title: Ricolinostat, the First Selective Histone Deacetylase 6 Inhibitor, in Combination with Bortezomib and Dexamethasone for Relapsed or Refractory Multiple Myeloma.
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.Clin Cancer Res; 23(13); 3307-15. ©2017 AACR.
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. dan.vogl@uphs.upenn.edu.
authors.forename: Dan T
authors.initials: DT
authors.lastname: Vogl
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
authors.affiliation: Mount Sinai Medical Center, New York, New York.
authors.forename: Sundar
authors.initials: S
authors.lastname: Jagannath
authors.affiliation: Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.affiliation: Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Hari
authors.affiliation: MD Anderson Cancer Center, Houston, Texas.
authors.forename: Robert
authors.initials: R
authors.lastname: Orlowski
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.affiliation: Acetylon Pharmaceuticals Inc., Boston, Massachusetts.
authors.forename: David
authors.initials: D
authors.lastname: Tamang
authors.affiliation: Acetylon Pharmaceuticals Inc., Boston, Massachusetts.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: Acetylon Pharmaceuticals Inc., Boston, Massachusetts.
authors.forename: Simon S
authors.initials: SS
authors.lastname: Jones
authors.affiliation: Acetylon Pharmaceuticals Inc., Boston, Massachusetts.
authors.forename: Catherine
authors.initials: C
authors.lastname: Wheeler
authors.affiliation: Acetylon Pharmaceuticals Inc., Boston, Massachusetts.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Markelewicz
authors.affiliation: Emory University, Atlanta, Georgia.
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D000073864:Histone Deacetylase 6 / Q000037:antagonists & inhibitors / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011743:Pyrimidines; D000069286:Bortezomib; D003907:Dexamethasone; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; C572255:ricolinostat