(IDH-305) - 药物靶点：IDH1_在研适应症：肿瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

IDH1

作用机制

IDH1抑制剂(细胞质异柠檬酸脱氢酶[NADP]抑制剂)

治疗领域

肿瘤

在研适应症

肿瘤

非在研适应症

IDH1突变急性髓性白血病IDH1突变胶质瘤

原研机构

Novartis Pharma AG

在研机构

Novartis Pharmaceuticals Corp.

非在研机构

Novartis AG

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C23H22F4N6O2

InChIKeyDCGDPJCUIKLTDU-SUNYJGFJSA-N

CAS号1628805-46-8

关联

4

项与 IDH-305 相关的临床试验

NCT02977689 / Withdrawn临床2期

Phase 2 Study of IDH305 in Subjects With IDH1 Mutant Grade II or III Glioma That Has Progressed After Observation or Radiation Therapy

The purpose of this study is to found out if the drug IDH305 is safe and effective in subjects with IDH1 mutant grade II or III glioma that has progressed after observation or radiation therapy.

开始日期2018-04-01

申办/合作机构

NYU Langone Health

[+1]

NCT02987010 / Withdrawn临床2期IIT

A Phase 2 Study of the IDH1 Inhibitor, IDH305, for the Treatment of IDH1 Mutated Low Grade Glioma Patients Who Have Measurable 2HG by MR Spectroscopy

Cohort A - neoadjuvant administration of IDH305 at 550 mg BID for 6 weeks followed by surgical resection at 6 weeks. If there is no evidence of progressive disease at 6 weeks (clinical, radiographic or histopathologic exam), the patient will continue on IDH305 at 550 mg BID post-operatively for a maximum of 11 additional 28 day cycles. Subsequent assessment of disease will occur every 2 months starting in Cycle 2.
Cohort B - patients who have inoperable tumors but measurable 2HG pre-treatment will be treated with IDH305 at 550 mg BID x 6 weeks. If there is adequate sustained knockdown of 2HG on MRS and disease is stable or improved, then the patient will continue on treatment for a maximum of 11 additional 28 day cycles.

开始日期2017-01-01

申办/合作机构

The University of Texas Southwestern Medical Center

NCT02826642 / Withdrawn临床1期

A Phase I, Open Label, Multicenter, Dose Finding Study of IDH305 With Standard of Care in IDH1 Mutant Acute Myeloid Leukemia

The purpose of this study is to evaluate the safety, tolerability and potential efficacy of IDH305 with standard treatments for newly diagnosed IDH1R132 mutant acute myeloid leukemia (AML).

开始日期2016-08-26

申办/合作机构

Novartis Pharmaceuticals Corp.

100 项与 IDH-305 相关的临床结果

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100 项与 IDH-305 相关的转化医学

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100 项与 IDH-305 相关的专利（医药）

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3

项与 IDH-305 相关的文献（医药）

2023-03-01·Journal of Cancer Research and Clinical Oncology3区 · 医学

A phase 1 study of IDH305 in patients with IDH1R132-mutant acute myeloid leukemia or myelodysplastic syndrome

3区 · 医学

Article

作者: DiNardo, Courtney D ; Parikh, Nehal S ; Zander, Thomas ; Ji, Yan ; Choi, Joanne ; Chen, Xueying ; Krämer, Alwin ; Yee, Karen ; Hochhaus, Andreas ; Frattini, Mark G ; Wei, Andrew H

PURPOSEIsocitrate dehydrogenase enzyme 1 (IDH1) mutations at 132nd amino acid residue (R132*) result in the cellular accumulation of the oncometabolite, 2-hydroxyglutarate (2-HG). IDH305 is an orally bioavailable, brain-penetrant, mutant-selective allosteric IDH1 inhibitor demonstrating target engagement in preclinical models. This first-in human study was designed to identify the recommended dose for expansion/maximum tolerated dose of IDH305 in patients with IDH1^R132-mutant acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).METHODSIDH305 was given at doses 75-750 mg twice daily in 41 patients with IDH1^R132-mutant AML/MDS. Dose escalation was designed using Bayesian hierarchical model with overdose control principle and relationship with dose-limiting toxicity.RESULTSIDH305 exhibited rapid absorption with mean T_1/2 approximately 4-10 h across doses. Interpatient variability was moderate and exposure increased with dose in a less than dose proportional manner. Most patients (35/41) demonstrated target engagement with reduction in 2-HG concentration at all doses. Complete remission (CR) or CR with incomplete count recovery occurred in 10/37 (27%) patients with AML and 1/ 4 patients with MDS. Adverse events (AEs) suspected to be related to study drug were reported in 53.7% of patients: increased blood bilirubin (14.6%), nausea (14.6%), increased alanine aminotransferase and aspartate aminotransferase (12.2%, each); most frequent grade 3 or 4 AEs were differentiation syndrome and tumor lysis syndrome (n = 3; 7.3%, each). Hepatotoxicity was manageable with dose modification.CONCLUSIONDue to potentially narrow therapeutic window, the study was prematurely halted and recommended phase 2 dose could not be declared.TRIAL REGISTRATIONClinicaltrials.gov identifier: NCT02381886.

