Cancer Therapy: Clinical
Ricolinostat, the First Selective Histone
Deacetylase 6 Inhibitor, in Combination with
Bortezomib and Dexamethasone for Relapsed or
Refractory Multiple Myeloma
Dan T. Vogl
1
, Noopur Raje
2
, Sundar Jagannath
3
, Paul Richardson
4
, Parameswaran Hari
5
,
Robert Orlowski
6
, Jeffrey G. Supko
2
, David Tamang
7
, Min Yang
7
, Simon S. Jones
7
,
Catherine Wheeler
7
, Robert J. Markelewicz
7
, and Sagar Lonial
8
Abstract
Purpose: Histone deacetylase (HDAC) inhibition improves the
efficacy of proteasome inhibition for multiple myeloma but adds
substantial toxicity. Preclinical models suggest that the observed
synergy is due to the role of HDAC6 in mediating resistance to
proteasome inhibition via the aggresome/autophagy pathway of
protein degradation.
Experimental Design: We conducted a phase I/II trial of the
HDAC6-selective inhibitor ricolinostat to define the safety, pre-
liminary efficacy, and recommended phase II dose in combina-
tion with standard proteasome inhibitor therapy. Patients with
relapsed or refractory multiple myeloma received oral ricolinostat
on days 1–5 and 8–12 of each 21-day cycle.
Results: Si ngle-ag ent ricol inostat therapy resulted in neit her
significant toxicity nor clinical responses. Combinat ion therapy
with bortezomib and dex amethasone w as well- tolera ted duri ng
dose escal ation but led to dose-limiting diarrhea in an expan-
sion cohort at a ricolinostat dose of 16 0 mg twice daily.
Combination t herapy at a ricolinostat dose o f 160 mg daily in
a second expansion co hort was well t oler ated, with les s sever e
hematologic, gastrointestinal, and constitutional toxicities
compared with publ ished data on nonselective HDAC inhibi-
tors. The overall response rate in combination with daily rico-
linostat at 160 mg was 37%. The respo nse rate to combination
therapy among bo rtezomib -refract ory p atients was 14%. S am-
ples taken during therapy showed dose-dependent i ncreases of
acetylated tubulin in peri pheral blood lymphocytes .
Conclusions: At the recommended phase II dose of ricolinostat
of 160 mg daily, the combination with bortezomib and dexa-
methasone is safe, well-tolerated, and active, suggesting that
selective inhibition of HDAC6 is a promising approach to mul-
tiple myeloma therapy.
Clin Cancer Res; 23(13); 3307–15. 2017
AACR.
Introduction
Multiple myeloma is an incurable plasma cell malignancy with
a unique biology characterized by high levels of protein synthesis
and consequent endoplasmic reticulum (ER) stress and activation
of the unfolded protein response (UPR). Plasma cell differenti-
ation and survival depend on UPR activation, which results in
upregulation of protein degradation by the 26S proteasome. The
introduction of proteasome inhibitors into the multiple myeloma
therapeutic armamentarium has led to a dramatic improvement
in clinical outcomes (1–5). However, despite these advances,
multiple myeloma cells inevitably develop resistance to protea-
some inhibition, leading to disease progression.
The aggresome/autophagy pathway is a regulated degradative
process for cellular proteins (6) that is activated in response to
accumulation of cytosolic polyubiquitinated proteins in the set-
ting of proteasome inhibition, serving as an alternative route
for protein degradation (7) and thereby contributing to thera-
peutic resistance to proteasome inhibitor therapy. Histone dea-
cetylase 6 (HDAC6) is a cytosolic microtubule-associated deace-
tylase that mediates trafficking of ubiquitinated misfolded pro-
teins to the aggresome/autophagy pathway (8). Selective inhibi-
tion of HDAC6 increases a-tubulin acetylation and accumulation
of ubiquitinated proteins in multiple myeloma cells, with syner-
gistic cytotoxicity in combination with bortezomib (9). Clinical
trials with nonselective HDAC inhibitors in combination with
bortezomib and dexamethasone have shown improved outcomes
but also substantially increased toxicity (10, 11). The unique role
of HDAC6 in the aggresome/autophagy pathway raises the pos-
sibility that selective inhibition of HDAC6 may yield improved
efficacy and reduced toxicity when combined with proteasome
inhibition.
