The purpose of this first clinical study of the noval multiple AGC kinase inhibitor, AT13148, is to identify the recommended dose for future studies in cancer patients by exploring the safety and maximum tolerated dose and biological effects in patients with advanced solid tumours.

开始日期2012-05-01

申办/合作机构

Cancer Research UK

100 项与 AT-13148 相关的临床结果

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100 项与 AT-13148 相关的转化医学

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100 项与 AT-13148 相关的专利（医药）

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项与 AT-13148 相关的文献（医药）

2020-09-15·Clinical Cancer Research1区 · 医学

First-in-Human Study of AT13148, a Dual ROCK-AKT Inhibitor in Patients with Solid Tumors

1区 · 医学

Article

作者: Swales, Karen E. ; Garces, Alvaro H. Ingles ; Brown, Jessica S. ; McLeod, Robert ; Mellor, Sarah ; Garrett, Michelle D. ; Raynaud, Florence I. ; Papadatos-Pastos, Dionysis ; Ferraldeschi, Roberta ; Jones, Paul ; Mateo, Joaquin ; Sanz-Moreno, Victoria ; Ruddle, Ruth ; Maiques, Oscar ; Kumar, Rajiv ; Jueliger, Simone ; Halbert, Gavin ; Decordova, Shaun ; Traub, Stephanie ; Banerji, Udai

AbstractPurpose:AT13148 is an oral AGC kinase inhibitor, which potently inhibits ROCK and AKT kinases. In preclinical models, AT13148 has been shown to have antimetastatic and antiproliferative activity.Patients and Methods:The trial followed a rolling six design during dose escalation. An intrapatient dose escalation arm to evaluate tolerability and a biopsy cohort to study pharmacodynamic effects were later added. AT13148 was administered orally three days a week (Mon–Wed–Fri) in 28-day cycles. Pharmacokinetic profiles were assessed using mass spectrometry and pharmacodynamic studies included quantifying p-GSK3β levels in platelet-rich plasma (PRP) and p-cofilin and p-MLC2 levels in tumor biopsies.Results:Fifty-one patients were treated on study. The safety of 5–300 mg of AT13148 was studied. Further, the doses of 120–180–240 mg were studied in an intrapatient dose escalation cohort. The dose-limiting toxicities included hypotension (300 mg), pneumonitis, and elevated liver enzymes (240 mg), and skin rash (180 mg). The most common side effects were fatigue, nausea, headaches, and hypotension. On the basis of tolerability, 180 mg was considered the maximally tolerated dose. At 180 mg, mean Cmax and AUC were 400 nmol/L and 13,000 nmol/L/hour, respectively. At 180 mg, ≥50% reduction of p-cofilin was observed in 3 of 8 posttreatment biopsies.Conclusions:AT13148 was the first dual potent ROCK-AKT inhibitor to be investigated for the treatment of solid tumors. The narrow therapeutic index and the pharmacokinetic profile led to recommend not developing this compound further. There are significant lessons learned in designing and testing agents that simultaneously inhibit multiple kinases including AGC kinases in cancer.

2020-04-01·Metabolomics3区 · 医学

Metabolomic changes of the multi (-AGC-) kinase inhibitor AT13148 in cells, mice and patients are associated with NOS regulation

3区 · 医学

Article

作者: Eccles, Suzanne A ; Swales, Karen ; Banerji, Udai ; Decordova, Shaun ; Asad, Yasmin ; Ruddle, Ruth ; De Bono, Johann ; Raynaud, Florence I ; Collins, Ian ; Garrett, Michelle D ; Pal, Akos ; Henley, Alan T

AbstractIntroductionTo generate biomarkers of target engagement or predictive response for multi-target drugs is challenging. One such compound is the multi-AGC kinase inhibitor AT13148. Metabolic signatures of selective signal transduction inhibitors identified in preclinical models have previously been confirmed in early clinical studies. This study explores whether metabolic signatures could be used as biomarkers for the multi-AGC kinase inhibitor AT13148.ObjectivesTo identify metabolomic changes of biomarkers of multi-AGC kinase inhibitor AT13148 in cells, xenograft / mouse models and in patients in a Phase I clinical study.MethodsHILIC LC–MS/MS methods and Biocrates AbsoluteIDQ™ p180 kit were used for targeted metabolomics; followed by multivariate data analysis in SIMCA and statistical analysis in Graphpad. Metaboanalyst and String were used for network analysis.ResultsBT474 and PC3 cells treated with AT13148 affected metabolites which are in a gene protein metabolite network associated with Nitric oxide synthases (NOS). In mice bearing the human tumour xenografts BT474 and PC3, AT13148 treatment did not produce a common robust tumour specific metabolite change. However, AT13148 treatment of non-tumour bearing mice revealed 45 metabolites that were different from non-treated mice. These changes were also observed in patients at doses where biomarker modulation was observed. Further network analysis of these metabolites indicated enrichment for genes associated with the NOS pathway. The impact of AT13148 on the metabolite changes and the involvement of NOS-AT13148- Asymmetric dimethylarginine (ADMA) interaction were consistent with hypotension observed in patients in higher dose cohorts (160-300 mg).ConclusionAT13148 affects metabolites associated with NOS in cells, mice and patients which is consistent with the clinical dose-limiting hypotension.