2022-05-06·Open Medicine

Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis

Article

作者: Huang, Yi ; Zheng, Lei ; Li, Ping ; Wu, Yue ; Su, Li ; Zhu, Zhifa

AbstractThe present study intends to clarify the hypothesis that isocitrate dehydrogenase 1 (IDH1) mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis through the in vitro and in vivo experiments. Cholangiocarcinoma RBE cell line was transfected with IDH1 R132C mutation plasmids and treated with erastin to induce ferroptosis, which were then microscopically photographed. Cell viability rate was calculated by trypan blue staining. The lipid ROS level was determined by using flow cytometer. The BALB/c nude mice were injected subcutaneously with IDH1 knockout (KO), WT, or R132C mutation cell line, followed by injecting erastin intraperitoneally. The tumor tissue was surgically separated for the measurement of tumor volume and weight. The results showed that IDH1 mutant RBE cell line are sensitive to erastin-induced ferroptosis, evidenced by the increased number of propidium iodide-positive cells, the decreased cell viability, and increased lipid ROS level. However, current targeted inhibitors of IDH1 mutation (AG120 and IDH305) reversed these effects caused by IDH1 mutation. The in vivo experiment showed that IDH1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to erastin-induced ferroptosis. This study indicated that IDH1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to erastin-induced ferroptosis.

2017-10-12·ACS Medicinal Chemistry Letters3区 · 医学

Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor

3区 · 医学

Article

作者: Dooley, Julia ; Shultz, Michael ; Farsidjani, Ali ; Chen, Jinyun ; Caferro, Thomas ; Gould, Ty ; Xie, Xiaoling ; Cho, Young Shin ; Liu, Gang ; Costales, Abran ; Sendzik, Martin ; Shafer, Cynthia M. ; Firestone, Brant ; Heimbach, Tycho ; Villalba, Brian ; Sutton, James ; Dodd, Stephanie ; Pagliarini, Raymond ; Liang, Guiqing ; Growney, Joseph D. ; Chenail, Gregg ; Pu, Minying ; Levell, Julian R. ; Zhao, Qian ; Kulathila, Raviraj ; Manning, James R. ; Slocum, Kelly

Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg¹³². Having identified an allosteric, induced pocket of IDH1^R132H, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate IDH305 (13), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited in vivo correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. IDH305 (13) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.

100 项与 IDH-305 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
IDH1突变胶质瘤	临床3期	美国	Novartis AG	2018-04-01
IDH1突变急性髓性白血病	临床2期	-	Novartis Pharmaceuticals Corp.	2016-08-26
肿瘤	临床1期	新加坡	Novartis Pharmaceuticals Corp.	2015-03-06
肿瘤	临床1期	比利时	Novartis Pharmaceuticals Corp.	2015-03-06
肿瘤	临床1期	澳大利亚	Novartis Pharmaceuticals Corp.	2015-03-06
肿瘤	临床1期	美国	Novartis Pharmaceuticals Corp.	2015-03-06
肿瘤	临床1期	荷兰	Novartis Pharmaceuticals Corp.	2015-03-06
肿瘤	临床1期	西班牙	Novartis Pharmaceuticals Corp.	2015-03-06
肿瘤	临床1期	加拿大	Novartis Pharmaceuticals Corp.	2015-03-06
肿瘤	临床1期	德国	Novartis Pharmaceuticals Corp.	2015-03-06

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02381886 (Pubmed \| J Cancer Res Clin Oncol)	临床1期	骨髓增生异常综合征	41	IDH305	(膚艱鏇衊製網憲選衊鑰) = 12.2% 積夢鏇範網夢願鹽餘鹽 (壓鏇淵製鑰醖醖廠夢蓋 ) 更多	积极	2022-03-30
NCT02381886 (IDH305X2101, ASH2016) 人工标引	临床1期	肿瘤 IDH1 R132 Mutation	81	IDH-305	(築網積遞夢膚獵醖廠糧) = grade 3 elevated bilirubin were observed in 2 pts with solid tumors (2 at 550 mg BID), grade 3 elevated lipase in 1 pt with glioma (900 mg BID)， grade 3 rash in 1 pt with a solid tumor (750 mg BID) 顧廠齋積艱觸構遞範積 (鑰製襯憲選淵簾鹹鹹餘 ) 更多	积极	2016-12-02