(ricolinostat), a selective histone deacetylase 6 inhibitor, in

ACY-1215 (RICOLINOSTAT), A SELECTIVE HISTONE DEACETYLASE 6 INHIBITOR, IN COMBINATION WITH LENALIDOMIDE AND DEXAMETHASONE:
RESULTS OF A PHASE 1B TRIAL IN RELAPSED AND RELAPSED REFRACTORY MULTIPLE MYELOMA
Andrew J Yee1, Peter Voorhees2, William Bensinger3, Jesus Berdeja4, Jeffrey Supko1, Paul G. Richardson5, Simon S. Jones6, Gretchen Patrick6, Catherine Wheeler6 and Noopur Raje1
1Massachusetts
Poster # 4772
General Hospital Cancer Center, Boston, MA; 2University of North Carolina, Chapel Hill, NC; 3Fred Hutchinson Cancer Treatment Center, Seattle, WA; 4Sarah Cannon Research Institute, Nashville, TN; 5Dana-Farber Cancer Institute, Boston, MA; 6Acetylon Pharmaceuticals, Boston, MA
Background
Most Common Treatment Emergent
Adverse Events (≥15%) were Low Grade
Ricolinostat is the first oral, selective HDAC6 inhibitor in clinical trials and was well tolerated as
monotherapy up to 360 mg/day, the maximum dose examined (Raje, ASH 2012). Ricolinostat
synergizes in vitro with both lenalidomide (len) and pomalidomide in multiple myeloma (MM)
cell lines and down-regulates MYC and IRF4 protein expression (Quayle, ASH 2013).
Pharmacodynamics
Figure 2. Selective Increase in Acetylated Tubulin with Increasing Plasma Levels of Ricolinostat
Total*
N=27 (%)
Grade 1 & 2
N=27 (%)
Grade 3 & 4
N=27 (%)
Fatigue
14 (52)
9 (33)
5 (19)
Anaemia
11 (41)
10 (37)
1 (4)
Relapsed and relapsed-and-refractory MM patients who have progressed on at least one prior
treatment regimen, with creatinine clearance ≥50 mg/mL/min, adequate bone marrow and
hepatic function, and who gave informed consent were enrolled.
In Regimen A, patients were treated with escalating doses of oral ricolinostat on Days 1-5 and
8-12 of a 28-day cycle with lenalidomide 15-25 mg Days 1-21 and dexamethasone 40 mg
weekly.
In Regimen B, ricolinostat was also given on Days 15-19. Doses up to 240 mg QD and 160 mg
BID were explored.
A final cohort (Regimen C) treated with 160 mg ricolinostat BID for 21 of 28 days is currently
enrolling. Peripheral blood samples were obtained for pharmacokinetic (PK) and
pharmacodynamic (PD) analysis.
All response assessments were performed according to modified IMWG criteria.
