Delving into the Latest Updates on TLC-388 HCl with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Lipotecan

+ [1]

Target

HIF-1α x Top I

Mechanism

HIF-1α inhibitors(Hypoxia-inducible factor 1 alpha inhibitors), TOP1 inhibitors(DNA topoisomerase I inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neuroendocrine Tumors

Inactive Indication

Advanced Hepatocellular CarcinomaAdvanced Malignant Solid NeoplasmAdvanced Renal Cell Carcinoma+ [6]

Originator Organization

Taiwan Liposome Co., Ltd.

Active Organization

Taiwan Liposome Co., Ltd.

Inactive Organization

National Health Research InstitutesBeijing Famarich Technology Co., Ltd.

Beijing Famarisech Technology Co., Ltd.

+ [1]

Drug Highest PhasePhase 2

First Approval Date-

RegulationSpecial Review Project (CN)

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Structure/Sequence

Molecular FormulaC39H30N8O15

InChIKeyJCCCLGDYMMTBPM-HXDHBHDHSA-N

CAS Registry1432468-79-5

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

Start Date04 Jul 2015

Sponsor / Collaborator

National Taiwan University Hospital

[+5]

CTR20150149

/ CompletedPhase 2

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

[Translation] An open, single-arm, two-stage, multicenter Phase II clinical study to evaluate the efficacy and safety of TLC388 as a second-line treatment in subjects with advanced liver cancer

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。

[Translation]

The disease control rate (DCR) was evaluated and was defined as the percentage of patients with a best response of complete response (CR), partial response (PR), or stable disease (SD) (according to Response Evaluation Criteria in Solid Tumors [RECIST] v1.1; Appendix D) maintained for at least 28 days after every two cycles (up to 6 cycles) of study drug treatment.

Start Date12 Nov 2014

Sponsor / Collaborator

Alcami Carolinas Corp.

[+2]

100 Clinical Results associated with TLC-388 HCl

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100 Translational Medicine associated with TLC-388 HCl

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100 Patents (Medical) associated with TLC-388 HCl

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7

Literatures (Medical) associated with TLC-388 HCl

04 Jan 2023·Journal of Clinical and Translational Hepatology

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

Article

Author: 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.

01 Oct 2020·Cancer ControlQ4 · MEDICINE

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

Q4 · MEDICINE

ArticleOA

Author: 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.

01 May 2020·The OncologistQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Liu, Tsang-Wu ; Shan, Yan-Shen ; Hsiao, Chin-Fu ; Liu, Yi-Chang ; Hsu, Chiun ; Jiang, Shih Sheng ; Liu, Ta-Chih ; Hung, Yi-Ping ; Chou, Wen-Chi ; 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 Deals associated with TLC-388 HCl

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Neuroendocrine Tumors	Phase 2	-	Taiwan Liposome Co., Ltd.	-
Advanced Hepatocellular Carcinoma	Phase 1	CN	Taiwan Liposome Co., Ltd.	10 Apr 2014
Advanced Hepatocellular Carcinoma	Phase 1	TW	Taiwan Liposome Co., Ltd.	10 Apr 2014
Locally Advanced Hepatocellular Carcinoma	Phase 1	TW	Taiwan Liposome Co., Ltd.	27 Oct 2011
Rectal Cancer	Discovery	TW	Taiwan Liposome Co., Ltd.	26 Dec 2015
Liver Cancer	Discovery	CN	Beijing Famarisech Technology Co., Ltd.	12 Nov 2014
Liver Cancer	Discovery	CN	Taiwan Liposome Co., Ltd.	12 Nov 2014
Liver Cancer	Discovery	CN	Alcami Carolinas Corp.	12 Nov 2014
Advanced Renal Cell Carcinoma	Discovery	TW	Taiwan Liposome Co., Ltd.	30 Nov 2012
Metastatic Renal Cell Carcinoma	Discovery	TW	Taiwan Liposome Co., Ltd.	30 Nov 2012

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02457273 (Pubmed \| Oncologist) Manual	Phase 2	Neuroendocrine Carcinoma	23	TLC388 Hydrochloride	(ewfxucoagv) = abtlatnxbq tjpfuwytcr (ygnaeusnmn, 0.4 - 15) View more	Negative	01 May 2020
SNMMI2015	Not Applicable	Hepatocellular Carcinoma	-	Lipotecan	(ikbnvkarmz) = uzdkkkvyvu qkfapyfmox (vrrmtwxaeg, 1/5 MTD)	-	15 May 2015
ASCO2011	Phase 1	HR-positive/HER2-low Solid Tumors	-	Lipotecan	(vxzzjgwzjn) = thrombocytopenia and febrile neutropenia lkegzdhqmh (bpfxdceghb )	-	20 May 2011
ASCO2010	Phase 1	Advanced Malignant Solid Neoplasm	-	TLC388	(kfublzcdij) = mpotmlqlxr hdedaygmnd (fvgcgvdost )	-	20 May 2010