RICOLINOSTAT (ACY-1215), THE FIRST SELECTIVE HDAC6 INHIBITOR, COMBINED WITH POMALIDOMIDE AND DEXAMETHASONE SHOWS PROMISING EARLY PHASE 2 RESULTS IN RELAPSED-AND-REFRACTORY MULTIPLE MYELOMA: ACE-MM-102
(Abstract release date: 05/19/16)
EHA Library. Raje N. 06/12/16; 135307; S813
Dr. Noopur Raje
Contributions
Contributions
Abstract
Abstract: S813
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:00 - 08:15
Location: Hall C14
Background
Ricolinostat (Rico, ACY-1215), an oral selective HDAC6 inhibitor, is well tolerated as monotherapy (Raje Blood 2012) and demonstrates potent synergistic activity with lenalidomide (Len) and pomalidomide (Pom) in preclinical models (Quayle Blood 2013). Pan-HDAC inhibitors vorinostat and panobinostat are active in MM in combo with bortezomib (Btz) and Len, but toxicities limit dosing and treatment exposure, with resulting diminished efficacy. Rico selectively targets HDAC6 while retaining reduced and tolerable levels of HDAC1, 2, 3 inhibition that down-regulates expression of critical transcription factors regulating cancer cell proliferation, such as c-Myc and IRF4.
Aims
This trial explored activity of Rico in combo with Pom and dexamethasone (Dex) in a population comparable to both the MM-002 and MM-003 trials for Pom/Dex (Richardson Blood 2015; San Miguel Lancet Oncol 2013). At the primary endpoint of PFS in MM-003, the ORR was 16.6% at 18.1 wks med follow-up, and was 31% at 10 mos. In our trial, 7 pts were treated and no DLTs were observed in Phase 1b (Raje Blood 2015), and Phase 2 results are now presented.
Methods
Pts had measurable paraprotein, adequate BM reserve and hepatic function with CrCl ≥45 mL/min. Refractory disease was defined as progression on or within 60 days of last therapy (RRMM). Pts with non-secretory MM, prior Pom or HDAC inhibitor therapy were excluded. Blood samples were obtained for PK/PD assessment of acetylated tubulin and histones. A sample size of 66 was determined to be adequate to detect an ORR of 44% against a historical rate of 29%.
Results
Phase 2 opened at a dose of 160 mg BID, with a predetermined SRC review to occur after 6 pts had completed 1 cycle of therapy. No DLTs were observed with 160 mg BID dosing; however, diarrhea or fatigue leading to dose reductions prompted SRC recommendation for QD dosing in ongoing Phase 2 to maintain maximum therapeutic exposure. Enrollment was closed in Nov 2015 after 96 pts were enrolled in Phase 2. Med age was 67 (39-87) yrs and med number of prior regimens was 2 (2-7). 93% were refractory to Len, 64% were refractory to Btz, and 49% were refractory to both Len and Btz as defined in the entry criteria. Treatment was very well tolerated and common toxicities were predominantly low grade and included neutropenia (44%), fatigue (39%), anemia (30%), diarrhea (28%), thrombocytopenia (19%) and upper respiratory tract infection (16%). Important related grade 3/4 toxicities included neutropenia (22%), thrombocytopenia (7%), anemia (5%), diarrhea (4%), and fatigue (3%). Serious related adverse events reported included bradycardia (n=1), bronchitis (n=1), chronic cardiac failure (n=1), dehydration (n=1), dyspnea (n=1), febrile neutropenia (n=1), general physical health deterioration (n=1), hypoxia (n=1), pneumonia (n=2), renal failure (n=1), and thrombocytopenia (n=1). PK/PD relationship demonstrates selective inhibition of HDAC6 (increasing acetylated tubulin) vs. nonselective HDAC inhibition (increasing acetylated histones) at therapeutic doses. There was no evidence of Rico accumulation or drug-drug interaction with Pom. 84 efficacy evaluable pts at 4 mos med follow-up demonstrated: PR or better (ORR) of 36%, MR or better (clinical benefit rate, CBR) of 52%, SD or better (disease control rate, DCR) of 89%, med PFS of 5.5 mos, and med DOR of 9 mos. Of these pts, 51 were enrolled at least 6 mos prior to the data cut, with a 5 mos med follow-up and demonstrated an ORR of 47%, CBR of 63%, DCR of 90%, med PFS of 7 mos, and med DOR of 13 mos. This compares favorably to the MM-003 trial of 16.6% ORR at time of primary PFS analysis (med follow-up of 18.1 wks) and ORR of 31% (10 mos med follow-up), as well as similar data from MM -002, with efficacy data continuing to mature.
