Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2023 Dec 8;25(12):2262-2272.
doi: 10.1093/neuonc/noad141.

Phase I trial of panobinostat in children with diffuse intrinsic pontine glioma: A report from the Pediatric Brain Tumor Consortium (PBTC-047)

Michelle Monje  1 , Tabitha Cooney  2 , John Glod  3 , Jie Huang  4 , Cody J Peer  5 , Damien Faury  6 , Patricia Baxter  7 , Kim Kramer  8 , Alicia Lenzen  9 , Nathan J Robison  10 , Lindsay Kilburn  11 , Anna Vinitsky  4 , William D Figg  5 , Nada Jabado  6 , Maryam Fouladi  12 , Jason Fangusaro  13 , Arzu Onar-Thomas  4 , Ira J Dunkel  8 , Katherine E Warren  2   3
Affiliations
Clinical Trial

Phase I trial of panobinostat in children with diffuse intrinsic pontine glioma: A report from the Pediatric Brain Tumor Consortium (PBTC-047)

Michelle Monje et al. Neuro Oncol. .

Abstract

Background: Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood cancer with median survival of less than 1 year. Panobinostat is an oral multihistone deacetylase inhibitor with preclinical activity in DIPG models. Study objectives were to determine safety, tolerability, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of panobinostat in children with DIPG.

Patients and methods: In stratum 1, panobinostat was administered 3 days per week for 3 weeks on, 1 week off to children with progressive DIPG, with dose escalation following a two-stage continual reassessment method. After this MTD was determined, the study was amended to evaluate the MTD in children with nonprogressive DIPG/Diffuse midline glioma (DMG) (stratum 2) on an alternate schedule, 3 days a week every other week in an effort to escalate the dose.

Results: For stratum 1, 19 subjects enrolled with 17/19 evaluable for dose-finding. The MTD was 10 mg/m2/dose. Dose-limiting toxicities included thrombocytopenia and neutropenia. Posterior reversible encephalopathy syndrome was reported in 1 patient. For stratum 2, 34 eligible subjects enrolled with 29/34 evaluable for dose finding. The MTD on this schedule was 22 mg/m2/dose. DLTs included thrombocytopenia, neutropenia, neutropenia with grade 4 thrombocytopenia, prolonged intolerable nausea, and increased ALT.

Conclusions: The MTD of panobinostat is 10 mg/m2/dose administered 3 times per week for 3 weeks on/1 week off in children with progressive DIPG/DMG and 22 mg/m2/dose administered 3 times per week for 1 week on/1 week off when administered in a similar population preprogression. The most common toxicity for both schedules was myelosuppression.

Keywords: DIPG; HDAC inhibitors; brainstem glioma; epigenetics; midline glioma.

PubMed Disclaimer

Conflict of interest statement

Michelle Monje served on the scientific advisory board for Cygnal Therapeutics and her family holds equity in Maplight Therapeutics; Ira J. Dunkel serves on the advisory board for AstraZeneca and Bristol Meyers Squibb and is a consultant for DAY One Therapeutics, Fennel, Glaxo Smith Kline, Pyramid and QED; Jason Fangusaro serves on the advisory board for Alexion/AstraZeneca and Merck; Katherine E. Warren serves on the advisory board for DAY One Therapeutics and Glaxo Smith Kline. All other authors have nothing to disclose.

Figures

Figure 1.
Figure 1.
Mean log concentration of panobinostat versus time by dose level.
Figure 2.
Figure 2.
Dose proportional increases in panobinostat CMAX with absolute dose (mg).
Figure 3.
Figure 3.
Dose Proportional increases in panobinostat AUCLAST with absolute dose (mg).
See this image and copyright information in PMC

References

    1. Wu G, Broniscer A, McEachron T, et al. . Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet. 2012;44(3):251–253. - PMC - PubMed
    1. Schwartzentruber J, Korshunov A, Liu X, et al. . Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482(7384):226–231. - PubMed
    1. Khuong-Quang D, Buczkowicz P, Rakopoulos P, et al. . K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropath. 2012;124(3):439–447. - PMC - PubMed
    1. Louis D, Perry A, Wesseling P, et al. . The 2021 WHO Classification of tumors of the central nervous system: a summary. Neuro Oncol. 2021;23(8):1231–1251. - PMC - PubMed
    1. Jansen M, van Vuurden D, Vandertop W, Kaspers G.. Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology. Cancer Treat Rev. 2012;38(1):27–35. - PubMed

Publication types