Ricolinostat (ACY-1215) is an orally available selective
HDAC6 inhibitor, with p reclinical data showing anti-myeloma
efficacy in combination with proteasome inhibitors, mediated
by inhibition of aut ophagic protein degradat ion an d increased
ER stress. (12, 13). We th erefore conducted a first-in-human
dose-escalation study of ricolinostat as a single a gent and then
1
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylva-
nia.
2
Massachusetts General Hospital, Boston, Massachusetts.
3
Mount Sinai
Medical Center, New York, New York.
4
Dana Farber Cancer Institute, Boston,
Massachusetts.
5
Medical College of Wisconsin, Milwaukee, Wisconsin.
6
MD
Anderson Cancer Center, Houston, Texas.
7
Acetylon Pharmaceuticals Inc.,
Boston, Massachusetts.
8
Emory University, Atlanta, Georgia.
Corresponding Author: Dan T. Vogl, Perelman Center for Advanced Medicine –
South Tower 12-176, 3400 Civic Center Boulevard, Philadelphia, PA 19104.
Phone: 215-615-6508; Fax: 215-615-5887; E-mail: dan.vogl@uphs.upenn.edu
doi: 10.1158/1078-0432.CCR-16-2526
2017 American Associati on for Cancer Research.
Clinical
Cancer
Research
www.aacrjournals.org
3307
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in combination with bortezomib and dexamethasone in
patients with relapsed or re fractory multiple myelom a. We
aimedtodefine the dose-limiting toxicities (DLT), maximu m
tolerated dose (MTD), pharmacokinetics and pharmacodynam-
ics o f ricolinostat alone and in c ombina tion with bortezomib
and dexamethasone and t o define the response rate and toxicity
profile of the combination regimen.
Materials and Methods
Study design
This study was designed as a 3-part, phase I/II, single-arm,
multicenter, open-label study in patients with relapsed or refrac-
tory multiple myeloma. Parts 1 and 2 of the study employed a
sequential group dose-escalation design of ricolinostat as mono-
therapy (part 1) and in combination with bortezomib and dexa-
methasone (part 2), with planned enrollment of up to 20 patients
in an expansion cohort at the MTD. Part 3 was intended to be a
Simon optimal 2-stage phase II trial at the MTD; however, on
the basis of the preliminary results of the part 2 expansion cohort,
we did not proceed with a formal phase II cohort and instead
enrolled an additional expansion cohort to explore a daily dose of
ricolinostat.
Population
Patients were eligible for enroll ment if they had mult iple
myeloma that was relapsed (progressed after the most recent
therapy) or refractory (progressed on or within 60 days after
completion of the most recent therapy ) after at least 2 prio r
lines of therapy. Patients had to have received a proteasome
inhibitor, an immunomodulatory drug, and an autologous
stem cell transplant as part of their prior therapy, unless they
were considered not to b e a candidate for these therapies by
their t reating physician. At enrollment, patients had to have
measurable disease parameters according to the International
Myeloma Working Group (IMWG) criteria (14). Patients wer e
at le ast 18 years old and had a Karnof sky Performance Sta tus of
70, adequate bone marrow reserve [absolute neutrophil
count 1.010
9
/L and platelet count 7510
9
/L (50
10
9
/L in patients in whom 50% of bone marrow nucleated cells
were plasma cells), calculated creatinine clearance 30 mL/min,
adequate hepa tic function (serum bilirubin < 2.0 mg/dL, serum
alanine transaminase (ALT ) and aspartate trans aminase (AST)
<3 t imes the upper li mit of normal (ULN)], and corrected
serum calcium ULN. Patients could not have received radio-
therapy or systemic anticancer therapy within 2 weeks of
starting therapy, aut ologou s stem cell transplant within 12
weeks, or any al logenei c stem cell transplant or HDAC inhib-
itor. Patient s were excluded i f they had gr ade 2 or higher
neuropathy, an active systemic infection, other active malig-
nancies, known human immunodeficie ncy virus, active hepa-
titis B viru s, or a ctiv e hepat itis C virus infection. Patients wer e
also excluded if th ey had New York He art Associat ion Class 3 o r
4 congestive heart failure, unstable angina, cardiac arrhythmia,
QTcF > 480 msec, myoca rdial infarction or stroke within 6
months, or sev ere hypertension, diabetes mellit us, or chronic
obstructive pulmonary disease. All patients provided written
informed consent prior to study participation.
