TLC-388 HCl(TLC-388 HCl) - 药物靶点：HIF-1α x TOP1_在研适应症：神经内分泌肿瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Lipotecan

+ [1]

靶点

HIF-1α x TOP1

作用机制

HIF-1α抑制剂(缺氧诱导因子-1α抑制剂)、TOP1抑制剂(DNA拓扑异构酶I抑制剂)

治疗领域

肿瘤

在研适应症

神经内分泌肿瘤

非在研适应症

晚期肝细胞癌晚期恶性实体瘤晚期肾细胞癌+ [6]

原研机构

台湾微脂体股份有限公司

在研机构

台湾微脂体股份有限公司

非在研机构

National Health Research Institutes北京珐玛瑞驰科技有限公司

北京法玛瑞瑟驰科技有限公司

+ [1]

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)终止

特殊审评特殊审批 (中国)

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结构

分子式C39H30N8O15

InChIKeyJCCCLGDYMMTBPM-HXDHBHDHSA-N

CAS号1432468-79-5

关联

7

项与 TLC-388 HCl 相关的临床试验

NCT03035006 / Terminated临床1/2期

A Phase I/II, Dose-escalation Study of Lipotecan Based Concurrent Chemoradiotherapy in Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis

This is a phase I/II dose-escalation study of lipotecan based concurrent chemoradiotherapy in hepatocellular carcinoma with portal vein tumor thrombosis.

开始日期2017-04-14

申办/合作机构

台湾微脂体股份有限公司

NCT02457273 / Completed临床2期IIT

An Open-Label, Single-Arm, Two-Stage, Multicenter, Phase II Study to Evaluate the Efficacy and Safety of TLC388 as Second-line Treatment in Subjects With Poorly Differentiated Neuroendocrine Carcinomas

Title of Study:
An Open-Label, Single-Arm, Two-Stage, Multicenter, Phase II Study to Evaluate the Efficacy and Safety of TLC388 as Second-line Treatment in Subjects with Poorly Differentiated Neuroendocrine Carcinomas
Investigational product:
Lipotecan®*
*Lipotecan® is the trade name of TLC388 HCl, a Topoisomerase I inhibitor)
Phase of development:
Phase II
Number of subjects:
Plan to enroll 44 subjects
Objectives:
Primary objectives:
To determine the objective response rate
Secondary objectives:
To evaluate Disease control rate, Progression free survival, Overall survival, Safety profile and Biomarkers

开始日期2015-07-04

申办/合作机构

National Taiwan University Hospital

[+5]

CTR20150149 / Completed临床2期

评价TLC388作为二线治疗在晚期肝癌受试者中有效性及安全性的一项开放、单臂、两阶段、多中心II 期临床研究

评价疾病控制率（DCR），DCR定义为每两个周期（达6个周期）研究药物治疗后最佳缓释率为完全缓解（CR）、部分缓解（PR）或疾病稳定（SD）（根据实体瘤疗效评价标准[RECIST] v1.1；附录D）并至少维持28天的患者的百分比。

开始日期2014-11-12

申办/合作机构

Alcami Carolinas Corp.

[+2]

100 项与 TLC-388 HCl 相关的临床结果

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100 项与 TLC-388 HCl 相关的转化医学

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100 项与 TLC-388 HCl 相关的专利（医药）

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7

项与 TLC-388 HCl 相关的文献（医药）

2023-01-04·Journal of Clinical and Translational Hepatology

Topoisomerase I Inhibition Radiosensitizing Hepatocellular Carcinoma by RNF144A-mediated DNA-PKcs Ubiquitination and Natural Killer Cell Cytotoxicity

Article

作者: Tsai, Chiao-Ling ; Cheng, Jason Chia-Hsien ; Yu, Wan-Ni ; Hsu, Feng-Ming ; Cheng, Ann-Lii ; Yang, Po-Sheng

