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Title: | A phase I study of panobinostat in pediatric patients with refractory solid tumors, including CNS tumors. | Authors: | Ferguson M.;Ashley D.M.;Wood P.J.;Strong R.;McArthur G.A.;Michael M.;Algar E.;Muscat A.;Rigby L. | Institution: | (Wood) Department of Paediatrics, Monash University, Melbourne, Australia (Wood) Children's Cancer Centre, Monash Children's Hospital, Melbourne, Australia (Wood, McArthur) Molecular Oncology and Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia (Strong) Australian & New Zealand Children's Haematology/Oncology Group (ANZCHOG), Melbourne, Australia (McArthur) Department of Medicine, St. Vincent's Hospital, Melbourne, Australia (Michael) Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia (Algar) Monash University, Melbourne, Australia (Algar) Hudson Institute of Medical Research, Melbourne, Australia (Muscat, Ferguson) Deakin University, School of Medicine, Geelong, Australia (Rigby) Murdoch Children's Research Institute, Melbourne, Australia (Ashley) The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, United States | Issue Date: | 30-Aug-2018 | Copyright year: | 2018 | Publisher: | Springer Verlag (E-mail: service@springer.de) | Place of publication: | Germany | Publication information: | Cancer Chemotherapy and Pharmacology. 82 (3) (pp 493-503), 2018. Date of Publication: 01 Sep 2018. | Journal: | Cancer Chemotherapy and Pharmacology | Abstract: | Purpose: This was an open label, phase I (3 + 3 design), multi-centre study evaluating panobinostat in pediatric patients with refractory solid tumors. Method(s): 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. Result(s): 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(s): 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.Copyright © 2018, Springer-Verlag GmbH Germany, part of Springer Nature. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1007/s00280-018-3634-4 | ORCID: | Wood, Paul J.; ORCID: http://orcid.org/0000-0003-1383-3450 | Link to associated publication: | Click here for full text options | PubMed URL: | 29987369 [http://www.ncbi.nlm.nih.gov/pubmed/?term=29987369] | ISSN: | 0344-5704 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/37032 | Type: | Article | Subjects: | comparative study constipation/si [Side Effect] controlled study coughing/si [Side Effect] diarrhea/si [Side Effect] drug tolerability dyspnea/si [Side Effect] electrocardiogram ependymoma/di [Diagnosis] ependymoma/dt [Drug Therapy] facial nerve disease/si [Side Effect] fatigue/si [Side Effect] gait disorder/si [Side Effect] headache/si [Side Effect] heart arrhythmia/si [Side Effect] heart supraventricular arrhythmia/si [Side Effect] histone acetylation human hydrocephalus/si [Side Effect] infection complication/si [Side Effect] insomnia/si [Side Effect] leukocyte count limb pain/si [Side Effect] limb weakness/si [Side Effect] lymphocyte count magnesium blood level male maximum tolerated dose medulloblastoma/di [Diagnosis] medulloblastoma/dt [Drug Therapy] multicenter study muscle weakness/si [Side Effect] musculoskeletal disease/si [Side Effect] nausea/si [Side Effect] neck pain/si [Side Effect] nephroblastoma/di [Diagnosis] nephroblastoma/dt [Drug Therapy] neuroblastoma/di [Diagnosis] neuroblastoma/dt [Drug Therapy] neutropenia/si [Side Effect] neutrophil count nystagmus/si [Side Effect] pediatrics peripheral blood mononuclear cell personal experience pharmacokinetic parameters phase 1 clinical trial platelet count potassium blood level priority journal rhabdomyosarcoma/di [Diagnosis] rhabdomyosarcoma/dt [Drug Therapy] school child seizure/si [Side Effect] side effect/si [Side Effect] sinus arrhythmia/si [Side Effect] skin disease/si [Side Effect] sodium blood level *solid malignant neoplasm/di [Diagnosis] *solid malignant neoplasm/dt [Drug Therapy] stomach pain/si [Side Effect] supraventricular tachycardia/si [Side Effect] thrombocytopenia/si [Side Effect] time to maximum plasma concentration time to treatment urine retention/si [Side Effect] visual disorder/si [Side Effect] vomiting/si [Side Effect] Western blotting wound dehiscence/si [Side Effect] alanine aminotransferase/ec [Endogenous Compound] albumin/ec [Endogenous Compound] aspartate aminotransferase/ec [Endogenous Compound] bicarbonate/ec [Endogenous Compound] bilirubin/ec [Endogenous Compound] creatine kinase/ec [Endogenous Compound] creatinine/ec [Endogenous Compound] dexamethasone hemoglobin/ec [Endogenous Compound] histone H3/ec [Endogenous Compound] histone H4/ec [Endogenous Compound] magnesium/ec [Endogenous Compound] *panobinostat/ae [Adverse Drug Reaction] *panobinostat/ct [Clinical Trial] *panobinostat/dt [Drug Therapy] *panobinostat/iv [Intravenous Drug Administration] *panobinostat/pk [Pharmacokinetics] *panobinostat/pd [Pharmacology] potassium/ec [Endogenous Compound] sodium/ec [Endogenous Compound] hypokalemia/si [Side Effect] female fever/si [Side Effect] fracture/si [Side Effect] abdominal pain/si [Side Effect] abnormal laboratory result adverse drug reaction alkalosis/si [Side Effect] alopecia/si [Side Effect] anemia/si [Side Effect] antineoplastic activity apnea/si [Side Effect] area under the curve article ataxia/si [Side Effect] body weight loss cancer pain/si [Side Effect] *central nervous system tumor/di [Diagnosis] *central nervous system tumor/dt [Drug Therapy] child clinical article clinical evaluation child clinical article clinical evaluation comparative study constipation / side effect controlled study coughing / side effect diarrhea / side effect drug tolerability dyspnea / side effect electrocardiogram ependymoma / diagnosis / drug therapy facial nerve disease / side effect fatigue / side effect female fever / side effect fracture / side effect gait disorder / side effect headache / side effect heart arrhythmia / side effect heart supraventricular arrhythmia / side effect histone acetylation human hydrocephalus / side effect hypokalemia / side effect infection complication / side effect insomnia / side effect leukocyte count limb pain / side effect limb weakness / side effect lymphocyte count magnesium blood level male maximum tolerated dose medulloblastoma / diagnosis / drug therapy multicenter study muscle weakness / side effect musculoskeletal disease / side effect nausea / side effect neck pain / side effect nephroblastoma / diagnosis / drug therapy neuroblastoma / diagnosis / drug therapy neutropenia / side effect neutrophil count nystagmus / side effect pediatrics peripheral blood mononuclear cell personal experience pharmacokinetic parameters phase 1 clinical trial platelet count potassium blood level alopecia / side effect rhabdomyosarcoma / diagnosis / drug therapy school child seizure / side effect side effect / side effect sinus arrhythmia / side effect skin disease / side effect sodium blood level *solid malignant neoplasm / *diagnosis / *drug therapy stomach pain / side effect supraventricular tachycardia / side effect thrombocytopenia / side effect time to maximum plasma concentration time to treatment urine retention / side effect visual disorder / side effect vomiting / side effect Western blotting wound dehiscence / side effect alkalosis / side effect adverse drug reaction abnormal laboratory result abdominal pain / side effect priority journal anemia / side effect antineoplastic activity apnea / side effect area under the curve Article ataxia / side effect body weight loss cancer pain / side effect *central nervous system tumor / *diagnosis / *drug therapy |
Type of Clinical Study or Trial: | Clinical trial |
Appears in Collections: | Articles |
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