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
| Autor: | Rishi Lulla, Paul G. Fisher, Craig W. Beattie, Shengjie Wu, Girish Dhall, Arzu Onar, Roger J. Packer, Stewart Goldman, Tohru Yamada, Maryam Fouladi, Ira J. Dunkel, Michael J. Pacini, Linda R. Bressler, Ian F. Pollack, James M. Boyett |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology Adult Male Cancer Research medicine.medical_specialty Pathology Pediatric Brain Tumor Consortium Adolescent Maximum Tolerated Dose Antineoplastic Agents Central Nervous System Neoplasms 03 medical and health sciences Young Adult 0302 clinical medicine Pharmacokinetics Azurin Internal medicine medicine Humans Clinical Investigation Young adult Adverse effect Child Neoplasm Staging Dose-Response Relationship Drug business.industry Area under the curve Ubiquitination Prognosis Peptide Fragments 030104 developmental biology 030220 oncology & carcinogenesis Child Preschool Cancer cell Toxicity Immunohistochemistry Female Neurology (clinical) Neoplasm Recurrence Local Tumor Suppressor Protein p53 business Follow-Up Studies |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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