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

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

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Free PMC article
Clinical Trial

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

Rishi R Lulla et al. Neuro Oncol. .
Free PMC article

Abstract

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..

Figures

Fig. 1.
Fig. 1.
p28 Mechanism of antitumor action. p28 binds with high affinity to the p53 DNA binding domain blocking COP1-mediated proteasomal degradation of p53. The posttranslational increase in the level and activity of p53 regulates the activity of the downstream genes, p21, p27 and FoxM1, leading to inhibition of the cancer cell cycle at G2/M and subsequent apoptosis.
Fig. 2.
Fig. 2.
(A) Individual participant p28 serum concentration. Plots of p28 concentration versus time in pediatric patients receiving 4.16 mg/kg of p28. Serum samples were applied to liquid chromatography-tandem mass spectrometry and p28 concentration was determined from the elution profiles. (B) Concentration profiles of p28. p28 concentration versus time profiles of 16 pediatric patients (red) and 7 adult patients (blue) receiving 4.16 mg/kg dose.

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