PHASE 1B RESULTS OF RICOLINOSTAT (ACY-1215) COMBINATION THERAPY WITH BORTEZOMIB AND DEXAMETHASONE IN PATIENTS WITH RELAPSED OR RELAPSED AND REFRACTORY MULTIPLE MYELOMA
Dan T. Vogl1, Noopur Raje2, Parameswaran Hari3, Sundar Jagannath4, David Tamang5, Simon S. Jones5, Jeffrey Supko1, Gina Leone5, Catherine Wheeler5, Robert Z. Orlowski6, Paul G. Richardson7, Sagar Lonial8
1University
2
3Medical
Poster # 4764
4Mt.
of Pennsylvania, Philadelphia, PA; Massachusetts General Hospital, Boston, MA;
College of Wisconsin, Milwaukee, WI;
Sinai Medical Center, New York, NY;
5Acetylon Pharmaceuticals, Boston, MA: 6MD Anderson Cancer Center, Houston, TX; 7Dana Farber Cancer Institute, Boston, MA; 8Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA
2400
2000
1600
1200
1200
800
Ricolinostat + Bortezomib + Dexamethasone
Dose Escalation Schema
QD ricolinostat (mg)
BID ricolinostat (mg)
Bortezomib (mg/m2) + Dexamethasone (20 mg)
40 + 1.0
40 + 1.3
80 + 1.3
160 + 1.3
240 + 1.3
160 + 1.3
160 + 1.3
160 + 1.3
Cohort 1
Cohort 2
Cohort 3
Cohort 4
Cohort 5
Cohort 6
1Cohort 6’
Cohort 6’ expansion
1 Combo
cohort 6’ is a repeat of combo cohort 6 with a reduced strength of ricolinostat drug product (12 mg/mL)
Phase 1b patients received ricolinostat either QD or BID on days 1-5, 8-12 of a 21-day cycle, with IV
bortezomib days 1, 4, 8 & 11 with oral dexamethasone 20 mg on days 1, 2, 4, 5, and 8, 9, 11, 12.
Data from active database as of October 29, 2014
• 160 mg BID* and 160 mg
BID ex* - exposure from
0 – 6 hr after the first of
two daily doses
• Bortezomib dose 1.3 mg/m2
• Dose groups 40 – 160 BID
dosed with 20 mg/mL form
• Expansion cohort (160 mg
BID*) dose with 12 mg/mL
form
• N = number of patients for
PK analysis
800
400
We report the first part of a phase 1b open label dose escalation study of ricolinostat in
combination with Btz and dexamethasone (Dex) using a standard 3+3 design. Eligible pts 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. Ricolinostat was given
orally QD or BID on days 1-5 and 8-12 of a 21 day cycle, with Btz on days 1, 4, 8, 11 and Dex on
days 1, 2, 4, 5, 8, 9, 11, 12. Peripheral blood samples were obtained for pharmacokinetic (PK)
and pharmacodynamic assessments of acetylated tubulin (HDAC6 inhibition) and acetylated
histones (Class 1 HDAC inhibition). Definitions of response, relapsed and refractory were by
IMWG criteria (Rajkumar SV Blood:2011;117(18):4691-5) and included response less than
minimal response (MR) as refractory. Seventeen pts were treated in an expansion cohort.
Definitions and response criteria follow IMWG consensus panel (Rajkumar SV, et al. Blood
2011; 117(18):4691-5)
Ph 1b Cohorts
2000
1600
Methods
Most Common Treatment Emergent
Adverse Events (≥15%): All Cohorts/Grade 1 & 2
Serious Adverse Events (BID)
2400
AUC0-6 (ng/h/mL)
Ricolinostat is the first selective oral HDAC6 inhibitor studied clinically in the treatment of
multiple myeloma (MM). Preclinical and phase 1a clinical data support the hypothesis that the
safety profile of a selective HDAC inhibitor will facilitate combination therapy with other active
agents. No dose limiting toxicities (DLT) were noted in 15 patients (pts) in a phase 1a dose
escalation study of ricolinostat at doses up to 360 mg/day where the best response was stable
disease (SD) (Raje Blood 2012;120:4061). HDAC6 inhibition impairs the aggresome/autophagy
pathway, an alternate pathway to proteasome clearance of misfolded proteins (Santo L Blood
2012;119(11):2578-89) providing the rationale for combining ricolinostat with bortezomib (Btz).
