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.

Conflict of interest statement

All financial conflicts of interest are disclosed below:

1. DTV: Acetylon Pharmaceuticals (Grant funding), Millennium/Takeda Pharmaceuticals (Grant funding, consultancy), Karyopharm (Consultancy), Amgen (Consultancy), Teva Pharmaceutical Industries (Consultancy), GSK (Grant funding), Constellation Pharmaceuticals (Grant funding).

2. NR: Celgene, Takeda, BMS, Merck, Amgen, Novartis. Roche (Consulting), Eli Lilly and Astrazenca (Research Funding)

3. SJ: Advisory Board Meetings of Celgene, BMS, Merck, Janssen, Novartis and received Honoraria

4. PR: Served on advisory committees for Novartis, Takeda, Johnson & Johnson, and Celgene, and has received research funding from Celgene and Takeda.

5. JGS: Acetylon Pharmaceuticals (Research funding), Millennium/Takeda Pharmaceuticals (Consultancy)

6. DT: Employed by Acetylon Pharmaceuticals.

7. MY: Employed by Acetylon Pharmaceuticals.

8. SSJ: Employed by Acetylon Pharmaceuticals.

9. CW: Employed by Acetylon Pharmaceuticals.

10. RJM: Employed by Acetylon Pharmaceuticals.

©2017 American Association for Cancer Research.

Figures

Figure 1. Treatment responses

(A) Responses for the entire cohort of patients treated with (from left to right) single agent ricolinostat, ricolinostat with bortezomib (Bz) and dexamethasone (dex), ricolinostat ≥160 mg qd with Bz/dex, and ricolinostat 160 mg bid with Bz/dex. (B) Responses among patients with bortezomib-refractory myeloma treated with (from left to right) ricolinostat with Bz/dex, ricolinostat ≥160 mg qd with Bz/dex, or ricolinostat 160 mg bid with Bz/dex. Numbers indicate the percentage of patients in each category of response. VGPR, very good partial response; PR, partial response; MR, minimal response; SD, stable disease; PD, progressive disease; ORR, overall response rate; CBR, clinical benefit rate.

Figure 2

Pharmacokinetics of ricolinostat and bortezomib. (A) Observed maximum concentration of ricolinostat in plasma at each dose level for patients receiving single agent ricolinostat (open markers) or combination dosing with bortezomib (closed markers). (B) Observed maximum concentration of bortezomib (given at a dose of 1.0 mg/m2 in cohort 1 and 1.3 mg/m2 in all other cohorts) in combination with ricolinostat (doses outlined in table 1). Markers represent data for individual patients and the horizontal bars the geometric mean of the data for each group. Circles denote levels on treatment day 1 and squares day 11.

Figure 3

Pharmacodynamics for ricolinostat monotherapy. Peripheral blood from patients receiving dose-escalating ricolinostat monotherapy was collected and the CD3+ lymphocytes were assessed for acetylated tubulin (A) and acetylated histones (B) at 1 hour after dosing. Horizontal lines represent the arithmetic mean.

Figure 4

Pharmacodynamics of ricolinostat combination therapy. (A,B) Changes compared to baseline in levels of acetylated tubulin (A) and acetylated histones (B) in peripheral blood lymphocytes taken 1 hour after the first ricolinostat dose from patients receiving ricolinostat in combination with bortezomib and dexamethasone. Solid circles indicate patients receiving ricolinostat qd where open circles indicate bid dosing. Horizontal lines represent the arithmetic mean. (C) Changes over 24 hours after the first ricolinostat dose in peripheral blood lymphocyte levels of acetylated tubulin (red line, left axis), acetylated histones (blue line, left axis), and in plasma ricolinostat levels (black dashed line, right axis). Error bars represent the standard error of the mean.