ACY-241, A NOVEL, ORAL TABLET HDAC6 SELECTIVE INHIBITOR COMBINES SAFELY WITH POMALIDOMIDE AND DEXAMETHASONE IN PATIENTS WITH RELAPSED OR RELAPSED AND REFRACTORY MULTIPLE MYELOMA (ACE-MM-200 STUDY)
(Abstract release date: 05/19/16)
EHA Library. Niesvizky R. 06/09/16; 132819; E1270
Dr. Ruben Niesvizky
Contributions
Contributions
Abstract
Abstract: E1270
Type: Eposter Presentation
Background
Histone deacetylase (HDAC) enzymes are attractive therapeutic targets, but non-selective HDAC inhibitors have toxicities limiting exposure in patients (pts), particularly in combination with other agents. Ricolinostat (ACY-1215), is a first-in-class liquid orally available HDAC inhibitor 11-fold more selective for HDAC6, that synergizes in vitro and in vivo in models of multiple myeloma (MM) with bortezomib (Santo, Blood, 2012) and with carfilzomib (Mishima, Br J Haematol, 2015) and with lenalidomide (Len) and pomalidomide (Pom) (Quayle Blood 2013;122:1952). Ricolinostat, an oral liquid, has an excellent safety profile. (Raje, Haematologica, 2014, Suppl 1). We now identify ACY-241 as a structurally related, selective inhibitor of HDAC6 in tablet form.
Aims
Determine the safety, tolerability and preliminary efficacy of ACY-241 monotherapy and combination with pom and dexamethasone (dex).
Methods
Based on clinical experience with ricolinostat and non-clinical pharmacokinetics of ACY-241, we designed a 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 (Dex) in MM pts. A monotherapy/combination trial (mono/combo) design was chosen to grant pts access to combo therapy with an active regimen while exploring the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of ACY-241 monotherapy. Pts with relapsed or relapsed-and-refractory MM (RRMM) previously treated with > 2 cycles of Len and a proteasome inhibitor were eligible. Cohorts of 3 pts had ACY-241 PO QD as monotherapy (180, 360 and 480 mg) on days 1-21 of a 28 day cycle. If no mono DLT was noted, pts continued to cycle 2 of combo therapy with ACY-241/Pom/Dex. Safety review committee meetings for mono and combo therapy were separate. PK of ACY-241, Pom and Dex were analyzed. PD assessment were acetylated tubulin (HDAC6) and histones (HDAC 1, 2 and 3) in peripheral blood mononuclear cells.
Results
Since June 2015, 13 safety-evaluable pts have enrolled. Median age was 62 (46-82) years and median number of prior regimens 2 (1-7). All pts had RRMM. 62% were refractory to len and 46% to both Btz and Len. Fifty percent of pts had high risk cytogenetics. No dose relationship of the number or severity of AEs in either monotherapy or combination therapy were noted. Common toxicities in the safety population included grade 1/2 fatigue (38%), cough, back pain and dizziness (23% each), diarrhea, constipation and nausea (20% each ). Grade 3/4 toxicities included neutropenia (4 pts, 31%), thrombocytopenia (23%) and anemia (8%). No MTD was identified up to the highest dose of ACY-241 at 480 mg QD monotherapy and 180 and 360 mg po QD in combo with Pom/Dex. 360 mg QD was recommended for further clinical exploration of ACY-241 based on safety and PD data. PK results show dose-linear increase in exposure with no accumulation, drug-drug interaction with Pom and Dex, or exposure plateau (previously observed with ricolinostat.) Selective increase in acetylated tubulin was seen at 180 mg with increasing levels of acetylated tubulin and histones at higher doses. Confirmed efficacy data (minimum follow-up 3 months) for combo treatment in this refractory pt population (8 efficacy evaluable pts) shows 4 PR, 2 MR and 2 PD. Three pts had only one efficacy cycle reported and 2 are early.
