1. Safety, pharmacokinetics, and pharmacodynamics of panobinostat in children, adolescents, and young adults with relapsed acute myeloid leukemia
- Author
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Karol, Seth E, Cooper, Todd M, Mead, Paul E, Crews, Kristine R, Panetta, John C, Alexander, Thomas B, Taub, Jeffrey W, Lacayo, Norman J, Heym, Kenneth M, Kuo, Dennis J, Schiff, Deborah E, Bhojwani, Deepa, Ge, Yubin, Klco, Jeffery M, Ribeiro, Raul C, Inaba, Hiroto, Pui, Ching-Hon, and Rubnitz, Jeffrey E
- Subjects
Adult ,Male ,Myeloid ,Pediatric Research Initiative ,Adolescent ,Pediatric Cancer ,Childhood Leukemia ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Acute ,acute myeloid leukemia ,Young Adult ,Rare Diseases ,Clinical Research ,Panobinostat ,Genetics ,Humans ,Oncology & Carcinogenesis ,Child ,childhood ,Cancer ,relapse ,Pediatric ,Leukemia ,Evaluation of treatments and therapeutic interventions ,Hematology ,Neoplasm Recurrence ,Local ,6.1 Pharmaceuticals ,Public Health and Health Services ,Female - Abstract
BackgroundNovel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML).MethodsTo determine whether the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, a phase 1 trial was performed in which 17 pediatric patients with relapsed or refractory AML received panobinostat (10, 15, or 20 mg/m2 ) before and in combination with fludarabine and cytarabine.ResultsAll dose levels were tolerated, with no dose-limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the 9 patients who had sufficient (>2%) circulating blasts on which histone acetylation studies could be performed, 7 demonstrated at least 1.5-fold increases in acetylation. Although no patients had a decrease in circulating blasts after single-agent panobinostat, 8 of the 17 patients (47%), including 5 of the 6 patients treated at dose level 3, achieved complete remission. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status.ConclusionsPanobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation. This suggests that it should be further studied in AML.
- Published
- 2020