Actr-31. Phase 1 Study of Ag-881, an Inhibitor of Mutant Idh1 and Idh2: Results From the Recurrent/Progressive Glioma Population

Mellinghoff, Ingo K.; Penas‐Prado, Marta; Peters, Katherine B.; Cloughesy, Timothy F.; Burris, Howard; Maher, Elizabeth A.; Janků, Filip; Coté, Gregory M.; Fuente, Macarena De La; Clarke, Jennifer; Steelman, Lori; Le, Kha; Xu, Huansheng; Sonderfan, Alison; Hummel, Diana; Schoenfeld, Steven; Yen, Katharine; Pandya, Shuchi S.; Wen, Patrick Y.

doi:10.1093/neuonc/noy148.064

Cited by 18 publications

(19 citation statements)

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“…Several clinical trials studying mutIDH inhibitors in glioma and other solid tumors are ongoing or in planning stages and involve both pan and specific inhibitors (Table 3). Early results from ongoing phase 1 safety and dose-escalation trials continue to be updated annually during national conferences (69, 95–100).…”

Section: Clinical Trialsmentioning

confidence: 99%

“…In a similarly designed, phase 1, multicenter, open-label, dose-escalation and expansion trial, the safety and pharmacokinetic profiles of AG-881 is being investigated in both mutIDH1 and mutIDH2 gliomas and other solid tumors (ClinicalTrials.gov NCT02481154) (69, 98). According to the most recent data presented at the 2018 Society for Neuro-Oncology Annual Meeting, 52 glioma patients have received treatment with AG-881 on a 28-days cycle either as part of the dose-escalation arm (dose range 25–300 mg daily) or as part of the dose-expansion arm (10 or 50 mg daily) (69). While preliminary efficacy data has yet to be published, the most frequently observed adverse events included elevation of transaminases (ALT 44.2 and AST 38.5%) and headache (34.6%).…”

Section: Clinical Trialsmentioning

confidence: 99%

“…While preliminary efficacy data has yet to be published, the most frequently observed adverse events included elevation of transaminases (ALT 44.2 and AST 38.5%) and headache (34.6%). Furthermore, at doses >100 mg, five subjects experienced dose-limiting toxicity presenting as liver injury (69). Forthcoming work with AG-881 includes an additional ongoing phase 1 randomized open-label trial evaluating the ability of pre-treatment with either AG-881 or AG-120 to suppress intra-tumoral 2HG levels in surgical pathology specimens as a measure of pharmacological efficacy (ClinicalTrials.gov NCT03343197).…”

Section: Clinical Trialsmentioning

confidence: 99%

“…Forthcoming work with AG-881 includes an additional ongoing phase 1 randomized open-label trial evaluating the ability of pre-treatment with either AG-881 or AG-120 to suppress intra-tumoral 2HG levels in surgical pathology specimens as a measure of pharmacological efficacy (ClinicalTrials.gov NCT03343197). This trial will use the 10 or 50 mg daily dosing (69, 98, 101). The protocol for the latter study was likewise recently presented at the 2018 Society for Neuro-Oncology Annual Meeting (101).…”

Section: Clinical Trialsmentioning

confidence: 99%

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Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics

et al. 2019

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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 our understanding of oncogenesis in these malignancies and the potential for targeted therapeutics using small molecule inhibitors. The 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 2 years, two mutant IDH (mutIDH) inhibitors, Enasidenib (AG-221), and Ivosidenib (AG-120), have been FDA-approved for IDH-mutant relapsed or refractory acute myeloid leukemia (AML) based on phase 1 safety and efficacy data and continue to be studied in trials in hematologic malignancies, as well as in glioma, cholangiocarcinoma, and chondrosarcoma. In this review, we will summarize the molecular pathways and oncogenic consequences associated with mutIDH with a particular emphasis on glioma and AML, and systematically review the development and preclinical testing of mutIDH inhibitors. Existing clinical data in both hematologic and solid tumors will likewise be reviewed followed by a discussion on the potential limitations of mutIDH inhibitor monotherapy and potential routes for treatment optimization using combination therapy.