Conclusion
ACY-241 is well-tolerated in combination with Pom/Dex with at least dose proportional PK. Early response data to combo treatment parallel those observed with ricolinostat/Pom/Dex and compare favorably to historic controls of Pom/Dex. Cohort expansion at biologically relevant combination doses is ongoing. Updated data will be presented.
Session topic: E-poster
Keyword(s): HDAC inhibitor, Multiple myeloma, Phase I
Type: Eposter Presentation
Background
Histone deacetylase (HDAC) enzymes are attractive therapeutic targets, but non-selective HDAC inhibitors have toxicities limiting exposure in patients (pts), particularly in combination with other agents. Ricolinostat (ACY-1215), is a first-in-class liquid orally available HDAC inhibitor 11-fold more selective for HDAC6, that synergizes in vitro and in vivo in models of multiple myeloma (MM) with bortezomib (Santo, Blood, 2012) and with carfilzomib (Mishima, Br J Haematol, 2015) and with lenalidomide (Len) and pomalidomide (Pom) (Quayle Blood 2013;122:1952). Ricolinostat, an oral liquid, has an excellent safety profile. (Raje, Haematologica, 2014, Suppl 1). We now identify ACY-241 as a structurally related, selective inhibitor of HDAC6 in tablet form.
Aims
Determine the safety, tolerability and preliminary efficacy of ACY-241 monotherapy and combination with pom and dexamethasone (dex).
Methods
Based on clinical experience with ricolinostat and non-clinical pharmacokinetics of ACY-241, we designed a 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 (Dex) in MM pts. A monotherapy/combination trial (mono/combo) design was chosen to grant pts access to combo therapy with an active regimen while exploring the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of ACY-241 monotherapy. Pts with relapsed or relapsed-and-refractory MM (RRMM) previously treated with > 2 cycles of Len and a proteasome inhibitor were eligible. Cohorts of 3 pts had ACY-241 PO QD as monotherapy (180, 360 and 480 mg) on days 1-21 of a 28 day cycle. If no mono DLT was noted, pts continued to cycle 2 of combo therapy with ACY-241/Pom/Dex. Safety review committee meetings for mono and combo therapy were separate. PK of ACY-241, Pom and Dex were analyzed. PD assessment were acetylated tubulin (HDAC6) and histones (HDAC 1, 2 and 3) in peripheral blood mononuclear cells.
Results
Since June 2015, 13 safety-evaluable pts have enrolled. Median age was 62 (46-82) years and median number of prior regimens 2 (1-7). All pts had RRMM. 62% were refractory to len and 46% to both Btz and Len. Fifty percent of pts had high risk cytogenetics. No dose relationship of the number or severity of AEs in either monotherapy or combination therapy were noted. Common toxicities in the safety population included grade 1/2 fatigue (38%), cough, back pain and dizziness (23% each), diarrhea, constipation and nausea (20% each ). Grade 3/4 toxicities included neutropenia (4 pts, 31%), thrombocytopenia (23%) and anemia (8%). No MTD was identified up to the highest dose of ACY-241 at 480 mg QD monotherapy and 180 and 360 mg po QD in combo with Pom/Dex. 360 mg QD was recommended for further clinical exploration of ACY-241 based on safety and PD data. PK results show dose-linear increase in exposure with no accumulation, drug-drug interaction with Pom and Dex, or exposure plateau (previously observed with ricolinostat.) Selective increase in acetylated tubulin was seen at 180 mg with increasing levels of acetylated tubulin and histones at higher doses. Confirmed efficacy data (minimum follow-up 3 months) for combo treatment in this refractory pt population (8 efficacy evaluable pts) shows 4 PR, 2 MR and 2 PD. Three pts had only one efficacy cycle reported and 2 are early.