Upper respiratory tract infection
10 (37)
10 (37)
0
Diarrhoea
8 (30)
7 (26)
1 (4)
Hypophosphataemia
8 (30)
6 (22)
2 (7)
Neutropenia
8 (30)
0
8 (30)
Amylase increased
7 (26)
7 (26)
0
Headache
6 (22)
6 (22)
0
Muscle spasms
6 (22)
6 (22)
1 (4)
Constipation
5 (19)
5 (19)
0
Hypertension
5 (19)
4 (15)
1 (4)
Nausea
5 (19)
5 (19)
0
5 (19)
5 (19)
0
Ricolinostat + Lenalidomide + Dexamethasone
Platelet count decreased
5 (19)
5 (19)
0
Total Absolute Events (≥15% )
103
85/103 (83)
18/103 (17)
Treatment Emergent Adverse Event
Methods
Cohort 1
40 + 15
Cohort 6
160 QD x 3 weeks + 25
Cohort 2
40 + 25
Cohort 7
160 BID x 3 weeks + 25
Lenalidomide Naïve
4
Lenalidomide Sensitive
9
Full Dose Lenalidomide Refractory
10
Maintenance Lenalidomide Refractory
2
Best Response to ricoliniostat
VGPR = 3
PR = 1
sCR = 2
VGPR = 2
PR = 3
MR = 1
SD = 1
PR = 5
MR = 2
SD = 3
VGPR = 1
MR = 1
Excludes one patient with unconfirmed PR and one patient not yet evaluable in Cohort 8
Maximum % Change in M-Protein by Cohort
Event
Description
Relationship to
ricolinostat
Severity
(Grade)
DLT
A/1/40
Neutropenia
Fatigue
Diarrhea
Neutropenia
Pneumonia
Atrial Fibrillation
Supraventricular
tachycardia
Bronchitis
Anemia
Neutropenia
Thrombocytopenia
Syncope
Neutropenia
Muscle Cramps
Migraine
Neutrophil count
decreased
Possible
Possible
Possible
Possible
Possible
Probable
3
3
3
3
3
3
No
No
No
No
No
No
Probable
3
No
Probable
Possible
Possible
Possible
Possible
Possible
Probable
Possible
3
3
4
3
3
3
3
3
No
No
No
No
Yes
No
Yes
No
Probable
3
No
A/4/160
Cohort 3
80 + 25
Cohort 4
160 + 25
A/5/240
Cohort 5
240 + 25
B/6/160
Cohort 8*
160 BID Days 1-21 + 25
*Regimen C per protocol
Data from active database as of October 29, 2014
B/7/160 BID
Patient Demographics & Disease Characteristics
Characteristic
B/7/160 BID
B/7/160 BID
B/8/160 BID D1-21
N (%)
Patients Enrolled
27
Age, years
Median (Range)
61 (46 - 77)
Sex
Male / Female
22/5 (81/19)
White
21 (78)
Black
4 (15)
Other
2 (7)
1
7 (26)
2
8 (30)
3
5 (19)
>3
7 (26)
Median (Range)
2 (1 – 9)
Relapsed to most recent MM therapy
12 (44)
Refractory to most recent MM therapy
15 (56)
Prior Lenalidomide Treatment
• Maximal biomarker signal (Cycle 1 Day 1) correlates with peak plasma levels of
ricolinostat (left) at ~1 hr post dose
• Selective inhibition of HDAC6 results in greater fold increase for Ac-tubulin (left) than
Class I HDAC marker Ac-histones (right)
Regimen/ Cohort/
ricolinostat (mg)
A/5/240
Number of Prior Therapies
Ac-Histone Fold Change (1hr)
Evaluable Patients
N=25
Cycle Duration and Prior Lenalidomide Status
Number Subjects (N = 27)
Grade 3 & 4 Adverse Events Related to Ricolinostat
Regimen B (mg)
ricolinostat QD or BID
Days 1-5, 8-12, 15-19 + Len Days 1-21
Weekly dose of Dexamethasone (40 mg) for All Cohorts
Race
(mg)
Ac-Tubulin Fold Change (1hr)
Prior Lenalidomide Status
*If a patient experiences more than one episode of an AE, event is noted once at highest severity grade
Data from active database as of October 29, 2014
Dose Escalation Schema
Regimen A (mg)
ricolinostat dose QD
Days 1-5, 8-12 + Len Days 1-21
ACY-1215
Oedema peripheral
Outcome by Prior Lenalidomide Treatment
B/8/160 BID D1-21
9 (43)
Lenalidomide Refractory
12 (57)
Responses to Ricolinostat in Combination
with Lenalidomide and Dexamethasone
¹ Incidences are displayed in order by dosing cohort. If a patient experiences more than one episode of a
related AE, event is noted once at highest severity grade
Ricolinostat is Well-Tolerated in Older Patients
21 (78)
Lenalidomide Sensitive
Excludes one patient with light chain only disease in Cohort 3; two patients with light chain only
disease in Cohort 7; one patient with IgD MM in Cohort 7; and one patient too early to assess in
Cohort 8 as of October 29, 2014 (from active database).
