Ricolinostat (ACY-1215), a Selective HDAC6 Inhibitor, in Combination with Lenalidomide and Dexamethasone: Results of a Phase 1b Trial in Relapsed and Relapsed Refractory Multiple Myeloma

Background

Ricolinostat is the first oral, selective HDAC6 inhibitor in clinical trials and was well tolerated as monotherapy up to 360 mg/day, the maximum dose examined (Raje, ASH 2012). Ricolinostat synergizes in vitro with both lenalidomide (len) and pomalidomide in MM cell lines and down-regulates MYC and IRF4 protein expression (Quayle, ASH 2013).

Methods

Relapsed and relapsed refractory patients (pts) who have progressed on at least one prior treatment regimen, with creatinine clearance >50 mg/mL/min, adequate bone marrow and hepatic function were enrolled. In Part A, pts were treated with escalating doses of ricolinostat on days 1-5 and 8-12 of a 28 day cycle with len 25 mg on days 1-21 and dexamethasone (dex) 40 mg weekly. In Part B, ricolinostat was also given on days 15-19. Doses up to 240 mg QD and 160 mg BID were explored, and a final cohort treated with 160 mg BID for 21 of 28 days is currently enrolling. Peripheral blood samples were obtained for pharmacokinetic (PK) and pharmacodynamic analysis.

Results

As of July 1, 2014, 25 pts have been enrolled; 12 were relapsed and 13 were refractory to the most recent therapy. Seven pts had more than three prior therapies. Twenty pts (80%) had received prior len with 11 previously refractory defined as having less than a minimal response (MR) to therapy or progressive disease on either full dose or maintenance len. Pts have completed 0 to 24+ cycles of therapy with 14 pts continuing on therapy. Six pts discontinued therapy due to progressive disease (PD,1), travel difficulties (1), adverse events (AE) of secondary malignancy (1), alternate therapy chosen after completion of 6 cycles (2), or missed doses of len (1). The latter pt was replaced.

The most common treatment emergent events (>15%) were fatigue, upper respiratory infection, anemia, neutropenia, diarrhea, nausea, thrombocytopenia, muscle spasms, dizziness and rash as well as asymptomatic laboratory abnormalities. Most were grade 1 and 2 with no clear relationship to ricolinostat dose. Seven grade 3 and 4 events in five patients were attributed to ricolinostat: neutropenia, thrombocytopenia, anemia, fatigue and syncope. Syncope, at 160 mg BID, was the only DLT; the pt continued on study with a dose reduction and there were no other DLTs in the expanded cohort.

PK for ricolinostat is similar to that observed in phase 1a monotherapy, suggesting that co-administration of len does not significantly impact ricolinostat exposure. Maximal blood levels of ricolinostat were ≥0.5 µM at ≥80 mg correlating with a >2x increase in acetylated tubulin (a marker of HDAC6 inhibition) with minimal increase in acetylated histones (a marker of class 1 HDAC inhibition).

Twenty-four pts at doses up to 160 mg ricolinostat BID Part B are evaluable for response (≥2 cycles). The overall response rate (ORR) was 63%: 15 pts have ≥partial responses (PR), including 1 stringent complete response (sCR), 5 very good partial responses (VGPR), 9 PR. Four pts had minimal response (MR) and 5 had stable disease (SD) as the best response. Responses are durable up to 23+ cycles of therapy. Of the 11 pts refractory to len, best responses included 1 VGPR, 3 PR, 3 MR and 2 SD. Median time on therapy for the len refractory pts was 4 months (range 3-13).

Conclusions

Ricolinostat at doses of 160 mg BID, which have biological activity as determined by PD marker in blood cells, can be combined with len and dex on a 21 day, schedule 5 or 7 days/week and was well tolerated. Durable and significant responses were observed, including responses in pts previously refractory to len. The last escalation cohort 160 BID 21/28 days is currently enrolling to determine the recommended phase 2 dose.