Conclusion
These results establish proof of concept and demonstrate that the addition of ricolinostat (a potent oral selective HDAC6 inhibitor) to Pom/Dex is an active regimen in RRMM, leading to superior and durable responses compared to the historical experience with Pom/Dex alone in RRMM.
Session topic: Experimental approaches for plasma cell disorders
Keyword(s): HDAC inhibitor, Multiple myeloma, Phase II
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:00 - 08:15
Location: Hall C14
Background
Ricolinostat (Rico, ACY-1215), an oral selective HDAC6 inhibitor, is well tolerated as monotherapy (Raje Blood 2012) and demonstrates potent synergistic activity with lenalidomide (Len) and pomalidomide (Pom) in preclinical models (Quayle Blood 2013). Pan-HDAC inhibitors vorinostat and panobinostat are active in MM in combo with bortezomib (Btz) and Len, but toxicities limit dosing and treatment exposure, with resulting diminished efficacy. Rico selectively targets HDAC6 while retaining reduced and tolerable levels of HDAC1, 2, 3 inhibition that down-regulates expression of critical transcription factors regulating cancer cell proliferation, such as c-Myc and IRF4.
Aims
This trial explored activity of Rico in combo with Pom and dexamethasone (Dex) in a population comparable to both the MM-002 and MM-003 trials for Pom/Dex (Richardson Blood 2015; San Miguel Lancet Oncol 2013). At the primary endpoint of PFS in MM-003, the ORR was 16.6% at 18.1 wks med follow-up, and was 31% at 10 mos. In our trial, 7 pts were treated and no DLTs were observed in Phase 1b (Raje Blood 2015), and Phase 2 results are now presented.
Methods
Pts had measurable paraprotein, adequate BM reserve and hepatic function with CrCl ≥45 mL/min. Refractory disease was defined as progression on or within 60 days of last therapy (RRMM). Pts with non-secretory MM, prior Pom or HDAC inhibitor therapy were excluded. Blood samples were obtained for PK/PD assessment of acetylated tubulin and histones. A sample size of 66 was determined to be adequate to detect an ORR of 44% against a historical rate of 29%.
Results
Phase 2 opened at a dose of 160 mg BID, with a predetermined SRC review to occur after 6 pts had completed 1 cycle of therapy. No DLTs were observed with 160 mg BID dosing; however, diarrhea or fatigue leading to dose reductions prompted SRC recommendation for QD dosing in ongoing Phase 2 to maintain maximum therapeutic exposure. Enrollment was closed in Nov 2015 after 96 pts were enrolled in Phase 2. Med age was 67 (39-87) yrs and med number of prior regimens was 2 (2-7). 93% were refractory to Len, 64% were refractory to Btz, and 49% were refractory to both Len and Btz as defined in the entry criteria. Treatment was very well tolerated and common toxicities were predominantly low grade and included neutropenia (44%), fatigue (39%), anemia (30%), diarrhea (28%), thrombocytopenia (19%) and upper respiratory tract infection (16%). Important related grade 3/4 toxicities included neutropenia (22%), thrombocytopenia (7%), anemia (5%), diarrhea (4%), and fatigue (3%). Serious related adverse events reported included bradycardia (n=1), bronchitis (n=1), chronic cardiac failure (n=1), dehydration (n=1), dyspnea (n=1), febrile neutropenia (n=1), general physical health deterioration (n=1), hypoxia (n=1), pneumonia (n=2), renal failure (n=1), and thrombocytopenia (n=1). PK/PD relationship demonstrates selective inhibition of HDAC6 (increasing acetylated tubulin) vs. nonselective HDAC inhibition (increasing acetylated histones) at therapeutic doses. There was no evidence of Rico accumulation or drug-drug interaction with Pom. 84 efficacy evaluable pts at 4 mos med follow-up demonstrated: PR or better (ORR) of 36%, MR or better (clinical benefit rate, CBR) of 52%, SD or better (disease control rate, DCR) of 89%, med PFS of 5.5 mos, and med DOR of 9 mos. Of these pts, 51 were enrolled at least 6 mos prior to the data cut, with a 5 mos med follow-up and demonstrated an ORR of 47%, CBR of 63%, DCR of 90%, med PFS of 7 mos, and med DOR of 13 mos. This compares favorably to the MM-003 trial of 16.6% ORR at time of primary PFS analysis (med follow-up of 18.1 wks) and ORR of 31% (10 mos med follow-up), as well as similar data from MM -002, with efficacy data continuing to mature.
Conclusion
These results establish proof of concept and demonstrate that the addition of ricolinostat (a potent oral selective HDAC6 inhibitor) to Pom/Dex is an active regimen in RRMM, leading to superior and durable responses compared to the historical experience with Pom/Dex alone in RRMM.
