[Translation] An open, multicenter, Phase Ia/Ib study to evaluate the safety, tolerability, pharmacokinetic, pharmacodynamic characteristics, and preliminary efficacy of TSN084 tablets in the treatment of subjects with advanced malignant tumors

主要研究目的：评估TSN084片在晚期或转移性恶性肿瘤受试者中的安全性、耐受性、剂量限制性毒性（DLTs）和初步抗肿瘤活性，确定最大耐受剂量（MTD）、扩展期推荐剂量（RDE）和II期临床研究推荐剂量。次要研究目的：评估TSN084片药代动力学（PK）特征和初步抗肿瘤活性。探索性研究目的：探索TSN084的暴露量/剂量与安全性以及临床疗效之间的关系以及生物标志物。

[Translation]

The main purpose of the study is to evaluate the safety, tolerability, dose-limiting toxicities (DLTs) and preliminary anti-tumor activity of TSN084 tablets in subjects with advanced or metastatic malignancies, and to determine the maximum tolerated dose (MTD), recommended dose for extension (RDE) and recommended dose for Phase II clinical studies. The secondary purpose of the study is to evaluate the pharmacokinetic (PK) characteristics and preliminary anti-tumor activity of TSN084 tablets. The purpose of the exploratory study is to explore the relationship between the exposure/dose of TSN084 and safety and clinical efficacy, as well as biomarkers.

Start Date20 Jul 2022

Sponsor / Collaborator

Taili Biotechnology Shanghai Co Ltd.

NCT06386705

/ RecruitingPhase 1

A Multicenter, Open-label, Phase Ia/Ib Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of TSN084 Tablets in Patients With Advanced Malignant Tumors.

TSN084 is a novel type II kinase inhibitor with demonstrated anti-tumor effects in vitro and in vivo and targets multiple tyrosine kinases, such as c-MET, FLT3, TRK and serine/threonine kinase CDK8/19. This phase 1a/1b study is conducted to assess the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT), to evaluate the pharmacokinetics, safety and preliminary anti-tumor activity of TSN084 in advanced or metastatic malignancies in China.

Start Date20 Jul 2022

Sponsor / Collaborator

Taili Biotechnology Shanghai Co Ltd.

NCT05300438

/ Active, not recruitingPhase 1

TSN084 is a novel type II protein kinase inhibitor with demonstrated anti-tumor effects in vitro and in vivo and targets multiple tyrosine kinases, such as c-MET, FLT3, TRK and serine/threonine kinase CDK8/19. This first-in-human study is conducted to assess the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT), to evaluate the pharmacokinetics, safety and preliminary anti-tumor activity of TSN084 in advanced or metastatic malignancies.

Start Date18 Feb 2022

Sponsor / Collaborator

Taili Biotechnology Shanghai Co Ltd.

100 Clinical Results associated with FLT3 x NTRK x AXL

100 Translational Medicine associated with FLT3 x NTRK x AXL

0 Patents (Medical) associated with FLT3 x NTRK x AXL

Literatures (Medical) associated with FLT3 x NTRK x AXL

01 Oct 2019·HaematologicaQ1 · MEDICINE

Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL

Q1 · MEDICINE

Article

Author: Pasquet, Jean-Max ; Artus, Alexandre ; Izac, Brigitte ; Desplat, Vanessa ; Kosmider, Olivier ; Praloran, Vincent ; Villacreces, Arnaud ; Vigon, Isabelle ; Mansier, Olivier ; Guitart, Amélie ; Dubus, Pierre ; Dufossée, Mélody ; Bidet, Audrey ; Dumas, Pierre-Yves ; Dusanter-Fourt, Isabelle ; Giese, Alban ; Pigneux, Arnaud ; Casetti, Luana ; Martin-Lannerée, Séverine ; Rousseau, Benoît ; Naudin, Cécile ; Milpied, Noël

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones.

