Phase i study of panobinostat plus everolimus in patients with relapsed or refractory lymphoma

Yasuhiro Oki, Daniela Buglio, Michelle Fanale, Luis Fayad, Amanda Copeland, Jorge Romaguera, Larry W. Kwak, Barbara Pro, Silvana De Castro Faria, Sattva Neelapu, Nathan Fowler, Fredrick Hagemeister, Jiexin Zhang, Shouhao Zhou, Lei Feng, Anas Younes

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

Purpose: To evaluate the safety and efficacy of panobinostat plus everolimus in patients with relapsed Hodgkin and non-Hodgkin lymphoma. The concept was supported by the single-agent clinical activity of histone deacetylase inhibitors and mTOR inhibitors, and on the in vitro mechanism-based synergistic antiproliferative activity. Experimental Design: This was a phase I study in patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma using panobinostat orally on Monday/Wednesday/Friday and everolimus orally daily. Toxicity and responses were assessed in dose-escalation cohort followed by expansion cohort at maximumtolerated dose. Exploratory analysis of serum cytokine levels was performed. Results: Thirty patients were enrolled onto four dose levels. The dose-limiting toxicity was thrombocytopenia. The maximal tolerated dose was panobinostat 20 mg and everolimus 10 mg. Grade 3/4 toxicity included thrombocytopenia (64%), neutropenia (47%), anemia (20%), infection (10%), fatigue (7%), and dyspnea (7%). A total of 10 patients (33%; indolent lymphoma, T-cell lymphoma, mantle cell lymphoma, and Hodgkin lymphoma) achieved objective responses. In patients with Hodgkin lymphoma (n 14), the overall response rate was 43% with complete response rate of 15%. In patients with Hodgkin lymphoma, multiple serum cytokine levels decreased significantly after treatment with this combination therapy. Of note, clinical responses were associated with a decrease in serum interleukin-5 levels (day 8, P 0.013, and day 15, P 0.021). Conclusions: Our data suggest that the combination therapy is active but with significant thrombocytopenia. Future studies should explore alternate scheduling and different compounds that target the same pathways to improve the tolerability of this novel combination.

Original languageEnglish (US)
Pages (from-to)6882-6890
Number of pages9
JournalClinical Cancer Research
Volume19
Issue number24
DOIs
StatePublished - Dec 15 2013

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Oki, Y., Buglio, D., Fanale, M., Fayad, L., Copeland, A., Romaguera, J., Kwak, L. W., Pro, B., De Castro Faria, S., Neelapu, S., Fowler, N., Hagemeister, F., Zhang, J., Zhou, S., Feng, L., & Younes, A. (2013). Phase i study of panobinostat plus everolimus in patients with relapsed or refractory lymphoma. Clinical Cancer Research, 19(24), 6882-6890. https://doi.org/10.1158/1078-0432.CCR-13-1906