A phase I study of panobinostat in children with relapsed and refractory hematologic malignancies Journal Article


Authors: Goldberg, J.; Sulis, M. L.; Bender, J.; Jeha, S.; Gardner, R.; Pollard, J.; Aquino, V.; Laetsch, T.; Winick, N.; Fu, C.; Marcus, L.; Sun, W.; Verma, A.; Burke, M.; Ho, P.; Manley, T.; Mody, R.; Tcheng, W.; Thomson, B.; Park, J.; Sposto, R.; Messinger, Y.; Hijiya, N.; Gaynon, P.; Barredo, J.
Article Title: A phase I study of panobinostat in children with relapsed and refractory hematologic malignancies
Abstract: Background: Panobinostat demonstrates activity against pediatric cancers in vitro. A phase I trial in children with refractory hematologic malignancies was conducted. Study design: The trial evaluated two schedules of oral panobinostat using 3 + 3 dose escalations in 28-day cycles. For children with leukemia, panobinostat was given once daily three days a week each week at 24, 30 and 34 mg/m2/day. For children with lymphoma, panobinostat was given once daily three days a week every other week at 16, 20 and 24 mg/m2/day. Cerebrospinal fluid (CSF) from Day 29 of the first cycle, when available, was evaluated for PK. The study was registered on clinicaltrials.gov (NCT01321346) Results: Twenty-two subjects enrolled with leukemia. Five enrolled at dose level 1, 6 at dose level 2, and 11 at dose level 3. There was one dose limiting toxicity (DLT) in the leukemia arm at dose level 3 (Grade 4 hypertriglyceridemia), but no maximum tolerated dose (MTD) was identified. No subjects required removal from protocol therapy for QTc prolongation. PK studies were available in 11 subjects with similar exposure in children as in adults. Four Day 29 CSF specimens were found to have panobinostat levels below the lower limit of quantification. Five subjects with lymphoma were enrolled and received study drug, and 4 were evaluable for DLT. A DLT was reported (Grade 3 enteritis) on the lymphoma arm. Conclusions: Panobinostat was tolerated in heavily pretreated pediatric subjects. Gastrointestinal effects were observed on this study. There were no cardiac findings. There were no responses. © 2020 Taylor & Francis Group, LLC.
Keywords: child; clinical article; human tissue; treatment response; drug tolerability; cancer recurrence; diarrhea; drug safety; hypophosphatemia; monotherapy; bortezomib; multiple cycle treatment; neutrophil count; anemia; clinical assessment; cohort analysis; abdominal pain; drug dose escalation; febrile neutropenia; hypoxia; alanine aminotransferase; alkaline phosphatase; bilirubin; gastrointestinal toxicity; hypokalemia; acute leukemia; cerebrospinal fluid; multicenter study; lymphoma; clinical evaluation; nausea and vomiting; enteritis; loperamide; leukocyte count; maximum tolerated dose; phase 1 clinical trial; methadone; panobinostat; aspergillosis; hypertriglyceridemia; lymphocyte count; drug exposure; platelet count; triacylglycerol lipase; acute leukemias; pharmacokinetic parameters; human; article; oncology (target therapy); phase i/ii studies
Journal Title: Pediatric Hematology and Oncology
Volume: 37
Issue: 6
ISSN: 0888-0018
Publisher: Taylor & Francis Group  
Date Published: 2020-01-01
Start Page: 465
End Page: 474
Language: English
DOI: 10.1080/08880018.2020.1752869
PUBMED: 32338562
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 1 October 2020 -- Source: Scopus
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  1. Maria Luisa Sulis
    26 Sulis