Phase I study of panobinostat plus everolimus in patients with relapsed or refractory lymphoma Short title: Panobinostat and everolimus in lymphoma Authors:

250 words, Text: 3718 words # of figures: 4, # of tables: 2 # of references: 25 Corresponding Author: Anas Younes, MD. Lymphoma Service, Memorial Sloan-Kettering Cancer Center 1275 York Avenue, Box 330, New York, NY 10065 email: [email protected], Phone 212-639-5059, Fax: 646-422-2291 Disclosure of Potential Conflict of Interest Y.O. received research funding from Novartis. L.Fayad. received research funding from Novartis. N.F. received research funding from Novartis. A.Y. received research funding and honorarium from Novartis. Other authors declared no conflict of interest. Translational relevance As a class, HDAC inhibitor and PI3K/AKT/mTOR pathway inhibitors have synergy in preclinical studies. In fact, this phase I study shows that the combination therapy of everolimus and panobinostat produced a response rate of 43% in patients with Hodgkin lymphoma, which warrants further investigation of this dualinhibition when compared to the activity ofeach drug as a single agent (27 37%). However, this combination therapy was associated with significant toxicity of thrombocytopenia requiring frequent dose interruptions. Exploratory analysis showed changes of multiple serum cytokine levels after treatment, and that clinical responses were associated with a decrease in serum interleukin-5 levels, warranting further investigation in larger studies. Future studies should investigate different combination regimens of PI3K/AKT/mTOR inhibitors with HDAC inhibitor, incorporating correlative analysis of serum cytokine levels to investigate the clinical relevance. on April 4, 2017. © 2013 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on October 4, 2013; DOI: 10.1158/1078-0432.CCR-13-1906