Session topic: Experimental approaches for plasma cell disorders
Keyword(s): HDAC inhibitor, Multiple myeloma, Phase II
Abstract: S813
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:00 - 08:15
Location: Hall C14
Background
Ricolinostat (Rico, ACY-1215), an oral selective HDAC6 inhibitor, is well tolerated as monotherapy (Raje Blood 2012) and demonstrates potent synergistic activity with lenalidomide (Len) and pomalidomide (Pom) in preclinical models (Quayle Blood 2013). Pan-HDAC inhibitors vorinostat and panobinostat are active in MM in combo with bortezomib (Btz) and Len, but toxicities limit dosing and treatment exposure, with resulting diminished efficacy. Rico selectively targets HDAC6 while retaining reduced and tolerable levels of HDAC1, 2, 3 inhibition that down-regulates expression of critical transcription factors regulating cancer cell proliferation, such as c-Myc and IRF4.
Aims
This trial explored activity of Rico in combo with Pom and dexamethasone (Dex) in a population comparable to both the MM-002 and MM-003 trials for Pom/Dex (Richardson Blood 2015; San Miguel Lancet Oncol 2013). At the primary endpoint of PFS in MM-003, the ORR was 16.6% at 18.1 wks med follow-up, and was 31% at 10 mos. In our trial, 7 pts were treated and no DLTs were observed in Phase 1b (Raje Blood 2015), and Phase 2 results are now presented.
Methods
Pts had measurable paraprotein, adequate BM reserve and hepatic function with CrCl ≥45 mL/min. Refractory disease was defined as progression on or within 60 days of last therapy (RRMM). Pts with non-secretory MM, prior Pom or HDAC inhibitor therapy were excluded. Blood samples were obtained for PK/PD assessment of acetylated tubulin and histones. A sample size of 66 was determined to be adequate to detect an ORR of 44% against a historical rate of 29%.
Results
Phase 2 opened at a dose of 160 mg BID, with a predetermined SRC review to occur after 6 pts had completed 1 cycle of therapy. No DLTs were observed with 160 mg BID dosing; however, diarrhea or fatigue leading to dose reductions prompted SRC recommendation for QD dosing in ongoing Phase 2 to maintain maximum therapeutic exposure. Enrollment was closed in Nov 2015 after 96 pts were enrolled in Phase 2. Med age was 67 (39-87) yrs and med number of prior regimens was 2 (2-7). 93% were refractory to Len, 64% were refractory to Btz, and 49% were refractory to both Len and Btz as defined in the entry criteria. Treatment was very well tolerated and common toxicities were predominantly low grade and included neutropenia (44%), fatigue (39%), anemia (30%), diarrhea (28%), thrombocytopenia (19%) and upper respiratory tract infection (16%). Important related grade 3/4 toxicities included neutropenia (22%), thrombocytopenia (7%), anemia (5%), diarrhea (4%), and fatigue (3%). Serious related adverse events reported included bradycardia (n=1), bronchitis (n=1), chronic cardiac failure (n=1), dehydration (n=1), dyspnea (n=1), febrile neutropenia (n=1), general physical health deterioration (n=1), hypoxia (n=1), pneumonia (n=2), renal failure (n=1), and thrombocytopenia (n=1). PK/PD relationship demonstrates selective inhibition of HDAC6 (increasing acetylated tubulin) vs. nonselective HDAC inhibition (increasing acetylated histones) at therapeutic doses. There was no evidence of Rico accumulation or drug-drug interaction with Pom. 84 efficacy evaluable pts at 4 mos med follow-up demonstrated: PR or better (ORR) of 36%, MR or better (clinical benefit rate, CBR) of 52%, SD or better (disease control rate, DCR) of 89%, med PFS of 5.5 mos, and med DOR of 9 mos. Of these pts, 51 were enrolled at least 6 mos prior to the data cut, with a 5 mos med follow-up and demonstrated an ORR of 47%, CBR of 63%, DCR of 90%, med PFS of 7 mos, and med DOR of 13 mos. This compares favorably to the MM-003 trial of 16.6% ORR at time of primary PFS analysis (med follow-up of 18.1 wks) and ORR of 31% (10 mos med follow-up), as well as similar data from MM -002, with efficacy data continuing to mature.
Conclusion
These results establish proof of concept and demonstrate that the addition of ricolinostat (a potent oral selective HDAC6 inhibitor) to Pom/Dex is an active regimen in RRMM, leading to superior and durable responses compared to the historical experience with Pom/Dex alone in RRMM.