Figure 1. Pharmacokinetics of Ricolinostat on Cycle 1 Day 1 and Day 11 in Combination with
Bortezomib
Cmax (ng/mL)
Background
400
0
0
40 QD (n=3)
80 QD (n=3)
Cmax Day 1
160 QD (n=3)
240 QD (n=3)
Ricoinostat Dose (mg)
Cmax Day 11
160 BID* (n=3)
AUC(0-6) Day 1
160 BID ex*
(n=12)
AUC(0-6) Day 11
• Ricolinostat exposure (AUC0-6h) increases with dose up to ≥ 160 mg
• Ricolinostat exposures at ≥ 160 mg QD and after the 1st of two daily doses (160 mg BID or 160 mg BID
expansion cohort) are similar – no accumulation observed Day 1 vs Day 11
• Ricolinostat PK similar in the presence of bortezomib compared to ricolinostat alone (data not shown)
Responses to Ricolinostat in Combination
with
Bortezomib
ACY-1215
(mg) and Dexamethasone
All Patients
Bortezomib Refractory
43
29
14
27
14
13
Enrolled
Evaluable for response
Withdrew prior to C2D15
Responses
CR
VGPR
PR
MR
SD
PD
ORR (>PR) in evaluable pts
ORR (>PR) in all pts
Clinical benefit (>MR) in all pts
0
3
10
2
10
4
45%
30%
34%
Preferred Term
Any Grade 1 or 2
Treatment-Emergent AE
Diarrhoea
Thrombocytopenia [1]
Blood creatinine increased
Fatigue
Nausea
Hypokalaemia
Throat Irritation [2]
Cough
Anaemia
Decreased appetite
Neuropathy peripheral
Oedema peripheral
Upper respiratory tract infection
Dizziness
Pyrexia
Vomiting
Cohorts
1-5
Combined
N (%)
Cohorts
6 and 6'
N (%)
Cohort 6
N (%)
Cohort 6'
N (%)
Overall
N (%)
19 (100)
7 (37)
7 (37)
9 (47)
6 (32)
4 (21)
4 (21)
2 (10)
4 (21)
4 (21)
5 (26)
4 (21)
3 (16)
4 (21)
3 (16)
4 (21)
1 ( 5)
24 (100)
16 (67)
10 (42)
5 (21)
8 (33)
9 (37)
7 (29)
9 (37)
6 (25)
5 (21)
4 (17)
4 (17)
5 (21)
4 (17)
4 (17)
3 (12)
6 (25)
3 (100)
2 (67)
2 (67)
0
2 (67)
1 (33)
2 (67)
1 (33)
1 (33)
1 (33)
1 (33)
1 (33)
1 (33)
1 (33)
0
0
0
21 (100)
14 (67)
8 (38)
5 (24)
6 (27)
8 (38)
5 (24)
8 (38)
5 (24)
4 (19)
3 (14)
3 (14)
4 (19)
3 (14)
4 (19)
3 (14)
6 (29)
43 (100)
23 (53)
17 (40)
14 (33)
14 (33)
13 (30)
11 (26)
11 (26)
10 (23)
9 (21)
9 (21)
8 (19)
8 (19)
8 (19)
7 (16)
7 (16)
7 (16)
Most Common Treatment Emergent
Adverse Events (≥15%) All Cohorts / Grade 3 & 4
0
1
3
2
5
3
29%
14%
21%
Term 1
40 QD +
1.0 + dex
N (%)
40 QD +
1.3 + dex
N (%)
80 QD +
1.3 + dex
N (%)
160 QD +
1.3 + dex
N (%)
240 QD+
1.3 + dex
N (%)
160 BID +
1.3 + dex
N (%)
Total
N = 43
N (%)
Thrombocytopenia [1]
3 (43)
1 (33)
0
2 (67)
0
12 (50)
18 (42)
0
1 (33)
1 (33)
1 (33)
0
5 (21)
8 (19)
Anemia
Note: If a patient experienced more than one episode of an adverse event, the patient is
counted once for that Preferred Term.
Note: Incidences are displayed in descending order of frequency by preferred term based on
the overall frequency.
[1] Thrombocytopenia includes thrombocytopenia and platelet count decreased.
