ACY-1215, a Selective Histone Deacetylase (HDAC) 6 Inhibitor: Interim Results Of Combination Therapy With Bortezomib In Patients With Multiple Myeloma (MM)

Although non-selective HDAC inhibitors are active in MM, combination therapy is limited by significant adverse effects (AEs) including severe fatigue, gastrointestinal toxicity, and myelosuppression. ACY-1215 is the first-in-class selective oral HDAC6 inhibitor that inhibits the aggresome/autophagy pathway, an alternate pathway to proteasome clearance of misfolded proteins. ACY-1215 has demonstrated potent synergy with bortezomib preclinically in cell and animal models of MM (Santo, Blood, 119(1):2527).

ACY-100 is a three part single arm, open label study with cohort dose escalation in a standard 3+3 design as monotherapy (1a) and in combination with bortezomib (1b) followed by a phase 2 extension. Eligible patients (pts) for the phase 1a and 1b portions had relapsed or relapsed and refractory MM, previously received at least two lines of therapy including a proteasome inhibitor and an 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. ACY-1215 was given orally days 1-5 and 8-12 of a 21 day cycle, and bortezomib days 1,4,8,11 and dexamethasone 20 mg days 1,2,4,5,8,9,11,12. Peripheral blood samples were obtained for pharmacokinetic (PK) and pharmacodynamics (PD), assessment of acetylated tubulin (HDAC6 inhibition) and acetylated histones (Class 1 HDAC inhibition). Toxicity was assessed using CTCv4.0 and responses were evaluated by modified EMBT and Uniform Criteria.

The monotherapy portion of ACY-100 has been previously presented (Raje, Blood, V20(21):4061). Fifteen heavily pretreated pts received ACY-1215 monotherapy at doses of 40 mg to 360 mg. Most AEs were low grade and not related to ACY-1215. Two pts had grade 3 AEs, anemia and neutropenia, considered possibly related to ACY-1215. No dose limiting toxicities (DLTs) were observed. Stable disease (SD) was the best response in 6 patients.

Sixteen patients as of June 28, 2013 have received ACY-1215 at doses of 40 mg to 160 mg in combination with bortezomib (1.0 mg/m² first cohort and 1.3 mg/m² thereafter) and dexamethasone. Median age was 60, and 16 patients had previously received up to 11 lines of therapy. The first combination cohort was expanded due to a dose limiting toxicity (DLT) of asymptomatic increase in amylase. No other DLTs have been observed. Treatment emergent adverse events were predominantly low grade. Those occurring in >25% of patients were elevated creatinine, thrombocytopenia, anemia, fatigue, elevated ALT, AST and amylase, hypokalemia, cough, decreased appetite, dyspnea, hypoalbuminemia and peripheral neuropathy; most were not considered related to ACY-1215. Grade 3-4 AEs possibly related to ACY-1215 included asymptomatic elevated amylase (2), thrombocytopenia (3), anemia (1), stomach cramps (1) and elevated creatinine (1). Of 16 patients evaluable for response, VGPR (1), PR (2), MR (1) were seen, with 5 pts achieving SD. Responding patients were on study from 2 to 17 cycles. Eleven pts were refractory to bortezomib prior to study entry. Of those the best outcome was MR (1) and SD (4), with the remaining having either progressive disease (5) or not evaluable (1). PK and PD data is available from 16 patients including the 160 mg dose level. PK for ACY-1215 is similar to the same dose levels in phase 1a monotherapy suggesting coadministration of bortezomib does not 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.

ACY-1215 was well-tolerated when administered in combination with bortezomib and encouraging disease responses were observed in this heavily pretreated patient population. Future cohorts in phase 1b will explore twice daily dosing prior to start of phase 2.

Raje:Acetylon Pharmaceuticals, Inc: Research Funding; Eli Lilly: Research Funding; Celgene: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Amgen: Consultancy. Vogl:Otsuka: Consultancy; Celgene: Consultancy; Millennium: Research Funding; Acetylon Pharmaceuticals, Inc: Research Funding. Hari:Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Millenium: Consultancy, Research Funding. Jagannath:Celgene: Honoraria; Millenium: Honoraria. Jones:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Supko:Acetylon Pharmaceuticals, Inc: Research Funding. Leone:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Wheeler:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Richardson:Celgene: Membership on an entity’s Board of Directors or advisory committees; Millenium: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.