01 Aug 2016·Cell Biology and Toxicology

CBT profiles of cabozantinib approved for advanced renal cell carcinomas

Communications

Author: Wang, Xiangdong

Cabozantinib (CABOMETYX, Exelixis, Inc.) was recently approved by the US Food and Drug Administration (FDA) for the treatment of advanced renal cell carcinoma in patients who have received prior antiangiogenic therapy. The approval was based on a randomized study in which patients with advanced renal cell carcinoma, who had received a prior anti-angiogenic therapy, received either cabozantinib (60 mg orally once daily; N = 330) or everolimus (10 mg orally once daily; N = 328) [Approved drugs 2016]. There is increasing evidence that cabozantinib alone or in combination with other medications will be used to treat other cancers and has shown potency and efficacy in clinical preliminary trials. The more potential cabozantinib has, the greater our understanding of cabozantinib-associated cell biology and toxicology profiles should be. Cell biology and toxicology (CBT) profiles mainly include drug efficacy-driven or associated molecular interactions, mechanisms, or adverse effects on cells (Gu and Wang 2016). Cabozantinib as a small molecule receptor tyrosine kinase inhibitor, primarily targets ret protooncogene (RET)-encoded receptor tyrosine kinase (RTK), mesenchymal epithelial transition factor (MET), and the vascular endothelial cell growth factor receptor 2 (VEGFR2), of which VEGFR2 is more sensitive. Approximately 60 RTK proteins act as high-affinity cell surface receptors for many polypeptide growth factors, cytokines, hormones, and as key regulators of physiological and pathophysiological cellular processes, through the transmembrane and/or non-transmembrane domains (Kano et al. 2016; Li and Hristova 2010). One of the most important factors to influenceCBTprofiles of cabozantinib is the specificity and affinity of RTK binding types and efficacies in various conditions. In addition to bind RET, MET, and VEGFR2, cabozantinib can also inhibit KIT, VEGFR3, TRKB, VEGFR1, AXL, TIE2, and FLT3, in order of the efficacy according to IC50 values. RTK is also known as tyrosine receptor kinase or tyrosine kinase receptor depending on the permutation and has about 17 classes/families involved in major biological function and signaling through the cell membrane. Treatment with cabozantinib decreased tumor and endothelial cell proliferation and growth and increased apoptosis in a number of cancers though the inhibition of MET and VEGFR2 phosphorylation (Yakes et al. 2011). It is also reasonable to postulate the inhibitory effects of cabozantinib on tumor growth through targeting multi-RTKs, of which some may be unexpected. The binding specificity of cabozantinib as the critical part of biological function not only alters drug efficacy and efficiency but also drug side effects and toxicity, in tissues and systems or drug resistance to protein kinase inhibitors. The development of uncontrolled adverse effects and drug resistance of cabozantinib is a potential risk and challenge for clinicians to pay special attention to during application, due to the complex interplay of cabozantinib with multiRTKs, even though clinical trials have demonstrated Cell Biol Toxicol (2016) 32:259–261 DOI 10.1007/s10565-016-9349-6

BiomedicinesQ3 · ENGINEERING & TECHNOLOGY

Selective Inhibition of HDAC Class I Sensitizes Leukemia and Neuroblastoma Cells to Anticancer Drugs

Q3 · ENGINEERING & TECHNOLOGY

ArticleOA

Author: Leonova, Olga ; Kozlov, Maxim ; Kochetkov, Sergey ; Prassolov, Vladimir ; Popenko, Vladimir ; Spirin, Pavel ; Vagapova, Elmira ; Lebedev, Timofey ; Ivanenko, Karina

The acquired resistance of neuroblastoma (NB) and leukemia cells to anticancer therapy remains the major challenge in the treatment of patients with these diseases. Although targeted therapy, such as receptor tyrosine kinase (RTK) inhibitors, has been introduced into clinical practice, its efficacy is limited to patients harboring mutant kinases. Through the analysis of transcriptomic data of 701 leukemia and NB patient samples and cell lines, we revealed that the expression of RTK, such as KIT, FLT3, AXL, FGFR3, and NTRK1, is linked with HDAC class I. Although HDAC inhibitors have antitumor activity, they also have high whole-body toxicity. We developed a novel belinostat derivative named hydrazostat, which targets HDAC class I with limited off-target effects. We compared the toxicity of these drugs within the panel of leukemia and NB cell lines. Next, we revealed that HDAC inhibition with hydrazostat reactivates NTRK1, FGFR3, ROR2, KIT, and FLT3 expression. Based on this finding, we tested the efficacy of hydrazostat in combination with RTK inhibitor imatinib. Additionally, we show the ability of hydrazostat to enhance venetoclax-induced apoptosis. Thus, we reveal the connection between HDACs and RTK and describe a useful strategy to overcome the complications of single-agent therapies.

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