Study treatment
Ricolinostat was administered as an oral liquid formulation
on days 1–5and8–12 of ea ch 21-da y cycle. Ricolinostat was
initially prepared as a 20 mg /mL solu tion; mid- way d uring the
study a 12 mg/mL solut ion was introduced with improved
stability at room temperat ure. Prespecified ricolinostat doses
during single-agent d ose escalation (part 1) were 40, 8 0, 160,
240, and 360 mg daily in s uccessive cohorts. In the combina-
tion cohorts (part 2), patients received b ortezomi b immedi-
ately after ricolinostat on days 1, 4, 8, and 11, with dexameth-
asone 20 mg administered orally 30 minutes after ricol inostat
on days 1, 2, 4, 5, 8, 9, 11, and 12. During dose escalatio n,
bortezomib was administered intravenously; when data
became available reg arding su bcutaneo us admini strati on of
bortezomib, we permitted switching to subcutaneous dosing
after compl eti on of the first 3-week cycle. In cohort 4 (d ose
expansion at ricolinosta t 160 mg daily), pa tients could start
therapy with either intravenous or subcutaneou s bortezomib
administration, at the investigator's discretion. Prespecified
dose levels for the combination therapy dose-escalatio n
cohorts are shown in Table 1, with ricolino stat doses r anging
from 40 mg daily (q.d.) to 160 mg twice daily (b. i.d.) and
bortezomib ad ministered at 1.0 mg/m
2
in the first combined
dose cohort and the standard 1.3 mg/m
2
subsequently.
Endpoints
The primary endpoints in the dose-escalation cohorts were
identification of DLTs and the MTD. Dose escalation occurred
usingastandard3þ 3 design, with enrollment of 3 patients to
each dose cohort, enrollment ofasecondgroupof3patientsif
1ofthefirst 3 experienced an DLT, and enrollment to the next
dose level permitted if fewer than 1 o f 3 or 2 of 6 pa tients at a
given dose level e xperienced a DLT. Toxicities were assessed
using t he National Cancer Institute Common Terminology
Criteria fo r Adverse Events versio n 4.0. DLT was defined as
one of the following events occurring du ring the first cycle of
therapy and considered t o be rela ted to ricolinostat: grade 4
neutropenia lasting >5 days; febrile n eutrope nia; grade 4 nau-
sea, vomiting, or diarrhea; grad e 3 nausea or vomiting persi st-
ing >72 hours; grade 3 diarrhea persisting >48 ho urs; or any
Translational Rele vance
Ricolinostat is the first isoform-selective histone deacetylase
(HDAC) inhibitor in human clinical trials, an approach to
drug development that utilizes rational targeting to achieve an
improved therapeutic index. Our data show that the combi-
nation of HDAC6-selective inhibition using ricolinostat with
the proteasome inhibitor bortezomib overcomes bortezomib
resistance in relapsed multiple myeloma, with a favorable
safety profile that offers potential advantages compared with
nonselective HDAC inhibition. Our findings validate preclin-
ical data showing that HDAC6-mediated trafficking of ubi-
quitinated proteins to the aggresome/autophagy pathway is a
relevant alternative mechanism of protein degradation for
cells exposed to proteasome inhibition and therefore a mech-
anism of therapeutic resistance to proteasome inhibition.
Incorporation of HDAC6-selective inhibition into the anti-
myeloma armamentarium therefore offers the prospect of
improved myeloma outcomes.
Vogl et al.
Clin Cancer Res; 23(13) July 1, 2017 Clinical Cancer Research3308
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other grade 3 nonhematologic tox icity, with the ex ception of
hyperglycemia in diabetic patients. Thrombocytopenia was
considered a DLT for p atients r eceiving single-agent ricolinostat
if it was grade 3 with grade 2 bleeding or grade 4 and for
patients receiving comb ination t herapy if it wa s grade 4 on 2
separate occasi ons unre sponsiv e to transfusion support. The
MTD w as defined as the dose immediately below the dose level
at which 2 of up to 6 pa tients expe rienced a DLT.
Responses were assessed according to standard IMWG crite-
ria (15). The overall response rate (ORR) was defined as the
sumoftheratesofstringentcompleteresponse(sCR),com-
plete response (CR), very good parti al response, and part ial
response (PR). The clinica l benefitrate(CBR)wasdefined as the
sumoftheORRandtherateofminimalresponse.Response
assessments (serum and urine) were conducted on day 15 of
each cycl e, with a bone marrow aspirate and biopsy requi red to
confirm CR.
