Phase I trial of panobinostat in children with diffuse intrinsic pontine glioma: A report from the Pediatric Brain Tumor Consortium (PBTC-047) Journal Article
| Authors: | Monje, M.; Cooney, T.; Glod, J.; Huang, J.; Peer, C. J.; Faury, D.; Baxter, P.; Kramer, K.; Lenzen, A.; Robison, N. J.; Kilburn, L.; Vinitsky, A.; Figg, W. D.; Jabado, N.; Fouladi, M.; Fangusaro, J.; Onar-Thomas, A.; Dunkel, I. J.; Warren, K. E. |
| Article Title: | Phase I trial of panobinostat in children with diffuse intrinsic pontine glioma: A report from the Pediatric Brain Tumor Consortium (PBTC-047) |
| 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. © 2023 The Author(s). |
| Keywords: | adolescent; adult; child; clinical article; human tissue; overall survival; clinical trial; drug tolerability; neutropenia; diarrhea; drug safety; drug withdrawal; brain tumor; glioma; progression free survival; bone marrow suppression; nausea; thrombocytopenia; antineoplastic activity; pathology; histology; childhood cancer; drug dose escalation; fever; alanine aminotransferase; bilirubin; karnofsky performance status; algorithm; epigenetics; histone h3; irradiation; brain disease; radiography; hyperbilirubinemia; maximum tolerated dose; phase 1 clinical trial; toxicity; heart left ventricle ejection fraction; brain stem tumor; brain stem neoplasms; neurologic disease; panobinostat; disease exacerbation; heart ventricle arrhythmia; pharmacokinetics; electrolyte disturbance; platelet count; body surface; posterior reversible encephalopathy syndrome; hypertransaminasemia; demographics; limit of detection; liquid chromatography-mass spectrometry; posterior leukoencephalopathy syndrome; hdac inhibitors; interdisciplinary research; diffuse intrinsic pontine glioma; dipg; pontine glioma; bleeding disorder; preclinical study; microfluidic analysis; humans; human; male; female; article; median survival time; absolute neutrophil count; brainstem glioma; qtc interval; circulating free dna; midline glioma; pediatric brain tumor consortium |
| Journal Title: | Neuro-Oncology |
| Volume: | 25 |
| Issue: | 12 |
| ISSN: | 1522-8517 |
| Publisher: | Oxford University Press |
| Date Published: | 2023-12-01 |
| Start Page: | 2262 |
| End Page: | 2272 |
| Language: | English |
| DOI: | 10.1093/neuonc/noad141 |
| PUBMED: | 37526549 |
| PROVIDER: | scopus |
| PMCID: | PMC10708931 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF -- Source: Scopus |
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