Conclusion
ACY-241 is well-tolerated in combination with Pom/Dex with at least dose proportional PK. Early response data to combo treatment parallel those observed with ricolinostat/Pom/Dex and compare favorably to historic controls of Pom/Dex. Cohort expansion at biologically relevant combination doses is ongoing. Updated data will be presented.
Session topic: E-poster
Keyword(s): HDAC inhibitor, Multiple myeloma, Phase I
Abstract: E1270
Type: Eposter Presentation
Background
Histone deacetylase (HDAC) enzymes are attractive therapeutic targets, but non-selective HDAC inhibitors have toxicities limiting exposure in patients (pts), particularly in combination with other agents. Ricolinostat (ACY-1215), is a first-in-class liquid orally available HDAC inhibitor 11-fold more selective for HDAC6, that synergizes in vitro and in vivo in models of multiple myeloma (MM) with bortezomib (Santo, Blood, 2012) and with carfilzomib (Mishima, Br J Haematol, 2015) and with lenalidomide (Len) and pomalidomide (Pom) (Quayle Blood 2013;122:1952). Ricolinostat, an oral liquid, has an excellent safety profile. (Raje, Haematologica, 2014, Suppl 1). We now identify ACY-241 as a structurally related, selective inhibitor of HDAC6 in tablet form.
Aims
Determine the safety, tolerability and preliminary efficacy of ACY-241 monotherapy and combination with pom and dexamethasone (dex).
Methods
Based on clinical experience with ricolinostat and non-clinical pharmacokinetics of ACY-241, we designed a 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 (Dex) in MM pts. A monotherapy/combination trial (mono/combo) design was chosen to grant pts access to combo therapy with an active regimen while exploring the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of ACY-241 monotherapy. Pts with relapsed or relapsed-and-refractory MM (RRMM) previously treated with > 2 cycles of Len and a proteasome inhibitor were eligible. Cohorts of 3 pts had ACY-241 PO QD as monotherapy (180, 360 and 480 mg) on days 1-21 of a 28 day cycle. If no mono DLT was noted, pts continued to cycle 2 of combo therapy with ACY-241/Pom/Dex. Safety review committee meetings for mono and combo therapy were separate. PK of ACY-241, Pom and Dex were analyzed. PD assessment were acetylated tubulin (HDAC6) and histones (HDAC 1, 2 and 3) in peripheral blood mononuclear cells.
Results
Since June 2015, 13 safety-evaluable pts have enrolled. Median age was 62 (46-82) years and median number of prior regimens 2 (1-7). All pts had RRMM. 62% were refractory to len and 46% to both Btz and Len. Fifty percent of pts had high risk cytogenetics. No dose relationship of the number or severity of AEs in either monotherapy or combination therapy were noted. Common toxicities in the safety population included grade 1/2 fatigue (38%), cough, back pain and dizziness (23% each), diarrhea, constipation and nausea (20% each ). Grade 3/4 toxicities included neutropenia (4 pts, 31%), thrombocytopenia (23%) and anemia (8%). No MTD was identified up to the highest dose of ACY-241 at 480 mg QD monotherapy and 180 and 360 mg po QD in combo with Pom/Dex. 360 mg QD was recommended for further clinical exploration of ACY-241 based on safety and PD data. PK results show dose-linear increase in exposure with no accumulation, drug-drug interaction with Pom and Dex, or exposure plateau (previously observed with ricolinostat.) Selective increase in acetylated tubulin was seen at 180 mg with increasing levels of acetylated tubulin and histones at higher doses. Confirmed efficacy data (minimum follow-up 3 months) for combo treatment in this refractory pt population (8 efficacy evaluable pts) shows 4 PR, 2 MR and 2 PD. Three pts had only one efficacy cycle reported and 2 are early.
Conclusion
ACY-241 is well-tolerated in combination with Pom/Dex with at least dose proportional PK. Early response data to combo treatment parallel those observed with ricolinostat/Pom/Dex and compare favorably to historic controls of Pom/Dex. Cohort expansion at biologically relevant combination doses is ongoing. Updated data will be presented.
