ACY-1215 is the first selective HDAC6 inhibitor in clinical trials and is well-tolerated as monotherapy up to 360 mg/day, the maximum dose examined. Cmax ≥ 1µM was achieved at dose levels >80 mg. Unlike nonselective HDAC inhibitors, which are associated with severe fatigue, vomiting, diarrhea and myelosuppression, DLTs have not been observed with ACY-1215. ACY-1215 synergizes in in vitro with both lenalidomide and dex in MM cell lines providing the rationale to conduct a phase 1b trial of ACY-1215 in combination with these agents.
Relapsed and relapsed and refractory pts who have progressed on at least one prior treatment regimen, who have creatinine clearance >50 mg/mL/min, adequate bone marrow and hepatic function, and who gave informed consent were enrolled. In Part A, patients were treated with escalating doses of oral ACY-1215 on days 1-5 and 8-12 of a 28 day cycle with lenalidomide 25 mg d 1-21 and dex 40 mg weekly. In Part B, the schedule includes ACY-1215 on days 15-19. Subsequent cohorts will explore twice daily dosing based on emerging clinical, pharmacokinetic (PK) and pharmacodynamic (PD) data. Peripheral blood samples were obtained for PK and PD analysis. PD assessment measured the fold increase of acetylated tubulin (a marker of HDAC6 inhibition) and acetylated histones (a marker of class 1 HDAC inhibition) in peripheral blood mononuclear cells (PBMC).
As of July 3, 2013, 15 pts who progressed after 1 to >3 prior therapies have been enrolled; 8 were relapsed and 7 were refractory to the most recent therapy. Patients were treated daily at up to 240 mg ACY-1215. Fourteen pts had received prior lenalidomide of which 6 were previously refractory as defined by having less than a minimal response (MR) to therapy (1) or progressive disease on either full dose or maintenance therapy (5). Pts have completed 0 to 11+ cycles of therapy with 10 pts continuing on therapy. Five pts have discontinued therapy due to progressive disease (PD) (3), travel difficulties (1), or missed doses of lenalidomide (1). The latter pt was replaced.
The most common treatment emergent events were fatigue (43%), upper respiratory infection (36%), anemia and peripheral edema (21% each), neutropenia (29%) and muscle spasms (21%). Most were grade 1 and 2 and there was no dose relationship to ACY-1215. There were 9 grade 3-4 events in 6 pts, primarily hematologic, as well as fatigue and asymptomatic laboratory investigations. Only 1 event, grade 3 neutropenia, was considered possibly related to ACY-1215 by the investigator.
PK and PD data is available from 12 pts up to 160 mg dose level. PK for ACY-1215 is similar to the analogous dose levels in phase 1a monotherapy suggesting coadministration of lenalidomide does not significantly impact the PK of ACY-1215. Maximal levels were ≥ 1µM at ≥ 80 mg correlating with measurable increases >2x in acetylated tubulin with a minimal increase in acetylated histones.
Twelve pts, at doses up to 160 mg ACY-1215, are evaluable for response (after at least two cycles). In addition, 1 pt who discontinued therapy after one cycle had response data available. Nine patients (69%) have ≥ PR, including 1 CR, 4 VGPR, 3 PR, and 1 PRu. Two pts had MR and 2 had SD as the best response. Reponses are durable up to 11+ cycles of therapy. Of the 6 patients who were refractory to lenalidomide, best responses included 1 PR, 1 VGPR, 2 MR and 2 SD.
ACY-1215 at doses which have biological activity (as determined by PD data in PBMC) can be safely combined with lenalidomide and dex with favorable toxicity to date. Significant responses were observed in pts, and responses have been seen in pts previously refractory to lenalidomide. Future cohorts will explore longer duration of exposure as well as a twice daily dosing schedule for ACY-1215.