Background and AimsTopoisomerase I (TOP1) participates the repair of DNA double-strand breaks (DSBs) upon radiation therapy (RT). RNF144A mediates ubiquitination of catalytic subunit of DNA protein kinase (DNA-PKcs), a critical factor in DSB repair. This study aimed to investigate the natural killer (NK) cell-mediated radiosensitization with TOP1 inhibition and the mechanism by DNA-PKcs/RNF144A.MethodsIn vitro synergism with TOP1i or cocultured NK cells and RT were evaluated in human hepatocellular carcinoma (HCC) cell lines (Huh7/PLC5) by clonogenic survivals. Orthotopic xenografts were treated with Lipotecan and/or RT. Protein expression was analyzed by western blotting, immunoprecipitation, subcellular fractionation, and confocal microscopy.ResultsLipotecan/RT had a superior synergistic effect to RT on HCC cells. Combined RT/Lipotecan reduced the xenograft size by 7-fold than RT (p<0.05). Lipotecan caused more radiation-induced DNA damage and DNA-PKcs signaling. The expression of major histocompatibility complex class I-related chain A and B (MICA/B) on tumor cells is associated with the sensitivity to NK cell-mediated lysis. Cocultured NK and HCC cells with Lipotecan radiosensitized HCC cells/tissues with the expression of MICA/B. RNF144A increased more in Huh7 cells with combined RT/TOP1i, and reduced the prosurvival function of DNA-PKcs. The effect was reversed by inhibiting the ubiquitin/proteasome system. In comparison, RNF144A decreased through nuclear translocation with the cumulated DNA-PKcs and radio-resistance of PLC5 cells.ConclusionsTOP1i reinforces NK cell-activated anti-HCC effect of RT through RNF144A mediated DNA-PKcs ubiquitination. RNF144A provides a reason for differentiating radiosensitization effect between HCC cells.

2020-10-01·Cancer Control4区 · 医学

TLC388 Induces DNA Damage and G2 Phase Cell Cycle Arrest in Human Non-Small Cell Lung Cancer Cells

4区 · 医学

ArticleOA

作者: Kou, Yu Ru ; Wu, Kun-Ming ; Lai, Jerry Cheng-Yen ; Chen, Yu-Jen ; Chi, Chih-Wen

TLC388, a camptothecin-derivative targeting topoisomerase I, is a potential anticancer drug. In this study, its effect on A549 and H838 human non-small cell lung cancer (NSCLC) cells was investigated. Cell viability and proliferation were determined by thiazolyl blue tetrazolium bromide and clonogenic assays, respectively, and cell cycle analysis and detection of phosphorylated histone H3 (Ser10) were performed by flow cytometry. γ-H2AX protein; G2/M phase-associated molecules ataxia-telangiectasia mutated (ATM), CHK1, CHK2, CDC25C, CDC2, and cyclin B1; and apoptosis were assessed with immunofluorescence staining, immunoblotting, and an annexin V assay, respectively. The effect of co-treatment with CHIR124 (a checkpoint kinase 1 [CHK1] inhibitor) was also studied. TLC388 decreased the viability and proliferation of cells of both NSCLC lines in a dose-dependent manner. TLC388 inhibited the viability of NSCLC cell lines with an estimated concentration of 50% inhibition (IC50), which was 4.4 and 4.1 μM for A549 and H838 cells, respectively, after 24 hours. Moreover, it resulted in the accumulation of cells at the G2/M phase and increased γ-H2AX levels in A549 cells. Levels of the G2 phase–related molecules phosphorylated ATM, CHK1, CHK2, CDC25C, and cyclin B1 were increased in TLC388-treated cells. CHIR124 enhanced the cytotoxicity of TLC388 toward A549 and H838 cells and induced apoptosis of the former. TLC388 inhibits NSCLC cell growth by inflicting DNA damage and activating G2/M checkpoint proteins that trigger G2 phase cell cycle arrest to enable DNA repair. CHIR124 enhanced the cytotoxic effect of TLC388 and induced apoptosis.

2020-05-01·The Oncologist2区 · 医学

An Open-Label, Single-Arm, Two-Stage, Multicenter, Phase II Study to Evaluate the Efficacy of TLC388 and Genomic Analysis for Poorly Differentiated Neuroendocrine Carcinomas

2区 · 医学

Article

作者: Liu, Tsang-Wu ; Shan, Yan-Shen ; Hsiao, Chin-Fu ; Liu, Yi-Chang ; Hsu, Chiun ; Jiang, Shih Sheng ; Liu, Ta-Chih ; Chou, Wen-Chi ; Hung, Yi-Ping ; Chao, Yee ; Hsich, Chia-Hsun ; Chen, Ming-Huang ; Tsai, Hui-Jen ; Cho, Shih-Feng ; Chiu, Chao-Hua

