Phase I trial of p28 (NSC745104), a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in pediatric patients with recurrent or progressive central nervous system tumors: A Pediatric Brain Tumor Consortium Study

Neuro Oncol. 2016 Sep;18(9):1319-25. doi: 10.1093/neuonc/now047. Epub 2016 Mar 28.


Background: p53 is a promising target in human cancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G2/M. We conducted a phase I study to determine the maximum-tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) and pharmacokinetics (PKs) of p28 in children.

Methods: Children aged 3-21 years with recurrent or progressive central nervous system tumors were eligible. Intravenous p28 was administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult recommended phase II dose) using a rolling-6 study design. Expression status of p53 was characterized by immunohistochemistry, and serum PK parameters were established on the second dose.

Results: Of the 18 eligible patients enrolled in the study, 12 completed the DLT monitoring period and were evaluable for toxicity. p28 was well-tolerated; 7 participants received ≥2 courses, and the most common adverse event attributed to the drug was transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults; however, an increased area under the curve was observed in pediatric patients. High p53 expression in tumor cell nuclei was observed in 6 of 12 available tissue samples. There were no objective responses; 2 participants remained stable on the study for >4 cycles.

Conclusions: This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose.

Keywords: azurin; central nervous system tumors; p28; pediatric; phase I..

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adolescent
  • Adult
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Azurin / pharmacokinetics
  • Azurin / therapeutic use*
  • Central Nervous System Neoplasms / drug therapy*
  • Central Nervous System Neoplasms / metabolism
  • Central Nervous System Neoplasms / pathology
  • Child
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Staging
  • Peptide Fragments / pharmacokinetics
  • Peptide Fragments / therapeutic use*
  • Prognosis
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitination / drug effects*
  • Young Adult


  • Antineoplastic Agents
  • Peptide Fragments
  • Tumor Suppressor Protein p53
  • Azurin
  • azurin (50-77)