A Phase 1b/2 Study Evaluating the Activity of Tinengotinib (TT-00420) in Combination With Androgen Receptor Signaling Inhibitors (ARSIs) in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC)

The purpose of this study is to find out whether tinengotinib in combination with abiraterone acetate and prednisone or enzalutamide is a safe treatment that causes few or mild side effects in people with metastatic castration-resistant prostate cancer (mCRPC).

开始日期2024-06-04

申办/合作机构

Memorial Sloan Kettering Cancer Center

[+1]

CTIS2023-505660-11-00 / Recruiting

A Phase III, Randomized, Controlled, Global Multicenter Study to Evaluate the Efficacy and Safety of Oral Tinengotinib versus Physician’s Choice in Subjects with Fibroblast Growth Factor Receptor (FGFR) altered, Chemotherapy- and FGFR Inhibitor-Refractory/Relapsed Cholangiocarcinoma (FIRST-308) - TT420C2308

开始日期2024-04-25

申办/合作机构

药捷安康（南京）科技股份有限公司初创企业

100 项与 FGFRs x Aurora B x VEGFR 相关的临床结果

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100 项与 FGFRs x Aurora B x VEGFR 相关的转化医学

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0 项与 FGFRs x Aurora B x VEGFR 相关的专利（医药）

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项与 FGFRs x Aurora B x VEGFR 相关的文献（医药）

2024-04-04·The Oncologist

First-In-Human Phase I Study of Tinengotinib (TT-00420), a Multiple Kinase Inhibitor, as a Single Agent in Patients With Advanced Solid Tumors

Article

作者: Fan, Jean ; Mott, Frank ; Raghav, Kanwal ; Hong, David S ; Fu, Siqing ; Peng, Peng ; Wu, Frank ; Ajani, Jaffer A ; Ngo, Brenda ; Ni, Shumao ; Dumbrava, Ecaterina E ; Karp, Daniel D ; Conley, Anthony P ; Xu, Binghe ; Tsimberidou, Apostolia M ; Levin, Wendy J ; Sun, Caixia ; Qiang, Xiaoyan ; Meric-Bernstam, Funda ; Ru, Qinhua Cindy ; Wang, Hui ; Javle, Milind M ; Rodon, Jordi A ; Piha-Paul, Sarina A ; Fan, Ying

AbstractPurposeThis first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial growth factor receptors, and Aurora A/B, in patients with advanced solid tumors.Patients and MethodsPatients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using escalation with overdose control. The primary objective was to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and dose recommended for dose expansion (DRDE). Secondary objectives included pharmacokinetics and efficacy.ResultsForty-eight patients were enrolled (dose escalation, n = 40; dose expansion, n = 8). MTD was not reached; DRDE was 12 mg daily. DLTs were palmar-plantar erythrodysesthesia syndrome (8 mg, n = 1) and hypertension (15 mg, n = 2). The most common treatment-related adverse event was hypertension (50.0%). In 43 response-evaluable patients, 13 (30.2%) achieved partial response (PR; n = 7) or stable disease (SD) ≥ 24 weeks (n = 6), including 4/11 (36.4%) with FGFR2 mutations/fusions and cholangiocarcinoma (PR n = 3; SD ≥ 24 weeks n = 1), 3/3 (100.0%) with hormone receptor (HR)-positive/HER2-negative breast cancer (PR n = 2; SD ≥ 24 weeks n = 1), 2/5 (40.0%) with triple-negative breast cancer (TNBC; PR n = 1; SD ≥ 24 weeks n = 1), and 1/1 (100.0%) with castrate-resistant prostate cancer (CRPC; PR). Four of 12 patients (33.3%; HR-positive/HER2-negative breast cancer, TNBC, prostate cancer, and cholangiocarcinoma) treated at DRDE had PRs. Tinengotinib’s half-life was 28-34 hours.ConclusionsTinengotinib was well tolerated with favorable pharmacokinetic characteristics. Preliminary findings indicated potential clinical benefit in FGFR inhibitor-refractory cholangiocarcinoma, HER2-negative breast cancer (including TNBC), and CRPC. Continued evaluation of tinengotinib is warranted in phase II trials.

2020-01-01·International journal of clinical and experimental pathology

Semi-comprehensive analysis of gene amplification in thymic malignant tumors using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization.

Article

作者: Saito, Daisuke ; Takata, Munehisa ; Yoshida, Shuhei ; Takemura, Hirofumi ; Ooi, Akishi ; Tanaka, Yusuke ; Matsumoto, Isao ; Tamura, Masaya ; Kakegawa, Seiichi

Research on the amplification of oncogenes in thymic malignant tumor is limited. In this study, we aimed to determine the gene amplification status of receptor tyrosine kinases and other cell regulator genes in thymic malignant tumors, with a view toward the future introduction of molecular targeted therapy. In addition, we examined the usefulness of multiplex, ligation-dependent probe amplification (MLPA) in the semi-comprehensive detection of these gene amplifications. The participants of this study were nine patients with thymic carcinoma and one patient with atypical carcinoid who underwent resection at our department from 1999 to 2016. Twenty-four oncogenes (MDM4, MYCN, ALK, PDGFRA, KIT, KDR, DHFR, EGFR, MET, SMO, BRAF, FGFR1, MYC, ABL1, RET, CCND1, CCND2, CDK4, MDM2, AURKB, ERBB2, TOP2A, AURKA, AR) were analyzed for amplification by MLPA. In cases where amplification by MLPA was suspected, confirmation was performed by fluorescence in situ hybridization (FISH). Immunostaining for detected oncoproteins and p53 were performed in cases with confirmed oncogene amplification. MYC (2/10, 20%) and MDM2 (1/10, 10%) amplifications were detected using MLPA and FISH. Immunostaining in both cases was positive. The MDM2-amplified tumor relapsed and spread rapidly after operation despite the use of post-operative chemo-radiotherapy. MYC amplification may be involved in the carcinogenesis of thymic malignant tumors. In addition, MDM2 amplification may be a concern in the increased malignancy.

