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A phase I study of panobinostat in pediatric patients with refractory solid tumors, including CNS tumors

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Abstract

Purpose

This was an open label, phase I (3 + 3 design), multi-centre study evaluating panobinostat in pediatric patients with refractory solid tumors.

Methods

Primary endpoints were to establish MTD, define and describe associated toxicities, including dose limiting toxicities (DLT) and to characterize its pharmacokinetics (PK). Secondary endpoints included assessing the anti-tumour activity of panobinostat, and its biologic activity, by measuring acetylation of histones in peripheral blood mononuclear cells.

Results

Nine patients were enrolled and treated with intravenous panobinostat at a dosing level of 15 mg/m2 which was tolerated. Six were evaluable for adverse events. Two (33%) patients experienced Grade 3–4 thrombocytopenia, 1 (17%) experienced Grade 3 anemia, and 2 (33%) experienced Grade 3 neutropenia. Grade 4 drug related pain occurred in 2 (33%) of the patients studied. Two (33%) patients experienced a Grade 2 QTcF change (0.478 ± 0.006 ms). One cardiac DLT (T wave changes) was reported. PK values for 15 mg/m2 (n = 9) dosing were: Tmax 0.8 h, Cmax 235.2 ng/mL, AUC0–t 346.8 h ng/mL and t1/2 7.3 h. Panobinostat significantly induced acetylation of histone H3 and H4 at all time points measured when compared to pre-treatment samples (p < 0.05). Pooled quantitative Western blot data confirmed that panobinostat significantly induced acetylation of histone H4 at 6 h (p < 0.01), 24 h (p < 0.01) and 28–70 h (p < 0.01) post dose.

Conclusion

A significant biological effect of panobinostat, measured by acetylation status of histone H3 and H4, was achieved at a dose of 15 mg/m2. PK data and drug tolerability at 15 mg/m2 was similar to that previously published.

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Acknowledgements

This research would not have been possible without the generous support of the You Are My Sunshine (YAMS) Foundation and the Kathleen Tinsley Fellowship.

Funding

This trial was sponsored by the Australian and New Zealand Children’s Haematology and Oncology Group (ANZCHOG), 27 - 31 Wright Street, Clayton, VIC, 3168, Australia. This trial was supported by unrestricted funding and drug supply from Novartis Pharmaceuticals, Australia PTY Ltd., 54 Waterloo Road, Macquarie Park, NSW, 2113, Australia.

Author information

Authors and Affiliations

  1. Department of Paediatrics, Monash University, Melbourne, Australia

    Paul J. Wood

  2. Children’s Cancer Centre, Monash Children’s Hospital, Melbourne, Australia

    Paul J. Wood

  3. Molecular Oncology and Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia

    Paul J. Wood & Grant A. McArthur

  4. Australian & New Zealand Children’s Haematology/Oncology Group (ANZCHOG), Melbourne, Australia

    Robyn Strong

  5. Department of Medicine, St. Vincent’s Hospital, Melbourne, Australia

    Grant A. McArthur

  6. Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia

    Michael Michael

  7. Monash University, Melbourne, Australia

    Elizabeth Algar

  8. Hudson Institute of Medical Research, Melbourne, Australia

    Elizabeth Algar

  9. Deakin University, School of Medicine, Geelong, Australia

    Andrea Muscat & Melissa Ferguson

  10. Murdoch Children’s Research Institute, Melbourne, Australia

    Lin Rigby

  11. The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA

    David M. Ashley

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  1. Paul J. Wood
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Correspondence to Paul J. Wood.

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The authors report no conflict of interest.

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.

Human and animal rights statement

This article does not contain any studies with animals performed by any of the authors.

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Patient and/or their legal guardians must have signed a written informed consent form.

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Wood, P.J., Strong, R., McArthur, G.A. et al. A phase I study of panobinostat in pediatric patients with refractory solid tumors, including CNS tumors. Cancer Chemother Pharmacol 82, 493–503 (2018). https://doi.org/10.1007/s00280-018-3634-4

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  • DOI: https://doi.org/10.1007/s00280-018-3634-4

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