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Neuro Oncol. 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.

Author information

1
Division of Hematology, Oncology, Neuro-Oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago and Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois (R.R.L., S.G.); Division of Surgical Oncology, Department of Surgery, University of Illinois College of Medicine, Chicago, Illinois (T.Y., C.W.B.); Pharmacy Investigational Drug Service, University of Illinois Hospital and Health Sciences System, University of Illinois College of Pharmacy, Chicago, Illinois (L.B., M.P.); Department of Neurosurgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (I.F.P.); Departments of Neurology, Pediatrics, Neurosurgery, and Human Biology, Stanford University, Palo Alto, California (P.G.F.); Center for Neuroscience and Behavioral Medicine, Brain Tumor Institute, Children's National Health System, Department of Neurology and Pediatrics, The George Washington University, Washington, DC (R.J.P.); Memorial Sloan Kettering Cancer Center, Department of Pediatrics, Weill Cornell Medical College, New York, New York (I.J.D.); Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California (G.D.); Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee (S.W., A.O., J.M.B.); Department of Hematology-Oncology, Cincinnati Children's Hospital Medical Center, Neuro-Oncology Program, Cincinnati, Ohio (M.F.) rlulla@luriechildrens.org.
2
Division of Hematology, Oncology, Neuro-Oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago and Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois (R.R.L., S.G.); Division of Surgical Oncology, Department of Surgery, University of Illinois College of Medicine, Chicago, Illinois (T.Y., C.W.B.); Pharmacy Investigational Drug Service, University of Illinois Hospital and Health Sciences System, University of Illinois College of Pharmacy, Chicago, Illinois (L.B., M.P.); Department of Neurosurgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (I.F.P.); Departments of Neurology, Pediatrics, Neurosurgery, and Human Biology, Stanford University, Palo Alto, California (P.G.F.); Center for Neuroscience and Behavioral Medicine, Brain Tumor Institute, Children's National Health System, Department of Neurology and Pediatrics, The George Washington University, Washington, DC (R.J.P.); Memorial Sloan Kettering Cancer Center, Department of Pediatrics, Weill Cornell Medical College, New York, New York (I.J.D.); Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California (G.D.); Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee (S.W., A.O., J.M.B.); Department of Hematology-Oncology, Cincinnati Children's Hospital Medical Center, Neuro-Oncology Program, Cincinnati, Ohio (M.F.).

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.

PMID:
27022131
PMCID:
PMC4999001
DOI:
10.1093/neuonc/now047
[Indexed for MEDLINE]
Free PMC Article

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