Patients receiving bortezomib completed a neurotoxicity-
directed questionnaire from the Functional Assessment of Can-
cer/Gynecology Oncology Group (FACT/GOG) survey of neuro-
toxicity (16, 17).
Pharmacokinetic studies
Serial blood samples for pharmacokinetic assessments were
collected during the first cycle of therapy. In part 1, samples were
collected before and at 0.25, 0.5, 1, 2, 4, and 24 hours after the first
dose of ricolinostat, on days 4 and 8 before, 0.25, and 1 hour after
the morning ricolinostat dose, on day 11 before and at 0.25, 0.5, 1,
2, and 4 hours after ricolinostat, and on day 15. In part 2, samples
were collected at the same time intervals after the administration
of ricolinostat and bortezomib, with additional samples obtain-
ed 6 hours after dosing on days 1 and 11. Blood (6 mL) was drawn
from a peripheral vein into plastic tubes containing freeze-dried
sodium heparin, mixed by inversion, and placed over ice until
centrifuged (1,300 g, 10 minutes, 4
C). Plasma was removed
and stored at 80
C until assayed. The concentrations of ricoli-
nostat and bortezomib were concurrently determined using an
analytical method involving high-performance liquid chroma-
tography with tandem mass spectrometric detection. The assay
was validated and applied to the analysis of study samples as
recommended by the FDA Guidance for Industry: Bioanalytical
Method Validation, May 2001 (https://www.fda.gov/Drugs/
GuidancecomplianceRegulatoryInformation/Guidances/default.
htm). The lower limit of quantitation for both compounds was
0.50 ng/mL. Pharmacokinetic parameters were estimated by
analysis of the ricolinostat and bortezomib plasma concentra-
tion–time curves for individual patients by standard noncompart-
mental methods using WinNonlin Professional 5.0 software
(Pharsight Corp.) and are reported as the geometric mean SD
at each dose level.
Pharmacodynamic studies
Blood samples for pharmacodynamic assessment of acetylated
tubulin and acetylated histone levels were collected at baseline
and (in part 1) 1 and 4 hours after the first ricolinostat dose or (in
part 2) 0.25, 0.5, 1, 2, 4, 6, and 24 hours after the first bortezomib
dose. Blood samples were cryopreserved in equal volume of
freezing solution (10% DMSO in PBS v/v) and stored at 80
C.
Upon thaw, samples were fixed with 3.8% formaldehyde (2:1
formaldehyde/sample v/v) and stained with primary antibodies
for anti-tubulin (Sigma-Aldrich, #T7451) and anti-histone
H2BK5 (Cell Signaling Technologies, #2574) or isotype controls
(Rabbit IgG polyclonal Control antibody, Cell Signaling Tech-
nologies, #2729; mouse IgG2b, clone MOPC-141,Sigma-Aldrich,
#M5534). Samples were labeled with secondary DyLight488
antibodies (DyLight 488 goat anti-Mu-IgG, KPL #072-03-18-
06; DyLight 488 goat anti-Rb-IgG, KPL #072-03-15-16). The target
population was labeled with anti-CD3 (PE-Cy5 mouse anti-
human CD3, clone UCHT1, eBioscience # 15-0038). Data anal-
ysis was performed by gating on the CD3
þ
cells in FlowJo software
(Treestar, Inc.) and applying a mean fluorescent intensity (MFI)
statistic. Fold change of tubulin or histone acetylation was cal-
culated by subtracting the control IgG MFI from the sample MFI
and dividing the MFI of treated groups by the MFI of the control
[Fold change ¼ (Postdose Acetyl-MFI – Postdose IgG-MFI)/(Pre-
dose Acetyl-MFI – Predose IgG-MFI)]. Horizontal bars represent
arithmetic means. Error bars represent the SEM.