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Section: Clinical Trialsmentioning

confidence: 99%

Section: Clinical Trialsmentioning

confidence: 99%

Section: Clinical Trialsmentioning

confidence: 99%

Section: Clinical Trialsmentioning

confidence: 99%

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Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics

et al. 2019

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“…The understanding of the role of IDH1/2 mutations in tumorigenesis and early occurrence has led to the development ofIDH1/2 mutation inhibitors. IDH inhibitors have shown promising efficacy not only in hematologic malignancies, but also in cholangiocarcinoma patients harboring IDH1 mutations, such as AG-120 (NCT02073994), AG-881 (NCT02481154) and BAY1436032 (NCT02746081) [6][7][8]. However, the landscape of IDH1/2 mutations in pan-cancer has not been fully characterized.…”

Section: Introductionmentioning

confidence: 99%

Landscape of IDH1/2 mutations in Chinese patients with solid tumors: a pan-cancer analysis

Shen

Zhang²,

Yuan

et al. 2020

Preprint

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Isocitrate dehydrogenase (IDH) is an enzyme family involved in cell aerobic metabolism of tricarboxylic acid cycle. However, the landscape of IDH mutations in pan-cancer has not been fully characterized. Tissue or blood samples were subjected to next-generation sequencing (NGS) for detection the IDH mutation. A total of 28.868 patients from more than 20 solid tumor species were analyzed. 374 cases (1.30%) with IDH mutations were identified. Among all the IDH mutations cases, 80 (21.4%) were biliary tract cancer, 80 (21.4%) were lung cancer, 57 (15.2%) were liver cancer and 42 (11.2%) were colorectal cancer. The most common IDH variant were IDH1 and IDH2 which were discovered in 0.81% cases and 0.47% cases, respectively. TP53, PBRM1 and BAP1 were the most significantly mutated genes in biliary tract cancer which were different from others cancer. Moreover TMB were significantly higher in lung cancer, colorectal cancer and gastric cancer than biliary tract cancer (p= 0.0164, p <0.0001, p= 0.0067, respectively) and biliary tract cancer patients with IDH mutation had lower TMB compared with wild-type IDH. Somatic IDH mutation was found in multiple solid tumors and IDH would be a driver gene in biliary tract cancer.

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Validated HPLC method for simultaneous quantification of mutant IDH1/2 inhibitors (enasidenib, ivosidenib and vorasidenib) in mouse plasma: Application to a pharmacokinetic study

Zakkula

Dittakavi

Maniyar

et al. 2019

Biomedical Chromatography

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Isocitrate dehydrogenase (IDH) inhibitors comprise a novel class of anticancer drugs, which are approved to treat acute myeloid leukemia patients having mutations on IDH1/2. We report the development and validation of a high‐performance liquid chromatography (HPLC) method for the simultaneous quantitation of IDH inhibitors, namely enasidenib (EDB), ivosidenib (IDB) and vorasidenib (VDB), in mouse plasma as per the US Food and Drug Administration regulatory guidelines. The method involves extraction of EDB, IDB and VDB along with internal standard (IS; phenacetin) from mouse plasma (100 μl) using a simple protein precipitation process. The chromatographic analysis was performed on an HPLC system using a gradient mobile phase (comprising 10 mm ammonium acetate and acetonitrile in a flow‐gradient) and an X‐Terra Phenyl column. The UV detection wave length was set at λmax 265 nm. EDB, IDB, VDB and the IS eluted at 7.36, 8.60, 9.50 and 5.12 min, respectively, with a total run time of 10 min. The calibration curve was linear over a concentration range of 0.20–12.5 μg/ml for EDB and 0.50–12.5 μg/ml for IDB and VDB (r2 = ≥0.998 for all of the analytes). Validation results met the acceptance criteria. The validated HPLC method was successfully applied to a pharmacokinetic study in mice.

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Actr-31. Phase 1 Study of Ag-881, an Inhibitor of Mutant Idh1 and Idh2: Results From the Recurrent/Progressive Glioma Population

Cited by 18 publications

References 0 publications

Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics

Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics

Landscape of IDH1/2 mutations in Chinese patients with solid tumors: a pan-cancer analysis

Validated HPLC method for simultaneous quantification of mutant IDH1/2 inhibitors (enasidenib, ivosidenib and vorasidenib) in mouse plasma: Application to a pharmacokinetic study

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