دورية أكاديمية
First-in-Human Study of AT13148, a Dual ROCK-AKT Inhibitor in Patients with Solid Tumors.
| العنوان: | First-in-Human Study of AT13148, a Dual ROCK-AKT Inhibitor in Patients with Solid Tumors. |
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| المؤلفون: | McLeod R; Cancer Research UK, London, United Kingdom., Kumar R; The Royal Marsden NHS Foundation Trust, London, United Kingdom., Papadatos-Pastos D; The Royal Marsden NHS Foundation Trust, London, United Kingdom., Mateo J; The Royal Marsden NHS Foundation Trust, London, United Kingdom., Brown JS; The Royal Marsden NHS Foundation Trust, London, United Kingdom., Garces AHI; The Royal Marsden NHS Foundation Trust, London, United Kingdom., Ruddle R; The Institute of Cancer Research, London, United Kingdom., Decordova S; The Institute of Cancer Research, London, United Kingdom., Jueliger S; Astex Pharmaceuticals, Cambridge, United Kingdom., Ferraldeschi R; Astex Pharmaceuticals, Cambridge, United Kingdom., Maiques O; Bart's Cancer Centre, Queen Mary University of London, London, United Kingdom., Sanz-Moreno V; Bart's Cancer Centre, Queen Mary University of London, London, United Kingdom., Jones P; Cancer Research UK, London, United Kingdom., Traub S; Cancer Research UK, London, United Kingdom., Halbert G; Strathclyde Institute of Pharmacy and Biomedical Sciences, Glasgow, United Kingdom., Mellor S; Cancer Research UK, London, United Kingdom., Swales KE; The Institute of Cancer Research, London, United Kingdom., Raynaud FI; The Institute of Cancer Research, London, United Kingdom., Garrett MD; The Institute of Cancer Research, London, United Kingdom.; University of Kent, Canterbury, United Kingdom., Banerji U; The Royal Marsden NHS Foundation Trust, London, United Kingdom. udai.banerji@icr.ac.uk.; The Institute of Cancer Research, London, United Kingdom. |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Sep 15; Vol. 26 (18), pp. 4777-4784. Date of Electronic Publication: 2020 Jul 02. |
| نوع المنشور: | Clinical Trial, Phase I; Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Denville, NJ : The Association, c1995- |
| مواضيع طبية MeSH: | 2-Hydroxyphenethylamine/*analogs & derivatives , Antineoplastic Agents/*adverse effects , Neoplasms/*drug therapy , Protein Kinase Inhibitors/*adverse effects , Pyrazoles/*adverse effects, 2-Hydroxyphenethylamine/administration & dosage ; 2-Hydroxyphenethylamine/adverse effects ; 2-Hydroxyphenethylamine/pharmacokinetics ; Adult ; Aged ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacokinetics ; Dose-Response Relationship, Drug ; Drug Eruptions/epidemiology ; Drug Eruptions/etiology ; Female ; Headache/chemically induced ; Headache/epidemiology ; Humans ; Hyperglycemia/chemically induced ; Hyperglycemia/epidemiology ; Hypotension/chemically induced ; Male ; Maximum Tolerated Dose ; Middle Aged ; Neoplasms/blood ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/pharmacokinetics ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Pyrazoles/administration & dosage ; Pyrazoles/pharmacokinetics ; rho-Associated Kinases/antagonists & inhibitors |
| مستخلص: | Purpose: 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 C 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 American Association for Cancer Research.) |
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| معلومات مُعتمدة: | 22897 United Kingdom CRUK_ Cancer Research UK; A9098 United Kingdom CRUK_ Cancer Research UK; 20974 United Kingdom CRUK_ Cancer Research UK; C2739/A22897 United Kingdom CRUK_ Cancer Research UK; A11566_4 United Kingdom CRUK_ Cancer Research UK; 11566 United Kingdom CRUK_ Cancer Research UK; 9098 United Kingdom CRUK_ Cancer Research UK; 20740 United Kingdom CRUK_ Cancer Research UK; RP-2016-07-028 United Kingdom DH_ Department of Health; 28424 United Kingdom CRUK_ Cancer Research UK; C12540/A25128 United Kingdom CRUK_ Cancer Research UK; 24478 United Kingdom CRUK_ Cancer Research UK; 11526 United Kingdom CRUK_ Cancer Research UK; C309/A25144 United Kingdom CRUK_ Cancer Research UK; C33043/A24478 United Kingdom CRUK_ Cancer Research UK |
| المشرفين على المادة: | 0 (AT13148) 0 (Antineoplastic Agents) 0 (Protein Kinase Inhibitors) 0 (Pyrazoles) 7568-93-6 (2-Hydroxyphenethylamine) EC 2.7.11.1 (AKT1 protein, human) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) EC 2.7.11.1 (rho-Associated Kinases) |
| تواريخ الأحداث: | Date Created: 20200704 Date Completed: 20211207 Latest Revision: 20240210 |
| رمز التحديث: | 20240210 |
| مُعرف محوري في PubMed: | PMC7611345 |
| DOI: | 10.1158/1078-0432.CCR-20-0700 |
| PMID: | 32616501 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1557-3265 |
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| DOI: | 10.1158/1078-0432.CCR-20-0700 |