Statistical analysis
The size of the dose-escalation cohort was based on the con-
ventional 3 þ 3 dose-escalation design for phase I trials; conse-
quently, a formal sample size estimation was not performed. All
patients who received at least one dose of ricolinostat were
included in the toxicity analysis. Patients who discontinued
the study before the first response evaluation at the beginning
of cycle 2 were considered unevaluable for response. Data were
summarized using descriptive statistics. Time-to-event analysis,
including progression-free survival, was estimated using the
Kaplan–Meier method. The MFI of pharmacodynamic samples
used to calculate the fold change were assessed for statistical
difference by comparing the pre-dose signal to the 1-hour post-
dose signal of a given group using a paired, 2-tailed t test. Groups
where P 0.05 are indicated with an "
". Groups where P > 0.05
are indicated by "ns" (not significant). Statistical analyses were
Table 1. Phase Ib dose-escalation schema
Phase Ib dose-escalation schema (21-d cycle)
Phase Ib cohorts n
Ricolinostat
(Days 1–5, 8–12)
Bortezomib
(Cycles 1–5: Days 1, 4, 8, 11
Cycles 6þ: Days 1, 8)
Dexamethasone
(Cycles 1–5: Days 1, 2, 4, 5, 8, 9, 11, 12
Cycles 6þ: Days 1, 2, 8, 9)
Cohort 1 7 40 mg q.d. 1.0 mg/m
2
20 mg
Cohort 2 3 40 mg q.d. 1.3 mg/m
2
20 mg
Cohort 3 3 80 mg q.d. 1.3 mg/m
2
20 mg
Cohort 4 3 160 mg q.d. 1.3 mg/m
2
20 mg
Cohort 5 3 240 mg q.d. 1.3 mg/m
2
20 mg
Cohort 6 3 160 mg b.i.d. 1.3 mg/m
2
20 mg
Cohort 6
0
expansion 21 160 mg b.i.d. 1.3 mg/m
2
20 mg
Cohort 4
0
expansion 14 160 mg q.d. 1.3 mg/m
2
20 mg
Ricolinostat, Bortezomib, and Dexamethasone for Myeloma
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performed using SAS version 9.3 (SAS Institute, Inc.) and R
version 3.2.3 (R Foundation).
Results
Population
We enrolled 15 patients to 5 single-agent ricolinostat co horts
between August 2011 a nd Sept ember 2012 and 57 pa tients to
9 combina tion dose cohorts b etween May 2012 and September
2015. Pa tien t characteristics in the single-agent ricolinostat
cohorts (Table 2) included a median age o f 70 years and
median number of prior regimens of 4 (range, 2–11). Patient
characteristics in the combination dose cohorts (Table 2)
included a median age of 65 ye ars and median number of
prior regimens of 5 ( range, 2–12) . All p atients had received
prior bortezomib, a nd 33 % in the sin gle-ag ent ricol inostat
cohorts and 63% in the co mbinatio n dose cohorts were refrac-
tory to bortezomib, respectively.
Single-agent ricolinostat
DLTs and adverse events. We did not observe any DLTs during
single-agent dose escalation and therefore did not identify an
MTD. We did not explore doses higher than 360 mg q.d. because
pharmacokinetic analysis showed evidence of a plateau in expo-
sure at dose levels 160 mg, suggestive of saturable absorption of
the drug (see below).
The most common advers e events o bserved during therapy
(many attributed to dis ease or intercurrent illness) were renal
insufficiency (33%), fatigue (27%), anemia (20%), and diar-
rhea (20%). Diarrhea occurred only at ricolinostat dose s 160
mg q.d. The only grade 3 or 4 adverse events assessed by the
investigator as possibly related to ricolinostat were seen at
doses 160 mg q.d. and were all hema tolog ic abnorma lities ,
including anemia (at 160 mg q.d.) and neutropenia and leu-
kopenia (at 360 mg q.d.). Two patients experienced a serious
adverse ev ent (SAE), including grade 5 (fatal ) cardiac ar rest at
40 mg q.d. (which occurred 27 days after study treatment
was discontinued for disease progression) and an exacerbation
of chronic pulmonary disease at 16 0 mg q.d.; neit her was
considered to be rela ted to ricolinostat. No patient d iscontin-
ued single-agent ricolinostat because of a treatment-emergent
adverse event. Serial triplicate electro cardiograms show ed no
evidence of QT interval prolongation.
Response. Of the 15 patients treated with single-agent ricolinostat,
6 had stable disease for a median of 11 weeks (range, 5–30), and
no patient had a minor response or PR (Fig. 1).
Combination dosing with ricolinostat, bortezomib, and
dexamethasone
DLTs and adverse events. The first combination cohort was expand-
ed to 6 patients due to an asymptomatic increase in amylase. No
other DLTs were observed during dose escalation. Toxicities
observed during dose escalation (Table 3) were primarily low-
grade gastrointestinal toxicities, cytopenias, and fatigue. On the
basis of the combined pharmacokinetic and pharmacodynamic
data from the monotherapy and combination dose-escalation
cohorts, we enrolled an expansion cohort at the top dose of
ricolinostat (160 mg b.i.d.).
