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A first-in-class, first-in-human, phase I trial of p28, a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in patients with advanced solid tumours

Warso, M A ; Richards, J M ; Mehta, D ; Christov, K ; Schaeffer, C ; Rae Bressler, L ; Yamada, T ; Majumdar, D ; Kennedy, S A ; Beattie, C W ; Das Gupta, T K

British journal of cancer, 19 March 2013, Vol.108(5), pp.1061-70 [Tạp chí có phản biện]

E-ISSN: 1532-1827 ; PMID: 23449360 Version:1 ; DOI: 10.1038/bjc.2013.74

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  • Nhan đề:
    A first-in-class, first-in-human, phase I trial of p28, a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in patients with advanced solid tumours
  • Tác giả: Warso, M A ; Richards, J M ; Mehta, D ; Christov, K ; Schaeffer, C ; Rae Bressler, L ; Yamada, T ; Majumdar, D ; Kennedy, S A ; Beattie, C W ; Das Gupta, T K
  • Chủ đề: Antineoplastic Agents -- Therapeutic Use ; Azurin -- Adverse Effects ; Peptide Fragments -- Adverse Effects
  • Là 1 phần của: British journal of cancer, 19 March 2013, Vol.108(5), pp.1061-70
  • Mô tả: This first-in-human, phase I clinical trial of p28 (NSC745104), a 28-amino-acid fragment of the cupredoxin azurin, investigated the safety, tolerability, pharmacokinetics and preliminary activity of p28 in patients with p53(+) metastatic solid tumours. A total of 15 patients were administered p28 i.v. as a short infusion three times per week for 4 weeks followed by a 2-week rest under an accelerated titration 3+3 dose escalation design until either a grade 3-related adverse event occurred or the maximum tolerated dose (MTD) was reached. Single-dose and steady-state serum pharmacokinetics were characterised. Assessments included toxicity, best objective response by RECIST 1.1 Criteria, and overall survival. No patients exhibited any dose-limiting toxicities (DLTs), significant adverse events or exhibited an immune response (IgG) to the peptide. The No Observed Adverse Effect Level (NOAEL) and MTD were not reached. Seven patients demonstrated stable disease for 7-61 weeks, three a partial response for 44-125 weeks, and one a complete response for 139 weeks. Three patients are still alive at 158, 140, and 110 weeks post therapy completion. p28 was tolerated with no significant adverse events. An MTD was not reached. Evidence of anti-tumour activity indicates a highly favourable therapeutic index and demonstrates proof of concept for this new class of non-HDM2-mediated peptide inhibitors of p53 ubiquitination.
  • Ngôn ngữ: English
  • Số nhận dạng: E-ISSN: 1532-1827 ; PMID: 23449360 Version:1 ; DOI: 10.1038/bjc.2013.74

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