Diarrhea Events Occur Earlier with BID Dosing in Expansion Cohort
1 Definitions
and response criteria follow IMWG consensus panel (Rajkumar SV, et al. Blood 2011;
117(18):4691-5)
Cycle Duration and Prior Bortezomib Status
N (%)
Patients Enrolled
Dosage
Adverse Event
6
6
6
6
6
160 BID + 1.3 + Dex
160 BID + 1.3 + Dex
160 BID + 1.3 + Dex
160 BID + 1.3 + Dex
160 BID + 1.3 + Dex
6’
160 BID + 1.3 + Dex
6’
160 BID + 1.3 + Dex
6’
160 BID + 1.3 + Dex
6’
160 BID + 1.3 + Dex
6’
160 BID + 1.3 + Dex
6’
160 BID + 1.3 + Dex
6’
160 BID + 1.3 + Dex
6’
160 BID + 1.3 + Dex
6’
160 BID + 1.3 + Dex
RSV PNEUMONIA
PNEUMONIA
ORTHOSTATIC HYPOTENSION
PULMONARY EMBOLUS
TUMOR PAIN
ALTERED MENTAL STATUS
ASPIRATION PNEUMONIA
BRONCHITIS
DIARRHEA
PNEUMONIA
ACUTE KIDNEY INJURY
HERPES ZOSTER
ABDOMINAL PAIN
ALTERED MENTAL STATUS
DIARRHEA
ALTERED MENTAL STATUS
HYPOKALEMIA
INFLUENZA B
LUNG INFECTION-PNEUMONIA
SEPTIC SHOCK
INFLUENZA 3 VIRUS
ENTERITIS
FEVER
FEVER OF UNKNOWN ORIGIN
BILATERAL PULMONARY EMBOLISM
NAUSEA
VOMITING
DIARRHEA
43
Relationship to
ricolinostat
Possible
Unrelated
Possible
Possible
Unrelated
Unrelated
Unrelated
Unrelated
Possible
Unrelated
Possible
Possible
Possible
Unrelated
Possible
Unrelated
Unrelated
Unrelated
Unrelated
Unrelated
Severity (Grade)
2
3
3
5
3
2
2
3
2
5
1
3
2
1
2
5
3
3
4
5
3
3
3
3
3
3
3
2
Unrelated
Unrelated
Unrelated
Unrelated
Possible
Possible
Possible
Data from active database as of October 29, 2014
Responses for Ricolinostat in Combination with
Bortezomib and Dexamethasone, All Cohorts (QD vs BID)
All cohorts
QD (N)
BID (N)
Enrolled
Evaluable for response
Withdrew prior to C2D15
19
13
6
Responses
0
2
4
0
5
2
46%
32%
24
16
8
CR
VGPR
PR
MR
SD
PD
ORR (≥PR) in evaluable pts
Clinical benefit (>MR) in all pts
Part 2: Patient Demographics & Disease Characteristics
Characteristic
Cohort
0
1
6
2
5
2
44%
38%
Age, years
Median (range)
64 (46 - 83)
Sex
Male / Female
28 (65) / 15 (35)
White
28 (65)
Black
10 (23)
Patients
QD (N)
BID (N)
Asian
2 (5)
Other
3 (7)
Enrolled
Evaluable for response
Withdrew prior to C2D15
13
8
7
2
2 (5)
3
6 (14)
4
7 (16)
>4
Median (range)
Relapsed (not refractory)
28 (65)
5 (2-13)
10 (23)
Refractory to most recent therapy
33 (77)
Prior Treatment with Lenalidomide
38 (88)
14
6
8
Responses
0
1
0
0
4
1
17%
7%
Bortezomib Refractory
27 (63)
Race
Prior Therapies
Patients with Reports
Available
Any
FISH
Abnormality*
24/43 (56)
Responses for Ricolinostat in Bortezomib Refractory Patients Only (QD vs BID)
Characteristics of Early Withdrawal Patients
• QD patients (6/19) (32%)
• 1 DLT (elevated amylase)
• 4 PD after cycle 1
• AE: 1 asymptomatic elevated amylase in cycle 2 that did not resolve to <2.
• BID patients (8/24) (33%)
• 3 PD
• 5 AE
• Fatal sepsis, considered unrelated
• Fatal pneumonia, unrelated, after hospitalization for grade 2 diarrhea
• Grade 3 related fatigue (no dose reduction)
• Grade 3 nausea and vomiting, grade 2 diarrhea despite dose reduction
• Missed doses due to zoster, grade 2 diarrhea; elevated LFTs (AE) despite dose
reduction led to discontinuation in cycle 2
Expanded Cohort Rationale
For cohorts 1 – 5 (40 – 240 mg QD) and cohort 6 (160 mg BID) the 20 mg/mL strength
16 (66)
formulation of ricolinostat was used. In cohort 6’ (160 mg BID) the 12 mg/mL reduced
del(17p), t(4;14), or t(14;16)
5 (21)
strength formulation was introduced. The two strength formulations at the 160 mg dose level
t(11;14)
1 (4)
3+
2 (8)
Other abnormality
8 (33)
*Not all subcategories of abnormalities are presented, and patient could present with more than 1
abnormality.
expansion cohort 6’ of 17 additional patients using the 12 mg/mL strength formulation.
