RegistrationClinicalTrials.gov (NCT02073994).
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research

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The identification of heterozygous neomorphic isocitrate dehydrogenase (IDH) mutations across multiple cancer types including both solid and hematologic malignancies has revolutionized both our understanding of oncogenesis in these malignancies and the potential for targeted therapeutics using small molecule inhibitors. This neomorphic mutation in IDH generates an oncometabolite product, 2-hydroxyglutarate (2HG), which has been linked to the disruption of metabolic and epigenetic mechanisms responsible for cellular differentiation and is likely an early and critical contributor to oncogenesis. In the past two years, two mu...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conditions:   Cohort 1a and 1b: Glioma;   Cohort 1a and 1b: Glioblastoma Multiforme;   Cohort 2a and 2b: Hepatobiliary Tumors (Hepatocellular Carcinoma, Bile Duct Carcinoma, Intrahepatic Cholangiocarcinoma, Other Hepatobiliary Carcinomas);   Cohort 3a and 3b: Chondrosarcoma;   Cohort 4a and  4b: Intrahepatic Cholangiocarcinoma;   Cohort 5a: Other Solid Tumors With IDH1 Mutations Interventions:   Drug: FT-2102;   Drug: Azacitidine;   Biological:&n...
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
In conclusion, IHC, MRS, and 2-HG detection all are clinically useful and comparable with DNA sequencing in identifying IDH mutations in different neoplasms. 2-HG and MRS can be utilized for monitoring treatment response in a variety of neoplasms.
Source: Applied Immunohistochemistry and Molecular Morphology - Category: Chemistry Tags: Research Article Source Type: research
In conclusion, we developed a pan-inhibitor targeting tumors with different IDH1R132 mutations.
Source: Acta Neuropathologica - Category: Neurology Source Type: research
Authors: Fujii T, Khawaja MR, DiNardo CD, Atkins JT, Janku F Abstract Isocitrate dehydrogenase (IDH) is an essential enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle. Recurrent mutations in IDH1 or IDH2 are prevalent in several cancers including glioma, acute myeloid leukemia (AML), cholangiocarcinoma and chondrosarcoma. The mutated IDH1 and IDH2 proteins have a gain-of-function, neomorphic activity, catalyzing the reduction of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG) by NADPH. Cancer-associated IDH mutations block normal cellular differentiation and promote tumorigenesis...
Source: Discovery Medicine - Category: Research Tags: Discov Med Source Type: research
This article summarizes recent progress in our understanding of the role of mutant IDH in tumorigenesis. PMID: 26819452 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
IDH1 and IDH2 mutations have now been described in a variety of cancers including gliomas, acute myelogenous leukemias, chondrosarcomas, cholangiocarcinomas, and angioimmunoblastic T-cell lymphoma. Tumor-associated IDH1 and IDH2 mutants produce large amounts of the R enantiomer of 2-hydroxyglutarate (R-2HG), which accumulates to mM levels in IDH mutant tumor cells. R-2HG modulates (usually inhibits) various 2-oxoglutarate-dependent enzymes, including various 2-oxoglutarate-dependent dioxygenases. Examples of such dioxygenases include the JmjC family of histone demethylases and the TET methylcytosine hydroxylases. The chall...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Metabolism/IDH/Epigenetics Source Type: research
The isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are mutated in acute myelogenous leukemia, low-grade glioma, intrahepatic cholangiocarcinoma, and chondrosarcomas. IDH1 and IDH2 normally function to convert isocitrate into alpha-ketoglutarate. However, when these enzymes are mutated at select residues the mutant enzymes now convert α-KG into 2-hydroxyglutarate (2-HG). In normal cells, 2-HG levels are typically extremely low, but IDH1/2 mutant cells can accumulate up to 10 mM 2-HG. In an effort to counteract the neomorphic activity of mutant IDH enzymes, we identified and developed potent inhibitors of IDH1. The c...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Experimental and Molecular Therapeutics Source Type: research
Conditions:   Cholangiocarcinoma;   Chondrosarcoma;   GliomaIntervention:   Drug: AG881Sponsor:   Agios Pharmaceuticals, Inc.Recruiting - verified June 2015
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
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