Abstract
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.
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Acknowledgements
We thank the patients and their families who participated in this trial, Linda Ellison-Dejewski for research nursing support, Natasha Brunson for assistance with data management, Dr. Seth Steinberg for assistance with the statistical design of the study, and Jeff Roth for technical support in the performance of pharmacokinetic assays.
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The authors declare that they have no conflicts of interest relating to this study.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
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Informed consent was obtained from all individual participants included in the study.
Additional information
Patrick J. Grohar and John Glod Co first authors.
Lee J. Helman and Brigitte C. Widemann Co senior authors.
This work was supported in part by the Intramural Research Program of the Center for Cancer Research National Cancer Institute National Institutes of Health.
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Grohar, P.J., Glod, J., Peer, C.J. et al. A phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS–FLI1 fusion transcript. Cancer Chemother Pharmacol 80, 645–652 (2017). https://doi.org/10.1007/s00280-017-3382-x
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DOI: https://doi.org/10.1007/s00280-017-3382-x