Rocilinostat (ACY-1215), a Selective HDAC6 Inhibitor, Alone and in Combination with Bortezomib in Multiple Myeloma: Preliminary Results From the First-in-Humans Phase I/II Study

The rate of relapse in multiple myeloma (MM) remains high despite novel therapies such as the proteasome inhibitor bortezomib. Histone deacetylase (HDAC) inhibitors (panobinostat and vorinostat) in combination with bortezomib have demonstrated activity in patients (pts) with relapsed and refractory MM. However, pan-HDAC inhibitors target multiple HDAC enzymes, including HDAC6 and Class 1 enzymes, and are associated with adverse effects such as severe fatigue, nausea, vomiting, diarrhea, and myelosuppression. HDAC6 regulates acetylation of cytoplasmic tubulin, an essential component of aggresome formation in an alternative pathway to the proteasome to remove unfolded or misfolded proteins. Therefore selective inhibition of HDAC6 may lead to efficacy in MM with an improved safety profile. Rocilinostat is a novel selective inhibitor of HDAC6 with 11-fold selectivity over Class 1 HDACs. Preclinical results in models of MM demonstrate synergy between bortezomib and rocilinostat (Blood 119(11):2579-89) and a superior safety profile compared with pan-HDAC inhibitors. We examined the pharmacokinetics, pharmacodynamics, safety, and preliminary activity of rocilinostat, alone and in combination with bortezomib and dexamethasone, in pts with relapsed or relapsed/refractory MM.

Patients with relapsed or relapsed/refractory MM, previously exposed to both proteasome inhibitor and immunomodulatory agents, were enrolled in an ongoing, 3-part, phase I/II, single-arm, open-label study. A group sequential dose-escalation design was used to identify optimal dosing of rocilinostat alone (Part 1) and in combination with bortezomib and dexamethasone (Part 2), followed by evaluation of the objective response rate and safety of the combination (Part 3). In Part 1, pts received single oral daily doses of rocilinostat for 5 consecutive days during Weeks 1 (Days 1–5) and 2 (Days 8–12) every 3 weeks, with a starting dose of 40 mg and planned escalation to 80, 160, 240, 360, and 480 mg. Part 2 began in parallel after completion of the third monotherapy cohort, with a starting dose of 40 mg rocilinostat plus bortezomib 1.0 mg/m²twice weekly (Days 1, 4, 8, and 11) and 20 mg dexamethasone given on the day of and day after each bortezomib dose. Pharmacokinetics were assessed on Days 1, 4, 8, 11 and 15 and pharmacodynamics in blood mononuclear cells were measured on Day 1. Patients received up to 6 cycles of therapy, or more if experiencing clinical benefit. Available data are for the first 4 monotherapy cohorts (40, 80, 160, 240 mg) and the initial 3 pts in the first combination cohort (16 pts total).

Of the 16 pts, 13 were treated with monotherapy and 3 with combination. Median age was 70 yrs (range: 51–79), and 56% of pts were male. The majority of pts were either white (8, 50%) or black (7, 44%). Fourteen pts had relapsed/refractory MM and 2 had relapsed disease; 88% of pts received ≥ 3 prior treatments. Patients received a median of 2 cycles of rocilinostat (range: 1–10). Monotherapy was well tolerated with no dose-limiting toxicities (DLTs) and mostly grade 1–2 adverse events (AEs). The most common AEs with monotherapy were elevated creatinine, diarrhea, fatigue, and upper respiratory tract infection (n=3 each). Grade 3/4 treatment-related AEs on monotherapy occurred in 1 pt (grade 3 anemia). In the first combination cohort, 1 pt had a DLT (elevated amylase). Five monotherapy pts had stable disease. One combination pt with relapsed/refractory disease had a 26% reduction of serum M protein at Cycle 2. Rocilinostat was rapidly absorbed (Table) and displayed approximately dose-linear pharmacokinetics with no accumulation of drug. Maximal levels of acetylated tubulin in peripheral blood were observed 1 hr post dose. The magnitude of the signal increased with dose and exposure (Table), with all cohort 3 pts having at least a doubling of acetylated tubulin levels.

Preliminary results from this first clinical evaluation of rocilinostat suggest that selective inhibition of HDAC6 with rocilinostat, alone or in combination with bortezomib and dexamethasone, may provide a well-tolerated treatment option for relapsed or relapsed/refractory MM. Updated data will be presented.

Raje:Onyx: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding. Hari:Celgene: Consultancy, Honoraria. Vogl:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Research Funding; Otsuka: Consultancy; Acetylon: Research Funding. Jagannath:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Milenium Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees. Supko:Acetlon: Research Funding. Wheeler:Acetylon: Employment.