Data is from review of
active database as of
October 29, 2014
Grade 3 & 4 AEs
Median (Range)
All Study Patients (N=27)
1 (0-5)
Cycles on Study
Median (Range)
Patients Ongoing
N (%)
6 (1-27)
14 (52)
Best response
N (%)
sCR
2 (8)
VGPR
6 (24)
PR
8 (32)
MR
4 (16)
Patient Age Group (N=27)
Median G 3 & 4 AEs
(Range)
Median Cycles
(Range)
N (%) Ongoing
SD
5 (20)
≥75 years – N=4
3 (2-5)
12 (3-24)
2 (50)
PD
0
≤74 years – N=23
1 (0-3)
6 (1-27)
12 (52)
ORR (≥PR)
12 (64)
CLINICAL BENEFIT (≥MR)
Most Common Treatment Emergent
Adverse Events (≥15%) by CTCAE Grade
Patient Age Group (N=27)
Median G 3 & 4 AEs
(Range)
Median Cycles
(Range)
N (%) Ongoing
≥65 years – N=9
2 (1-5)
13 (3-27)
6 (67)
≤64 years – N=18
1 (0-3)
6 (1-25)
8 (44)
Figure 1. No Drug-Drug Interaction Between Ricolinostat and Lenalidomide
20 (80)
• 25 patients evaluable for response (one too early
to assess and one off-study after Cycle 1)
• 16/25 (64%) had ≥ PR, and 11/13 (85%)
lenalidomide sensitive or naïve patients had ≥ PR
• 13/25 (52%) patients have been withdrawn from
study
• PD (7)
• Missed lenalidomide doses (1)
• Patient choice/travel constraints (1)
• AE of secondary malignancy (1)
• Completed Cycle 6/alternate therapy (2)
• AE not responsive to dose reductions after 19
cycles (1)
Conclusions
•
dexamethasone at doses of up to 160 mg BID (days 1-5, 8-12, 15-19)
Continuous BID treatment for 21 days is ongoing
•
Most AEs were low grade and manageable
•
Two DLTs have been observed to date (grade 3 syncope and grade 3 muscle
cramps) at ricolinostat dose levels of 160 mg BID (days 1-5, 8-12, 15-19) and 160
mg BID (days 1-21) have been observed
•
Responses to Ricolinostat in
Lenalidomide Refractory Patients
N (%)
sCR
0
VGPR
1 (8)
PR
5 (42)
MR
3 (25)
Overall response rate (≥ PR) was 64% and clinical benefit rate (≥ MR) was 80%,
with 2 sCR and 6 VGPR responses
•
Best Response
Ricolinostat is well-tolerated when combined with lenalidomide and
Response rate was 85% in lenalidomide sensitive and lenalidomide naïve
patients, and 50% in patients refractory to lenalidomide
Acknowledgements
2500
AUC0-6 (ng*hr/mL)
2000
1500
1000
160 BID* exposure for 0 – 6 hr
after the first of two daily
doses
500
0
40 QD
80 QD
Rico Day 1
Number of Subjects (N = 27)
•
•
•
•
160 QD
Ricolinostat Dose (mg)
Rico Day 8/15
Len Day 1
240 QD
160 BID*
Len Day 8/15
Ricolinostat exposure (AUC0-6h) increases with dose up to 160 mg QD
Ricolinostat exposure at 240 mg QD and after the 1st of two daily doses (160 mg BID) is similar
No accumulation in plasma observed
Lenalidomide exposure (fixed dose of 25 mg QD) is similar on Day 8/15 vs Day 1 and across
ricolinostat dose groups (40 – 160 mg) indicating a lack of drug-drug interaction
SD
3 (25)
PD
0
ORR (≥PR)
6 (50)
CLINICAL BENEFIT (≥MR)
9 (75)
• 21/25 (84%) patients had prior lenalidomide
(full dose or maintenance)
• 12/21 (57%) patients were refractory to prior
lenalidomide
•
This study is sponsored by Acetylon Pharmaceuticals Inc.
•
The authors would like to thank all patients and their families who participated
in this study. We also thank the physicians, research nurses, study coordinators
and research staff involved.

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