Session topic: Experimental approaches for plasma cell disorders
Keyword(s): HDAC inhibitor, Multiple myeloma, Phase II
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:00 - 08:15
Location: Hall C14
Background
Ricolinostat (Rico, ACY-1215), an oral selective HDAC6 inhibitor, is well tolerated as monotherapy (Raje Blood 2012) and demonstrates potent synergistic activity with lenalidomide (Len) and pomalidomide (Pom) in preclinical models (Quayle Blood 2013). Pan-HDAC inhibitors vorinostat and panobinostat are active in MM in combo with bortezomib (Btz) and Len, but toxicities limit dosing and treatment exposure, with resulting diminished efficacy. Rico selectively targets HDAC6 while retaining reduced and tolerable levels of HDAC1, 2, 3 inhibition that down-regulates expression of critical transcription factors regulating cancer cell proliferation, such as c-Myc and IRF4.
Aims
This trial explored activity of Rico in combo with Pom and dexamethasone (Dex) in a population comparable to both the MM-002 and MM-003 trials for Pom/Dex (Richardson Blood 2015; San Miguel Lancet Oncol 2013). At the primary endpoint of PFS in MM-003, the ORR was 16.6% at 18.1 wks med follow-up, and was 31% at 10 mos. In our trial, 7 pts were treated and no DLTs were observed in Phase 1b (Raje Blood 2015), and Phase 2 results are now presented.
Methods
Pts had measurable paraprotein, adequate BM reserve and hepatic function with CrCl ≥45 mL/min. Refractory disease was defined as progression on or within 60 days of last therapy (RRMM). Pts with non-secretory MM, prior Pom or HDAC inhibitor therapy were excluded. Blood samples were obtained for PK/PD assessment of acetylated tubulin and histones. A sample size of 66 was determined to be adequate to detect an ORR of 44% against a historical rate of 29%.
Results
Phase 2 opened at a dose of 160 mg BID, with a predetermined SRC review to occur after 6 pts had completed 1 cycle of therapy. No DLTs were observed with 160 mg BID dosing; however, diarrhea or fatigue leading to dose reductions prompted SRC recommendation for QD dosing in ongoing Phase 2 to maintain maximum therapeutic exposure. Enrollment was closed in Nov 2015 after 96 pts were enrolled in Phase 2. Med age was 67 (39-87) yrs and med number of prior regimens was 2 (2-7). 93% were refractory to Len, 64% were refractory to Btz, and 49% were refractory to both Len and Btz as defined in the entry criteria. Treatment was very well tolerated and common toxicities were predominantly low grade and included neutropenia (44%), fatigue (39%), anemia (30%), diarrhea (28%), thrombocytopenia (19%) and upper respiratory tract infection (16%). Important related grade 3/4 toxicities included neutropenia (22%), thrombocytopenia (7%), anemia (5%), diarrhea (4%), and fatigue (3%). Serious related adverse events reported included bradycardia (n=1), bronchitis (n=1), chronic cardiac failure (n=1), dehydration (n=1), dyspnea (n=1), febrile neutropenia (n=1), general physical health deterioration (n=1), hypoxia (n=1), pneumonia (n=2), renal failure (n=1), and thrombocytopenia (n=1). PK/PD relationship demonstrates selective inhibition of HDAC6 (increasing acetylated tubulin) vs. nonselective HDAC inhibition (increasing acetylated histones) at therapeutic doses. There was no evidence of Rico accumulation or drug-drug interaction with Pom. 84 efficacy evaluable pts at 4 mos med follow-up demonstrated: PR or better (ORR) of 36%, MR or better (clinical benefit rate, CBR) of 52%, SD or better (disease control rate, DCR) of 89%, med PFS of 5.5 mos, and med DOR of 9 mos. Of these pts, 51 were enrolled at least 6 mos prior to the data cut, with a 5 mos med follow-up and demonstrated an ORR of 47%, CBR of 63%, DCR of 90%, med PFS of 7 mos, and med DOR of 13 mos. This compares favorably to the MM-003 trial of 16.6% ORR at time of primary PFS analysis (med follow-up of 18.1 wks) and ORR of 31% (10 mos med follow-up), as well as similar data from MM -002, with efficacy data continuing to mature.
Conclusion
These results establish proof of concept and demonstrate that the addition of ricolinostat (a potent oral selective HDAC6 inhibitor) to Pom/Dex is an active regimen in RRMM, leading to superior and durable responses compared to the historical experience with Pom/Dex alone in RRMM.
Session topic: Experimental approaches for plasma cell disorders
Keyword(s): HDAC inhibitor, Multiple myeloma, Phase II
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