p28 is a cell-penetrating peptide that crosses the blood brain barrier, preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination. The decrease in ubiquitination results in increased levels of p53 and induction of cell cycle arrest at G2/M. Patients aged 3–19 years with recurrent or progressive central nervous system tumors received p28 at the adult recommended phase 2 dose. Seven of 12 evaluable participants received ≥ 2 cycles (12 weeks) of p28 with the most common adverse event attributed to the drug a transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults. Three (of 12; 25%) participants remained stable disease (SD) on the study; two for > 5 cycles (30 weeks) demonstrating that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase 2 dose.