2014-08-01·Modern Pathology1区 · 医学

Tyrosine kinase receptors as molecular targets in pheochromocytomas and paragangliomas

1区 · 医学

Article

作者: Liu, Wei ; Winer, Daniel ; Asa, Sylvia L ; Guo, Miao ; Cassol, Clarissa A ; Ezzat, Shereen

Pheochromocytomas and paragangliomas are neuroendocrine tumors shown to be responsive to multitargeted tyrosine kinase inhibitor (TKI) treatment. Despite growing knowledge regarding their genetic basis, the ability to predict behavior in these tumors remains challenging. There is also limited knowledge of their tyrosine kinase receptor expression and whether the clinical response observed to the TKI sunitinib relates only to its anti-angiogenic properties or also due to a direct effect on tumor cells. To answer these questions, an in vitro model of sunitinib treatment of a pheochromocytoma cell line was created. Sunitinib targets (VEGFRs, PDGFRs, and C-KIT), FGFRs, and cell cycle regulatory proteins were investigated in human tissue microarrays. SDHB immunohistochemistry was used as a surrogate marker for the presence of succinate dehydrogenase mutations. The FGFR4 G388R single nucleotide polymorphism was also investigated. Sunitinib treatment in vitro decreases cell proliferation mainly by targeting cell cycle, DNA metabolism, and cell organization genes. FGFR1, -2, and -4, VEGFR2, PDGFRα, and p16 were overexpressed in primary human pheochromocytomas and paragangliomas. Discordant results were observed for VEGFR1, p27, and p21 overexpressed in paragangliomas but underexpressed in pheochromocytomas; PDGFRβ, Rb, and Cyclin D1 overexpressed in paragangliomas only; and FGFR3 overexpressed in pheochromocytomas and underexpressed in paragangliomas. Low expression of C-KIT, p53, and Aurora kinase A and B was observed. Nuclear FGFR2 expression was associated with increased risk of metastasis (odds ratio (OR)=7.61, P=0.008), as was membranous PDGFRα (OR=13.71, P=0.015), membranous VEGFR1 (OR=8.01, P=0.037), nuclear MIB1 (OR=1.26, P=0.008), and cytoplasmic p27 (OR=1.037, P=0.030). FGFR3, VEGFR2, and C-KIT levels were associated with decreased risk of metastasis. We provide new insights into the mechanistic actions of sunitinib in pheochromocytomas and paragangliomas, and support current evidence that multitargeted TKIs might be a suitable treatment alternative for these tumors.

项与 FGFRs x Aurora B x VEGFR 相关的新闻（医药）

2023-03-17

·医药观澜

针对小细胞肺癌，爱德程医药1类新药拟纳入突破性治疗品种

3月16日，中国国家药监局药品审评中心（CDE）官网公示，爱德程医药申请的1类新药AL8326片拟纳入突破性治疗品种，拟用于治疗至少接受二线治疗方案（包括一线含铂治疗、二线单药或其他治疗）后进展或复发的小细胞肺癌。公开资料显示，AL8326是一款多靶点酪氨酸激酶抑制剂，目前正在中国开展2/3临床研究。肺癌是癌症死亡的主要原因之一，其病理分型可大致分为非小细胞肺癌（NSCLC）和小细胞肺癌（SCLC）两大类。其中，SCLC约占肺癌病例15%~20%。与NSCLC相比，SCLC的疾病进展速度更快。大多数SCLC患者在确诊时已经处于广泛期或者无法切除的局限期，很少有患者能够通过手术被治愈。根据爱德程医药官网介绍，AL8326是一款多靶点酪氨酸激酶抑制剂，主要抑制FGFR、VEGFR、Aurora B等蛋白。此前，该产品已在多个异种移植模型中证实了其功效。在宫颈癌、卵巢癌、肝癌、淋巴瘤、急性淋巴细胞性白血病以及原髓细胞白血病裸小鼠肿瘤模型中，该产品已被证实具有较好的体内活性。根据中国药物临床试验登记与信息公示平台，此前AL8326已完成一项治疗小细胞肺癌为主的晚期肿瘤患者的剂量递增耐受性1期临床研究。目前，该产品正在开展多项临床试验，针对适应症包括小细胞肺癌、非小细胞肺癌、妇科恶性肿瘤、胰腺癌为主的晚期肿瘤，以及携带FGFR突变等以胆管癌、膀胱癌为主的晚期肿瘤等。参考资料：[1]中国国家药监局药品审评中心（CDE）官网.Retrieved Feb 16，2023, From https://www.cde.org.cn/main/xxgk/listpage/2f78f372d351c6851af7431c7710a731[2] 爱德程医药官网. From http://www.advenchen.com.cn/xnews.asp?newsid=367 内容来源于网络，如有侵权，请联系删除。