A phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS-FLI1 fusion transcript.
Purpose: In a preclinical drug screen, mithramycin was identified as a potent inhibitor of the Ewing sarcoma EWS-FLI1 transcription factor. We conducted a phase I/II trial to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of mithramycin in child...
| Publicado en: | Cancer Chemotherapy & Pharmacology Vol. 80; no. 3; pp. 645 - 653 |
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| Autores principales: | , , , , , , , , , , , , , , , , |
| Formato: | clinical trial research tables/charts Journal Article |
| Publicado: |
Springer Nature
Sep2017
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=124846270&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 124846270 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 03445704 NO9 jtl: Cancer Chemotherapy & Pharmacology issn: 03445704 maglogo: N pubinfo: dt: Sep2017 vid: 80 iid: 3 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 124846270 124846270 144086382 NLM28735378 124846270 10.1007/s00280-017-3382-x NLM28735378 124846270 ppf: 645 ppct: 8 formats: tig: atl: A phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS-FLI1 fusion transcript. aug: au: Grohar, Patrick Glod, John Peer, Cody Sissung, Tristan Arnaldez, Fernanda Long, Lauren Figg, William Whitcomb, Patricia Helman, Lee Widemann, Brigitte Grohar, Patrick J Peer, Cody J Sissung, Tristan M Arnaldez, Fernanda I Figg, William D Helman, Lee J Widemann, Brigitte C affil: Pediatric Oncology Branch, Center for Cancer Research , National Cancer Institute , Bethesda USA sug: subj: Aminoglycosides Therapeutic Use Osteosarcoma Drug Therapy Proteins Metabolism Antibiotics, Antineoplastic Therapeutic Use Female Adolescence Human Child Antibiotics, Antineoplastic Pharmacokinetics Male Aminoglycosides Pharmacokinetics Adult Young Adult Osteosarcoma Pathology Clinical Trials Validation Studies Comparative Studies Evaluation Research Multicenter Studies Adolescent: 13-18 years Child: 6-12 years Adult: 19-44 years Female Male ab: Purpose: In a preclinical drug screen, mithramycin was identified as a potent inhibitor of the Ewing sarcoma EWS-FLI1 transcription factor. We conducted a phase I/II trial to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of mithramycin in children with refractory solid tumors, and the activity in children and adults with refractory Ewing sarcoma.Patients and Methods: Mithramycin was administered intravenously over 6 h once daily for 7 days for 28 day cycles. Adult patients (phase II) initially received mithramycin at the previously determined recommended dose of 25 µg/kg/dose. The planned starting dose for children (phase I) was 17.5 µg/kg/dose. Plasma samples were obtained for mithramycin PK analysis.Results: The first two adult patients experienced reversible grade 4 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation exceeding the MTD. Subsequent adult patients received mithramycin at 17.5 µg/kg/dose, and children at 13 µg/kg/dose with dexamethasone pretreatment. None of the four subsequent adult and two pediatric patients experienced cycle 1 DLT. No clinical responses were observed. The average maximal mithramycin plasma concentration in four patients was 17.8 ± 4.6 ng/mL. This is substantially below the sustained mithramycin concentrations ≥50 nmol/L required to suppress EWS-FLI1 transcriptional activity in preclinical studies. Due to inability to safely achieve the desired mithramycin exposure, the trial was closed to enrollment.Conclusions: Hepatotoxicity precluded the administration of a mithramycin at a dose required to inhibit EWS-FLI1. Evaluation of mithramycin in patients selected for decreased susceptibility to elevated transaminases may allow for improved drug exposure. pubtype: Academic Journal doctype: clinical trial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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