Phase 1B Results of Ricolinostat (ACY-1215) Combination Therapy with Bortezomib and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma (MM)
Authors: Vogl Dan T. , Raje Noopur , Hari Parameswaran , Jones Simon S , Supko Jeffrey G , Leone Gina , Wheeler Catherine , Orlowski Robert Z. , Richardson Paul G. , Lonial Sagar , Tamang David , Jagannath Sundar 
Published: November 2019

Abstract
Background
Ricolinostat is the first selective oral HDAC6 inhibitor studied clinically in the treatment of MM. Preclinical and phase 1a clinical data support the hypothesis that the safety profile of a selective HDAC inhibitor will facilitate combination therapy with other active agents. No dose limiting toxicities (DLT) were noted in 15 patients (pts) in a phase 1a dose escalation study of ricolinostat at doses up to 360 mg/day where the best response was stable disease (SD). (Raje Blood 2012;120:4061). HDAC6 inhibition impairs the aggresome/autophagy pathway, an alternate pathway to proteasome clearance of misfolded proteins (Santo L Blood 2012;119(11):2578-89) providing the rationale for combining ricolinostat with bortezomib (Btz).
Methods
We report the first part of a phase 1b open label dose escalation study of ricolinostat in combination with Btz and dexamethasone (Dex) using a standard 3+3 design. Eligible pts had relapsed or relapsed and refractory MM, previously received at least two lines of therapy including a proteasome inhibitor and an IMiD® immunomodulatory agent, had either progressed after or were ineligible for autologous stem cell transplant, and had adequate bone marrow reserve, hepatic function and creatinine clearance of >30 mg/mL/min. Ricolinostat was given orally days 1-5 and 8-12 of a 21 day cycle, with Btz on days 1,4,8,11 and Dex on days 1,2,4,5,8,9,11,12. Peripheral blood samples were obtained for pharmacokinetic (PK) and pharmacodynamic assessments of acetylated tubulin (HDAC6 inhibition) and acetylated histones (Class 1 HDAC inhibition). Definitions of response, relapsed and refractory were by IMWG criteria (Rajkumar SV Blood:2011;117(18):4691-5) and included response less than minimal response (MR) as refractory. Seventeen pts were treated in an expansion cohort at the potential recommended phase 2 dose and schedule.
Results
Forty-two pts were enrolled to 8 combination dose cohorts. The first cohort dosed ricolinostat 40 mg QD with Btz 1.0 mg/m2; subsequent cohorts used Btz 1.3 mg/m2 with ricolinostat doses of 40, 80 , 160, and 240 mg QD, and 160 mg BID. Median age was 65, and 79% were refractory to the most recent therapy. 34 pts had previously received >4 prior regimens. The first combination cohort was expanded due to a DLT of asymptomatic increase in amylase. No other DLTs have been observed in the cohort escalations. Treatment emergent adverse events (AEs) were predominantly grade 1-2. The most common AEs were diarrhea, increased creatinine, fatigue, anemia, nausea and thrombocytopenia and only diarrhea increased with ricolinostat dose. Grade 3-4 AEs possibly related to ricolinostat included thrombocytopenia (24%), anemia, diarrhea, and asymptomatic laboratory abnormalities (1%). Fatigue, dehydration, orthostatic hypotension, nausea, vomiting, stomach cramps and pulmonary embolism were seen in ≤1% of pts. Of 25 pts evaluable for response, overall response rate (ORR) was 44%: 2 pts had a very good partial response (VGPR), 9 had a partial response (PR), and 2 had an MR, with 9 pts achieving SD and 3 with progressive disease (PD). Responding pts remained on study for a median of 4 cycles (range 2 to 18). Pts who were not evaluable were those who were too early in treatment (3), or who came off study before cycle 2 (14). Of these 10 had early PD and 3 died due to disease or unrelated AE. 15 pts refractory to Btz prior to study entry were evaluable for response. Of those, response rate (PR or better) was 27% with best outcome VGPR (1), PR (3), SD (8) and PD (3). Pts with SD were on study a median of 3 (2-10) mos. PK and pharmacodynamic data from the first 16 pts were similar to the same dose levels in phase 1a monotherapy suggesting coadministration of Btz does not impact the PK of ricolinostat. Maximal levels were ≥1µM at ≥80 mg correlating with measurable increases >2x in acetylated tubulin with a minimal increase in acetylated histones. Updated PK and pharmacodynamic data will be provided.
Conclusions
Ricolinostat in combination with Btz and Dex was well tolerated at doses up to 240 mg QD and 160 mg BID in the dose escalation cohorts. Diarrhea was the only dose-related AE. Results of the expansion cohort as well as cytogenetic risk categories will be presented. Responses were observed even in Btz-refractory pts.

Disclosures
Vogl: Celgene Corporation: Consultancy; Amgen: Consultancy; Millennium/Takeda: Research Funding; GSK: Research Funding; Acetylon: Research Funding. Raje:Eli Lilly, Acetylon: Research Funding; novartis, Amgen, Celgene, Millenium, Onyx: Consultancy. Jones:Acetylon Pharmaceuticals Inc.: Employment. Supko:Acetylon Pharmaceuticals: Research Funding. Leone:Acetylon Pharmaceuticals: Employment. Wheeler:Acetylon Pharmaceuticals: Employment. Orlowski:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; JW Pharmaceutical: Research Funding; Spectrum Pharmaceuticals: Research Funding; Millennium: The Takeda Oncology Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Sanofi: Consultancy. Tamang:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Jagannath:Celgene Corporation: Consultancy; Millennium: Consultancy; Sanofi: Consultancy.