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

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 cy...

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Veröffentlicht in:Neuro-oncology (Charlottesville, Va.) Va.), 2016-09, Vol.18 (9), p.1319-1325
Hauptverfasser: Lulla, Rishi R, Goldman, Stewart, Yamada, Tohru, Beattie, Craig W, Bressler, Linda, Pacini, Michael, Pollack, Ian F, Fisher, Paul Graham, Packer, Roger J, Dunkel, Ira J, Dhall, Girish, Wu, Shengjie, Onar, Arzu, Boyett, James M, Fouladi, Maryam
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container_issue 9
container_start_page 1319
container_title Neuro-oncology (Charlottesville, Va.)
container_volume 18
creator Lulla, Rishi R
Goldman, Stewart
Yamada, Tohru
Beattie, Craig W
Bressler, Linda
Pacini, Michael
Pollack, Ian F
Fisher, Paul Graham
Packer, Roger J
Dunkel, Ira J
Dhall, Girish
Wu, Shengjie
Onar, Arzu
Boyett, James M
Fouladi, Maryam
description 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. 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. 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. This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose.
doi_str_mv 10.1093/neuonc/now047
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Goldman, Stewart ; Yamada, Tohru ; Beattie, Craig W ; Bressler, Linda ; Pacini, Michael ; Pollack, Ian F ; Fisher, Paul Graham ; Packer, Roger J ; Dunkel, Ira J ; Dhall, Girish ; Wu, Shengjie ; Onar, Arzu ; Boyett, James M ; Fouladi, Maryam</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3357-826c951b1eebcdc28a0c1a4b553e74afc0f710c490f928b2fa2b2bb3032e3fdf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Azurin - pharmacokinetics</topic><topic>Azurin - therapeutic use</topic><topic>Central Nervous System Neoplasms - drug therapy</topic><topic>Central Nervous System Neoplasms - metabolism</topic><topic>Central Nervous System Neoplasms - pathology</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Clinical Investigation</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Humans</topic><topic>Male</topic><topic>Maximum Tolerated Dose</topic><topic>Neoplasm Recurrence, Local - drug therapy</topic><topic>Neoplasm Recurrence, Local - metabolism</topic><topic>Neoplasm Recurrence, Local - pathology</topic><topic>Neoplasm Staging</topic><topic>Peptide Fragments - pharmacokinetics</topic><topic>Peptide Fragments - therapeutic use</topic><topic>Prognosis</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Ubiquitination - drug effects</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lulla, Rishi R</creatorcontrib><creatorcontrib>Goldman, Stewart</creatorcontrib><creatorcontrib>Yamada, Tohru</creatorcontrib><creatorcontrib>Beattie, Craig W</creatorcontrib><creatorcontrib>Bressler, Linda</creatorcontrib><creatorcontrib>Pacini, Michael</creatorcontrib><creatorcontrib>Pollack, Ian F</creatorcontrib><creatorcontrib>Fisher, Paul Graham</creatorcontrib><creatorcontrib>Packer, Roger J</creatorcontrib><creatorcontrib>Dunkel, Ira J</creatorcontrib><creatorcontrib>Dhall, Girish</creatorcontrib><creatorcontrib>Wu, Shengjie</creatorcontrib><creatorcontrib>Onar, Arzu</creatorcontrib><creatorcontrib>Boyett, James M</creatorcontrib><creatorcontrib>Fouladi, Maryam</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Neuro-oncology (Charlottesville, Va.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lulla, Rishi R</au><au>Goldman, Stewart</au><au>Yamada, Tohru</au><au>Beattie, Craig W</au><au>Bressler, Linda</au><au>Pacini, Michael</au><au>Pollack, Ian F</au><au>Fisher, Paul Graham</au><au>Packer, Roger J</au><au>Dunkel, Ira J</au><au>Dhall, Girish</au><au>Wu, Shengjie</au><au>Onar, Arzu</au><au>Boyett, James M</au><au>Fouladi, Maryam</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Neuro-oncology (Charlottesville, Va.)</jtitle><addtitle>Neuro Oncol</addtitle><date>2016-09-01</date><risdate>2016</risdate><volume>18</volume><issue>9</issue><spage>1319</spage><epage>1325</epage><pages>1319-1325</pages><issn>1522-8517</issn><eissn>1523-5866</eissn><abstract>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. 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. 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 &gt;4 cycles. This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>27022131</pmid><doi>10.1093/neuonc/now047</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record>
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source Oxford University Press Journals All Titles (1996-Current); MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central
subjects 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
Clinical Investigation
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
title 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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