Session topic: E-poster
Keyword(s): HDAC inhibitor, Multiple myeloma, Phase I
Type: Eposter Presentation
Background
Histone deacetylase (HDAC) enzymes are attractive therapeutic targets, but non-selective HDAC inhibitors have toxicities limiting exposure in patients (pts), particularly in combination with other agents. Ricolinostat (ACY-1215), is a first-in-class liquid orally available HDAC inhibitor 11-fold more selective for HDAC6, that synergizes in vitro and in vivo in models of multiple myeloma (MM) with bortezomib (Santo, Blood, 2012) and with carfilzomib (Mishima, Br J Haematol, 2015) and with lenalidomide (Len) and pomalidomide (Pom) (Quayle Blood 2013;122:1952). Ricolinostat, an oral liquid, has an excellent safety profile. (Raje, Haematologica, 2014, Suppl 1). We now identify ACY-241 as a structurally related, selective inhibitor of HDAC6 in tablet form.
Aims
Determine the safety, tolerability and preliminary efficacy of ACY-241 monotherapy and combination with pom and dexamethasone (dex).
Methods
Based on clinical experience with ricolinostat and non-clinical pharmacokinetics of ACY-241, we designed a 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 (Dex) in MM pts. A monotherapy/combination trial (mono/combo) design was chosen to grant pts access to combo therapy with an active regimen while exploring the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of ACY-241 monotherapy. Pts with relapsed or relapsed-and-refractory MM (RRMM) previously treated with > 2 cycles of Len and a proteasome inhibitor were eligible. Cohorts of 3 pts had ACY-241 PO QD as monotherapy (180, 360 and 480 mg) on days 1-21 of a 28 day cycle. If no mono DLT was noted, pts continued to cycle 2 of combo therapy with ACY-241/Pom/Dex. Safety review committee meetings for mono and combo therapy were separate. PK of ACY-241, Pom and Dex were analyzed. PD assessment were acetylated tubulin (HDAC6) and histones (HDAC 1, 2 and 3) in peripheral blood mononuclear cells.
Results
Since June 2015, 13 safety-evaluable pts have enrolled. Median age was 62 (46-82) years and median number of prior regimens 2 (1-7). All pts had RRMM. 62% were refractory to len and 46% to both Btz and Len. Fifty percent of pts had high risk cytogenetics. No dose relationship of the number or severity of AEs in either monotherapy or combination therapy were noted. Common toxicities in the safety population included grade 1/2 fatigue (38%), cough, back pain and dizziness (23% each), diarrhea, constipation and nausea (20% each ). Grade 3/4 toxicities included neutropenia (4 pts, 31%), thrombocytopenia (23%) and anemia (8%). No MTD was identified up to the highest dose of ACY-241 at 480 mg QD monotherapy and 180 and 360 mg po QD in combo with Pom/Dex. 360 mg QD was recommended for further clinical exploration of ACY-241 based on safety and PD data. PK results show dose-linear increase in exposure with no accumulation, drug-drug interaction with Pom and Dex, or exposure plateau (previously observed with ricolinostat.) Selective increase in acetylated tubulin was seen at 180 mg with increasing levels of acetylated tubulin and histones at higher doses. Confirmed efficacy data (minimum follow-up 3 months) for combo treatment in this refractory pt population (8 efficacy evaluable pts) shows 4 PR, 2 MR and 2 PD. Three pts had only one efficacy cycle reported and 2 are early.
Conclusion
ACY-241 is well-tolerated in combination with Pom/Dex with at least dose proportional PK. Early response data to combo treatment parallel those observed with ricolinostat/Pom/Dex and compare favorably to historic controls of Pom/Dex. Cohort expansion at biologically relevant combination doses is ongoing. Updated data will be presented.
Session topic: E-poster
Keyword(s): HDAC inhibitor, Multiple myeloma, Phase I
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