Of the 21 patients treated on the 160 mg b.i.d. expansion
cohort, 29% were hospitalized for reasons potentially related to
diarrhea and dehydration. Because of a concern that this repre-
sented excess toxicity with twice daily dosing, we enrolled a
second expansion cohort at a lower dose of ricolinostat (160
mg q.d.) to better understand the relationship between dose and
both toxicity and efficacy. Among the 24 patients who received
ricolinostat 160 mg b.i.d. (3 patients treated in the dose-escalation
cohort and 21 patients in the dose expansion cohort), the most
common treatment-emergent adverse events were thrombocyto-
penia (71%), diarrhea (67%), anemia (42%), fatigue (42%),
nausea (38%), hypokalemia (33%), vomiting (29%), peripheral
Table 2. Patient demographics
Characteristics Single-agent ricolinostat
Ricolinostat with
bortezomib and
dexamethasone
Combination therapy with
160 mg q.d. ricolinostat dosing
(cohorts 4, 4
0
,5)
Combination therapy with
160 mg b.i.d. ricolinostat dosing
(cohorts 6, 6
0
)
Patients enrolled N ¼ 15 N ¼ 57 N ¼ 20 N ¼ 24
Age, y
Median (range) 70 (51–79) 65 (47–84) 65 (47–83) 67 (48–84)
75 5 (33) 14 (25) 5 (25) 8 (33)
65–74 7 (47) 15 (26) 5 (25) 6 (25)
64 3 (20) 28 (49) 10 (50) 10 (42)
Sex
Male 10 (67) 35 (61) 12 (60) 15 (63)
Female 5 (33) 22 (39) 8 (40) 9 (38)
Race
White 8 (53) 39 (68) 16 (80) 14 (58)
Black or African American 6 (40) 13 (23) 4 (20) 6 (25)
Other 0 (0) 3 (5) 0 (0) 3 (13)
Asian 1 (7) 2 (4) 0 (0) 1 (4)
Prior regimens
Median (range) 4 (2–11) 5 (2–13) 5 (2–9) 7 (3–13)
Refractory to
Lenalidomide 7 (47) 38 (67) 13 (65) 17 (71)
Bortezomib 5 (33) 36 (63) 13 (65) 15 (63)
Pomalidomide 0 (0) 18 (32) 5 (25) 12 (50)
Cyclophosphamide 1 (7) 19 (33) 5 (25) 10 (42)
Carfilzomib 0 (0) 17 (30) 4 (20) 12 (50)
Thalidomide 0 (0) 12(21) 2 (10) 7 (29)
Vogl et al.
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neuropathy (29%), hyperglycemia (25%), and renal insufficiency
(21%; Table 3). Because of similar pharmacokinetic exposure at
doses of 240 mg daily and 160 mg daily (see below), we analyzed
patients treated at these 2 doses as a single cohort. Of the 20
patients receiving once daily ricolinostat at a dose of 160 mg or
greater (including 3 patients each treated at 160 mg q.d. and 240
mg q.d. during dose escalation and an additional 14 patients
treated at 160 mg q.d. during dose expansion), the most common
treatment-emergent adverse events were thrombocytopenia
(40%), anemia (35%), diarrhea (30%), hypertension (25%),
fatigue (25%), hyperglycemia (25%), renal insufficiency
(25%), nausea (25%), hypophosphatemia (20%), and hypona-
tremia (20%; Table 3). Similar to the single-agent cohort, we did
not observe any significant prolongation of the QT interval with
combination dosing.
Because the toxicity of bortezomib is greater with intravenous
dosing than with subcutaneous dosing (18), we analyzed toxicity
rates by route of bortezomib administration. Of the 20 subjects
treated with doses of ricolinostat 160 mg q.d. in combination
with bortezomib and dexamethasone, 10 received at least one full
Figure 1.
