Ricolinostat, the First Selective Histone Deacetylase 6 Inhibitor, in Combination with Bortezomib and Dexamethasone for Relapsed or Refractory Multiple Myeloma

• Type of Material: Article
• Authors: Dan T. Vogl, University of Pennsylvania; Noopur Raje, Massachusetts General Hospital; Sundar Jagannath, Mount Sinai Medical Center; Paul Richardson, Dana Farber Cancer Institut; Parameswaran Hari, Medical College of Wisconsin; Robert Orlowski, MD Anderson Cancer Center; Jeffrey G. Supko, Massachusetts General Hospital; David Tamang, Acetylon Pharmaceut Inc; Min Yang, Acetylon Pharmaceut Inc; Simon S. Jones, Acetylon Pharmaceut Inc; Catherine Wheeler, Acetylon Pharmaceut Inc; Robert J. Markelewicz, Acetylon Pharmaceut Inc; Sagar Lonial, Emory University
• Language: English
• Date: 2017-07-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/1078-0432.CCR-16-2526
• Title of Journal or Parent Work: Clinical Cancer Research
• ISSN: 1078-0432
• Volume: 23
• Issue: 13
• Start Page: 3307
• End Page: 3315
• Grant/Funding Information: Financial support for this clinical trial was provided by Acetylon Pharmaceuticals, Inc
• Keywords: Life Sciences & Biomedicine; PROTEASOME; CELL VIABILITY; CARFILZOMIB; ACY-1215; Science & Technology; AUTOPHAGY; MULTICENTER; PHASE-3; LENALIDOMIDE; PLACEBO; Oncology; AGGRESOME FORMATION
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology

Abstract

Purpose: Histone deacetylase (HDAC) inhibition improves the efficacy of proteasome inhibition for multiple myeloma but adds substantial toxicity. Preclinical models suggest that the observed synergy is due to the role of HDAC6 in mediating resistance to proteasome inhibition via the aggresome/autophagy pathway of protein degradation. Experimental Design: We conducted a phase I/II trial of the HDAC6-selective inhibitor ricolinostat to define the safety, preliminary efficacy, and recommended phase II dose in combination with standard proteasome inhibitor therapy. Patients with relapsed or refractory multiple myeloma received oral ricolinostat on days 1–5 and 8–12 of each 21-day cycle. Results: Single-agent ricolinostat therapy resulted in neither significant toxicity nor clinical responses. Combination therapy with bortezomib and dexamethasone was well-tolerated during dose escalation but led to dose-limiting diarrhea in an expansion cohort at a ricolinostat dose of 160 mg twice daily. Combination therapy at a ricolinostat dose of 160 mg daily in a second expansion cohort was well tolerated, with less severe hematologic, gastrointestinal, and constitutional toxicities compared with published data on nonselective HDAC inhibitors. The overall response rate in combination with daily ricolinostat at 160 mg was 37%. The response rate to combination therapy among bortezomib-refractory patients was 14%. Samples taken during therapy showed dose-dependent increases of acetylated tubulin in peripheral blood lymphocytes. Conclusions: At the recommended phase II dose of ricolinostat of 160 mg daily, the combination with bortezomib and dexamethasone is safe, well-tolerated, and active, suggesting that selective inhibition of HDAC6 is a promising approach to multiple myeloma therapy.