Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
In combination with ricolinostat, the immunomodulatory (IMiD®) class of drugs, including lenalidomide (Len) and pomalidomide (Pom), exhibit striking anti-myeloma properties in a variety of MM models (Quayle, AACR, 2014) and have demonstrated clinical activity in MM patients (Yee, ASH, 2014). In support of our ongoing development of ACY-241, we show here that combination with either Len or Pom leads to synergistic decrease in MM cell viability in vitro. Time course studies demonstrated cell cycle arrest followed by progressive induction of apoptosis after prolonged exposure to Len or Pom. Notably, the addition of ACY-241 to either Len or Pom resulted in synergistic increases in apoptosis of MM cells. At the molecular level, treatment with IMiDs reduced expression of the critical transcription factors MYC and IRF4, which was further reduced by combination treatment with ACY-241. Current studies are exploring the molecular mechanism underlying this effect, which may be a consequence of low level inhibition of HDAC1, 2, and 3 by ACY-241. Prolonged treatment with ACY-241 plus Pom was well tolerated in vivo with no evidence of toxicity, and the combination resulted in a significant extension of survival in a xenograft model of MM. Given the comparable tolerability profiles of ricolinostat and ACY-241 and the similar preclinical activity in combination with IMiDs, a clinical trial (NCT02400242) is currently evaluating ACY-241 in combination with Pom and low-dose dexamethasone in MM patients.
Predicated upon the clinical experience with ricolinostat and the non-clinical pharmacokinetics of ACY-241, we designed an expedited first-in-human phase 1a/1b clinical trial of a single cycle of ACY-241 monotherapy followed by ACY-241 in combination with Pom and dexamethasone in MM patients. A merged monotherapy/combination trial design was chosen to grant patients access to combination therapy with an established regimen while enabling insight into the safety, pharmacokinetics, and pharmacodynamics of ACY-241 monotherapy. Patients with relapsed or relapsed-and-refractory MM previously treated with at least two cycles of Len and a proteasome inhibitor were eligible for this trial. The first patient was enrolled in June 2015. This patient tolerated monotherapy well and pharmacokinetics showed maximal plasma levels of ACY-241 in the micromolar range, consistent with predictions. An update on enrollment, pharmacokinetic and pharmacodynamic profiles as well as safety of monotherapy and combination therapy will be provided.
Disclosures: Niesvizky: Celgene: Consultancy , Speakers Bureau . Richardson: Novartis: Membership on an entity’s Board of Directors or advisory committees ; Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees ; Millennium Takeda: Membership on an entity’s Board of Directors or advisory committees ; Gentium S.p.A.: Membership on an entity’s Board of Directors or advisory committees , Research Funding ; Jazz Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees , Research Funding . Gabrail: Onyx: Honoraria , Speakers Bureau ; BI: Honoraria , Speakers Bureau ; Janssen: Speakers Bureau ; Sanofi: Honoraria , Speakers Bureau . Madan: Onyx: Speakers Bureau ; Celgene: Speakers Bureau . Quayle: Acetylon Pharmaceuticals, Inc.: Employment , Equity Ownership . Almeciga-Pinto: Acetylon Pharmaceuticals, Inc: Employment . Jones: Acetylon Pharmaceuticals, Inc.: Employment , Equity Ownership . Houston: Acetylon Pharmaceuticals, Inc: Employment . Hayes: Acetylon Pharmaceuticals, Inc: Employment . Van Duzer: Acetylon Pharmaceuticals, Inc: Employment . Wheeler: Acetylon Pharmaceuticals, INC: Employment . Trede: Acetylon Pharmaceuticals, Inc: Employment . Raje: Eli Lilly: Research Funding ; Takeda: Consultancy ; AstraZeneca: Research Funding ; Celgene Corporation: Consultancy ; Amgen: Consultancy ; BMS: Consultancy .
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*signifies non-member of ASH