Treatment responses. A, Responses for the entire cohort of patients treated with (from left to right) single-agent ricolinostat, ricolinostat with bortezomib (Bz) and
dexamethasone (dex), ricolinostat 160 mg q.d. with Bz/dex, and ricolinostat 160 mg b.i.d. with Bz/dex. B, Responses among patients with bortezomib-
refractory myeloma treated with (from left to right) ricolinostat with Bz/dex, ricolinostat 160 mg q.d. with Bz/d ex, or ricolinostat 160 mg b.i.d. with Bz/dex. Numbers
indicate the percentage of patients in each category of response. MR, minimal response; PD, progressive disease; SD, stable disease; VGPR, very good partial
response.
Table 3. Treatment-emergent adverse events (in order of frequency of grade 3/4 events in patients receiving combined therapy with ricolinostat, bortezomib,and
dexamethasone)
Single-agent ricolinostat
Ricolinostat with
bortezomib and dexameth asone
Ricolinostat 160
mg q.d. with
bortezomib and
dexamethasone
(cohorts 4, 4
0
,5)
Ricolinostat 160 mg
b.i.d. with
bortezomib and
dexamethasone
(cohorts 6, 6
0
)
N ¼ 15 (%) N ¼ 57 (%) N ¼ 20 (%) N ¼ 24 (%)
Adverse event All grades Grade 3/4 All grades Grade 3/4 All grades Grade 3/4 All grades Grade 3/4
Thrombocytopenia 2 (13) 2 (13) 31 (54) 21 (37) 8 (40) 4 (20) 17 (71) 13 (54)
Anemia 3 (20) 1 (7) 23 (40) 11 (19) 7 (35) 4 (20) 10 (42) 5 (21)
Amylase elevation 0 (0) 0 (0) 8 (14) 6 (11) 1 (5) 1 (5) 3 (13) 1 (4)
Hypertension 0 (0) 0 (0) 8 (14) 6 (11) 5 (25) 4 (20) 2 (8) 1 (4)
Hypophosphatemia 2 (13) 1 (7) 10 (18) 5 (9) 4 (20) 2 (10) 2 (8) 1 (4)
Fatigue 4 (27) 0 (0) 20 (35) 4 (7) 5 (25) 1 (5) 10 (42) 2 (8)
Hypokalemia 1 (7) 0 (0) 15 (26) 4 (7) 3 (15) 1 (5) 8 (33) 2 (8)
Hyperglycemia 0 (0) 0 (0) 13 (23) 4 (7) 5 (25) 1 (5) 6 (25) 2 (8)
Pneumonia 0 (0) 0 (0) 6 (11) 4 (7) 0 (0) 0 (0) 4 (17) 3 (13)
Diarrhea 3 (20) 0 (0) 25 (44) 3 (5) 6 (30) 1 (5) 16 (67) 2 (8)
Peripheral neuropathy 0 (0) 0 (0) 15 (26) 3 (5) 3 (15) 0 (0) 7 (29) 1 (4)
Hyponatremia 1 (7) 0 (0) 9 (16) 3 (5) 4 (20) 1 (5) 3 (13) 1 (4)
Transaminase elevation 1 (7) 0 (0) 9 (16) 3 (5) 3 (15) 2 (10) 2 (8) 0 (0)
Febrile neutropenia 0 (0) 0 (0) 3 (5) 3 (5) 1 (5) 1 (5) 0 (0) 0 (0)
Blood creatinine elevation 5 (33) 0 (0) 16 (28) 2 (4) 5 (25) 2 (10) 5 (21) 0 (0)
Neutropenia 2 (13) 1 (7) 7 (12) 2 (4) 3 (15) 2 (10) 2 (8) 0 (0)
Bronchitis 0 (0) 0 (0) 2 (4) 2 (4) 1 (5) 1 (5) 1 (4) 1 (4)
Pulmonary embolism 0 (0) 0 (0) 2 (4) 2 (4) 0 (0) 0 (0) 2 (8) 2 (8)
Influenza 0 (0) 0 (0) 2 (4) 2 (4) 0 (0) 0 (0) 1 (4) 1 (4)
Nausea 2 (13) 0 (0) 16 (28) 1 (2) 5 (25) 0 (0) 9 (38) 1 (4)
Vomiting 0 (0) 0 (0) 8 (14) 1 (2) 0 (0) 0 (0) 7 (29) 1 (4)
Dyspnea 1 (7) 0 (0) 8 (14) 1 (2) 2 (10) 0 (0) 3 (13) 0 (0)
Ricolinostat, Bortezomib, and Dexamethasone for Myeloma
www.aacrjournals.org Clin Cancer Res; 23(13) July 1, 2017 3311
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