2018-06-15·Cancer Research1区 · 医学

Rho Kinase Inhibition by AT13148 Blocks Pancreatic Ductal Adenocarcinoma Invasion and Tumor Growth

1区 · 医学

Article

作者: Vennin, Claire ; Unbekandt, Mathieu ; Gadegaard, Nikolaj ; Pajic, Marina ; McGarry, Lynn ; Munro, June ; Michalopoulou, Evdokia ; Jagiełło, Alicja ; Rath, Nicola ; Mackay, Gillian ; Olson, Michael F. ; Sumpton, David ; Cutiongco, Marie Francene ; Timpson, Paul ; Kamphorst, Jurre J.

AbstractThe high mortality of pancreatic cancer demands that new therapeutic avenues be developed. The orally available small-molecule inhibitor AT13148 potently inhibits ROCK1 and ROCK2 kinases that regulate the actomyosin cytoskeleton. We previously reported that ROCK kinase expression increases with human and mouse pancreatic cancer progression and that conditional ROCK activation accelerates mortality in a genetically modified LSL-KrasG12D; LSL-p53R172H; Pdx1-Cre; (KPC) mouse pancreatic cancer model. In this study, we show that treatment of KPC mouse and human TKCC5 patient-derived pancreatic tumor cells with AT13148, as well as the ROCK-selective inhibitors Y27632 and H1152, act comparably in blocking ROCK substrate phosphorylation. AT13148, Y27632, and H1152 induced morphologic changes and reduced cellular contractile force generation, motility on pliable discontinuous substrates, and three-dimensional collagen matrix invasion. AT13148 treatment reduced subcutaneous tumor growth and blocked invasion of healthy pancreatic tissue by KPC tumor cells in vivo without affecting proliferation, suggesting a role for local tissue invasion as a contributor to primary tumor growth. These results suggest that AT13148 has antitumor properties that may be beneficial in combination therapies or in the adjuvant setting to reduce pancreatic cancer cell invasion and slow primary tumor growth. AT13148 might also have the additional benefit of enabling tumor resection by maintaining separation between tumor and healthy tissue boundaries.Significance: Preclinical evaluation of a small-molecule ROCK inhibitor reveals significant effects on PDAC invasion and tumor growth, further validating ROCK kinases as viable therapeutic targets in pancreatic cancer. Cancer Res; 78(12); 3321–36. ©2018 AACR.

100 项与 AT-13148 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
实体瘤	临床1期	英国	-	2012-05-16
肿瘤	临床1期	-	Astex Pharmaceuticals, Inc.	-

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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


NCT01585701 (Pubmed \| Clin Cancer Res) 人工标引	临床1期	实体瘤	51	at13148	(繭築壓築鬱構膚窪廠糧) = fatigue, nausea, headaches, and hypotension. On the basis of tolerability 艱鹽膚觸顧鑰鹽憲淵廠 (廠顧選鹹網網範繭願蓋 ) 更多	不佳	2020-09-15
NCT01585701 (ASCO2014)	临床1期	HR阳性/HER2低表达实体瘤	14	AT13148 5mg	(簾襯鏇遞夢繭餘網醖壓) = 鑰構築憲範繭醖鬱鏇壓遞鹽鹹築蓋壓襯齋築觸 (築壓鹽構遞蓋選餘簾觸 )	-	2014-05-20
NCT01585701 (ASCO2014)	临床1期	HR阳性/HER2低表达实体瘤	14	AT13148 10mg	(簾襯鏇遞夢繭餘網醖壓) = 觸淵獵窪膚夢衊醖簾夢遞鹽鹹築蓋壓襯齋築觸 (築壓鹽構遞蓋選餘簾觸 )	-	2014-05-20