Patient Population: QD vs BID
Most Common Treatment Emergent
Adverse Events (≥15%) by CTCAE Grade
QD (Cohorts 1-5)
Characteristics
N (%)
Characteristics
N (%)
Patients enrolled
19
Patients enrolled
24
Age, years
Sex
Median (range)
64 (48-84)
Male / Female
13 (68) / 6 (32)
White
Age, years
Median (range)
15 (63) / 9 (38)
14 (74 )
White
14 (58 )
Black
4 (21 )
Black
6 (25 )
Asian
1 (5 )
Asian
1 (4 )
Other
0 (0)
Other
3 (13 )
2
2 (11)
2
0 (0)
3
2 (11)
3
4 (17)
4
4 (21)
4
3 (13)
>4
11 (58)
>4
17 (71)
Median (range)
5 (2-10)
Median (range)
5.5 (3-13)
Prior therapies
Sex
Race
Prior therapies
• Ricolinostat is tolerable with clinical benefit in combination with
bortezomib/dexamethasone
• No differences in PK were observed for the strength formulations
• Toxicities were generally manageable
• Diarrhea and vomiting were more prevalent with BID dosing, but severe
diarrhea was rare (grade 3, 7%)
• Other grade 3 and 4 toxicities were mainly hematologic and all manageable
• BID dosing led to more SAEs and early treatment discontinuation
• Responses were observed in this heavily pretreated population:
• Efficacy Evaluable Population (ORR 45%)
• ITT population (ORR 30%)
• An expansion cohort at 160 mg QD is ongoing in order to better define a
recommended Phase 2 dose.
Of the 43 pts enrolled:
 QD
7 of 19 pts (37%) experienced at least 1 SAE with a total of
10 SAEs
 BID
15 of 24 pts (63%) experienced at least 1 SAE with a total
of 29 SAEs
 BID cohorts experienced a greater incidence of SAEs
Serious Adverse Events (QD)
68 (49-84)
Male / Female
Race
Number of Subjects (N = 43)
BID (Cohorts 6, 6’ & 6’ Exp)
0
0
3
2
1
2
38%
38%
Summary and Conclusions
Serious Adverse Events (QD vs BID)
are comparable in exposure (see Fig. 1). Based on the safety data and the pharmacologic
exposure plateau between 80 and 160 mg the SRC chose 160 mg BID as the dose for the
CR
VGPR
PR
MR
SD
PD
ORR (≥PR) in evaluable pts
Clinical benefit (≥MR) in all pts
Acknowledgements
Cohort
Dosage
Adverse Event
Relationship to
ricolinostat
Severity
(Grade)
1
40 QD + 1.0 + Dex
SQUAMOUS CELL CARCINOMA
Unrelated
3
CONGESTIVE HEART FAILURE
Unrelated
4
1
40 QD + 1.0 + Dex
INCREASE IN AMYLASE
NEUTROPENIC FEVER
SHORTNESS OF BREATH
Possible
Unrelated
Unrelated
4
3
4
1
40 QD + 1.0 + Dex
DYSPNEA ON EXERTION, NO HYPOXIA
Unrelated
2
1
40 QD + 1.0 + Dex
PRESUMED BACTERIAL PNEUMONIA
Unrelated
3
2
40 QD + 1.3 + Dex
STREPTOCOCCUS PNEUMONIA BACTEREMIA
Unrelated
1
Relapsed myeloma
6 (32)
Relapsed myeloma
4 (17)
2
40 QD + 1.3 + Dex
INFLUENZA A
Unrelated
3
Refractory myeloma
13 (68)
Refractory myeloma
20 (83)
5
240 QD + 1.3 + Dex
BRONCHIAL INFECTION
Unrelated
3
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.

Madrid, 6 de Abril de 2.015 Queridos compañeros Te informamos

DeinesGartens - Kaster-Schwollen

治療有効率