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

Background: 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. Methods: A total of 15 patients were...

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Bibliographic Details
Published in:	British journal of cancer Vol. 108; no. 5; pp. 1061 - 1070
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 19-03-2013 Nature Publishing Group
Subjects:	631/154/436/108 631/154/436/1729 692/699/67 Aged Aged, 80 and over Amino acids Antineoplastic Agents - adverse effects Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Azurin - adverse effects Azurin - pharmacokinetics Azurin - therapeutic use Biological and medical sciences Biomedicine Cancer Cancer Research Cell cycle Clinical Study Cyclin-dependent kinases Drug Administration Schedule Drug Resistance Epidemiology Female Humans Indexing in process Kinases Male Maximum Tolerated Dose Medical sciences Metastasis Middle Aged Molecular Medicine Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Neoplasm Metastasis No-Observed-Adverse-Effect Level Oncology Peptide Fragments - adverse effects Peptide Fragments - pharmacokinetics Peptide Fragments - therapeutic use Peptides Pharmacokinetics Proteins Toxicity Tumor Suppressor Protein p53 - metabolism Tumors Ubiquitination United States > US Chicago Illinois metastatic solid tumours p28 p53 Human Solid tumor Peptides Patient Malignant tumor Metastasis Ubiquitination Cancerology TP53 Gene C-Onc gene Phase I trial Advanced stage Inhibitor Cancer Tumor suppressor gene
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Summary:	Background: 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. Methods: 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. Results: 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. Conclusion: 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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0007-0920 1532-1827
DOI:	10.1038/bjc.2013.74