Abstract
Panobinostat is a potent oral pandeacetylase inhibitor that leads to acetylation of intracellular proteins, inhibits cellular proliferation and induces apoptosis in leukemic cell lines. A phase Ia/II study was designed to determine the maximum-tolerated dose (MTD) of daily panobinostat, administered on two schedules: three times a week every week or every other week on a 28-day treatment cycle in patients with advanced hematologic malignancies. The criteria for hematologic dose-limiting toxicities differed between patients with indications associated with severe cytopenias at baseline (leukemia and myeloid disorders) and those less commonly associated with baseline cytopenias (lymphoma and myeloma). In patients with leukemia and myeloid disorders, 60 mg was the MTD for weekly as well as biweekly panobinostat. In patients with lymphoma and myeloma, 40 mg was the recommended dose for phase II evaluation (formal MTD not determined) of weekly panobinostat, and 60 mg was the MTD for biweekly panobinostat. Overall, panobinostat-related grade 3–4 adverse events included thrombocytopenia (41.5%), fatigue (21%) and neutropenia (21%). Single-agent activity was observed in several indications, including Hodgkin lymphoma and myelofibrosis. This phase Ia/II study provided a broad analysis of the safety profile and efficacy of single-agent panobinostat in patients with hematologic malignancies.
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Acknowledgements
Oliver G Ottmann is an endowed professor of the German Jose Carreras Leukemia Foundation. Financial support for this study was provided by Novartis Pharmaceuticals. We thank William Fazzone, PhD, for medical editorial assistance with this manuscript and Tracy Liu, Hannah Mosca and Glen Laird for assistance with data collection and analysis.
Author contributions
PA, KB, DJD, TF, FJG, AL, OGO, HMP and JWS designed research; PA, KB, DJD, TF, FJG, TK, OGO, HMP, AS and MW performed research; PA contributed new analytical tools; KB, DJD, TF, FJG, TK, OGO, HMP and AS collected data; and KM performed statistical analyses. All authors analyzed and interpreted the data and approved the final manuscript.
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TK: nothing to disclose; KB: Novartis research funding and honoraria; DJD: Novartis consultancy; TF: Novartis honoraria; FJG: Novartis consultancy and research funding; OGO: Novartis consultancy, research funding, honoraria and advisory committee; HMP: Novartis research funding, honoraria, speakers bureau and advisory committee; AS: Novartis research funding, honoraria and speakers bureau; PA, AL, KM, KP, JWS and MW: Novartis employment; and MW: Novartis equity ownership.
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DeAngelo, D., Spencer, A., Bhalla, K. et al. Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies. Leukemia 27, 1628–1636 (2013). https://doi.org/10.1038/leu.2013.38
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DOI: https://doi.org/10.1038/leu.2013.38
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