AbstractBackgroundThe discovery of effective therapeutic options for treating metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum-based chemotherapy remains elusive. This study analyzed the efficacy of TLC388 (Lipotecan) Hydrochloride, a novel camptothecin analog, for pretreated patients with metastatic NEC.MethodsThis single-arm, two-stage, phase II clinical trial was conducted at four community and academic centers in Taiwan. Patients aged 20 years or older with confirmed metastatic NEC and who had received prior systemic therapy with etoposide plus cisplatin were enrolled between July 2015 and May 2018. Patients received 40 mg/m2 of TLC388 intravenously on days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxic effects. Gene mutations were analyzed by next-generation sequencing.ResultsTwenty-three patients with a median age of 61 (range, 44–73) years, 18 of whom were men (78%), were enrolled. Patients received a median of 2 (range, 0–6) treatment cycles. Among 20 evaluable patients, 3 patients exhibited stable disease and no patient experienced a complete or partial remission, resulting in a disease control rate of 15%. Median progression-free survival was 1.8 (95% confidence interval [CI], 0.4–15) months, and the median overall survival was 4.3 (95% CI, 1.7–15) months. The most common treatment-related hematologic adverse events at grade 3 or higher were leukopenia (22.7%), anemia (31.8%), and thrombocytopenia (18.2%). The most frequent mutated genes in 35 patients with NEC were ARSA, DPYD, HEXB, BRCA1, HPD, MYBPC3, BBS2, IL7R, HSD17B4, and PRODH.ConclusionTLC388 demonstrates limited antitumor activity in metastatic NEC. ClinicalTrials.gov identifier: NCT02457273.Implications for PracticePoorly differentiated neuroendocrine carcinomas (NECs) are rare and aggressive. Currently, effective therapeutic options for treating metastatic poorly differentiated NECs beyond platinum-based chemotherapy remain elusive. In this single-arm, multicenter, phase II study, 23 patients with NEC were enrolled and received TLC388 (Lipotecan) Hydrochloride, which is a novel camptothecin analog. The results demonstrated the disease control rate of 15%, the median progression-free survival of 1.8 (95% confidence interval [CI], 0.4–15) months, and the median overall survival of 4.3 (95% CI, 1.7–15) months. Most importantly, several novel genetic mutations and pathways were identified. These results offer the opportunity to develop future treatment strategies in this rare cancer.

100 项与 TLC-388 HCl 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
晚期肾细胞癌	临床2期	中国台湾	台湾微脂体股份有限公司	2012-11-30
神经内分泌肿瘤	临床2期	-	台湾微脂体股份有限公司	-
直肠癌	临床前	中国台湾	台湾微脂体股份有限公司	2015-12-26
肝癌	临床前	中国	北京法玛瑞瑟驰科技有限公司	2014-11-12
肝癌	临床前	中国	台湾微脂体股份有限公司	2014-11-12
肝癌	临床前	中国	Alcami Carolinas Corp.	2014-11-12
晚期肝细胞癌	临床前	中国	台湾微脂体股份有限公司	2014-04-10
晚期肝细胞癌	临床前	中国台湾	台湾微脂体股份有限公司	2014-04-10
转移性肾细胞癌	临床前	中国台湾	台湾微脂体股份有限公司	2012-11-30
局部晚期肝细胞癌	临床前	中国台湾	台湾微脂体股份有限公司	2011-10-27

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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


NCT02457273 (Pubmed \| Oncologist) 人工标引	临床2期	神经内分泌癌	23	TLC388 Hydrochloride	(製繭蓋觸鑰繭製顧艱構) = 遞蓋獵構遞鑰淵鑰顧窪鏇蓋遞鬱夢襯淵獵網憲 (獵網淵淵窪糧簾構壓顧, 0.4 ~ 15) 更多	不佳	2020-05-01
NCT02457273 (TCOGT1Z14, ASCO2019)	临床2期	胰岛细胞癌二线	23	TLC388 (Lipotecan) Hydrochloride	(窪鏇範簾鬱願鏇築範蓋) = The most common treatment-related hematologic adverse events at grade 3 or higher were leukopenia (22.7%), anemia (31.8%), and thrombocytopenia (18.2%), respectively. 鬱顧構醖遞製襯鬱膚選 (選選觸夢廠願鬱鑰網憲 )	不佳	2019-05-26
SNMMI2015	N/A	肝细胞癌	-	Lipotecan	(醖積繭鹽憲壓壓窪窪鏇) = 選構網餘遞鏇憲壓積餘鹽繭廠遞獵夢衊鏇願範 (觸夢遞簾鏇觸網鏇壓選, 1/5 MTD)	-	2015-05-15
ASCO2011	临床1期	HR阳性/HER2低表达实体瘤	-	Lipotecan	(壓築淵範膚鏇範顧選廠) = thrombocytopenia and febrile neutropenia 獵顧壓淵壓膚淵糧鏇艱 (觸顧築鏇製窪積鹽積製 )	-	2011-05-20
ASCO2010	临床1期	晚期恶性实体瘤	-	TLC388	(簾網繭遞糧蓋膚壓窪淵) = 鹽選網醖蓋鏇糧蓋醖齋膚獵顧窪鑰蓋鑰觸鏇繭 (齋齋淵蓋窪餘鬱淵艱願 )	-	2010-05-20