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Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study

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Abstract

Purpose

Amplification and high levels of NOTCH ligand expression have been identified in several types of pediatric brain tumors. A phase I trial of weekly MK-0752, an oral inhibitor of gamma-secretase, was conducted in children with recurrent central nervous system (CNS) malignancies to estimate the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics of weekly MK-0752.

Methods

MK-0752 was administered once weekly at 1000 and 1400 mg/m2 using a rolling-6 design. PK analysis was performed during the first course. NOTCH and HES expression was assessed by immunohistochemistry and Western blot.

Results

Ten eligible patients were enrolled (median age 8.8 years; range 3.1–19.2) with diagnoses of brain stem glioma (n = 3), ependymoma (n = 2), anaplastic astrocytoma (n = 1), choroid plexus carcinoma (n = 2), medulloblastoma (n = 1), and primitive neuroectodermal tumor (n = 1). Nine were evaluable for toxicity. One DLT of fatigue occurred in the six evaluable patients enrolled at 1000 mg/m2/dose. No DLTs were experienced by three patients treated at 1400 mg/m2/dose. Non-dose-limiting grade 3 toxicities included lymphopenia, neutropenia, and anemia. Median number of treatment courses was 2 (range 1–10). Two patients continued on therapy for at least 6 months. The median (range) Cmax of MK-0752 was 88.2 μg/mL (40.6 to 109 μg/mL) and 60.3 μg/mL (59.2 to 91.9 μg/mL) in patients receiving 1000 and 1400 mg/m2/week, respectively. NOTCH expression was decreased in six of seven patients for whom tissue was available at 24 h post-MK-0752.

Conclusion

MK-0752 is well tolerated and exhibits target inhibition at 1000 and 1400 mg/m2/week in children with recurrent CNS malignancies.

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Acknowledgments

This study was funded in part by the National Institutes of Health Grant No. U01 CA81457 for the Pediatric Brain Tumor Consortium and by the American Lebanese Syrian Associated Charities. Maryam Fouladi received research funding by Merck.

Compliance with ethical standards

ᅟ

Informed consent

Informed consent was obtained from all individual participants included in the study.

Ethical approval

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.

Author information

Authors and Affiliations

  1. Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA

    Lindsey M. Hoffman, Maryam Fouladi & Lars Wagner

  2. Seattle Children’s Hospital, Seattle, WA, USA

    James Olson

  3. St. Jude Children’s Research Hospital, Memphis, TN, USA

    Vinay M. Daryani, Clinton F. Stewart, Cynthia Wetmore, Arzu Onar-Thomas, Amar Gajjar, Larry E. Kun, James M. Boyett & Richard J. Gilbertson

  4. Children’s National Medical Center, Washington, DC, USA

    Roger J. Packer

  5. Duke University Medical Center, Durham, NC, USA

    Sridharan Gururangan

  6. Texas Children’s Hospital, Houston, TX, USA

    Susan M. Blaney

  7. The University of Tennessee Health Sciences Center, Memphis, TN, USA

    Mehmet Kocak

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  1. Lindsey M. Hoffman
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  2. Maryam Fouladi
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Corresponding author

Correspondence to Lindsey M. Hoffman.

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Hoffman, L.M., Fouladi, M., Olson, J. et al. Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study. Childs Nerv Syst 31, 1283–1289 (2015). https://doi.org/10.1007/s00381-015-2725-3

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  • DOI: https://doi.org/10.1007/s00381-015-2725-3

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