title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: UIC Department of Surgery, Division of Surgical Oncology, Chicago, IL 60612, USA.
authors: M A
authors: MA
authors: Warso
authors: J M
authors: JM
authors: Richards
authors: D
authors: D
authors: Mehta
authors: K
authors: K
authors: Christov
authors: C
authors: C
authors: Schaeffer
authors: L
authors: L
authors: Rae Bressler
authors: T
authors: T
authors: Yamada
authors: D
authors: D
authors: Majumdar
authors: S A
authors: SA
authors: Kennedy
authors: C W
authors: CW
authors: Beattie
authors: T K
authors: TK
authors: Das Gupta
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001400:Azurin / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D019055:No-Observed-Adverse-Effect Level; D010446:Peptide Fragments / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D001400:Azurin; C561466:azurin (50-77)