Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial
Andrew J Yee, William I Bensinger, Jeﬀrey G Supko, Peter M Voorhees, Jesus G Berdeja, Paul G Richardson, Edward N Libby, Ellen E Wallace, Nicole E Birrer, Jill N Burke, David L Tamang, Min Yang, Simon S Jones, Catherine A Wheeler, Robert J Markelewicz, Noopur S Raje
Background Histone deacetylase (HDAC) inhibitors are an important new class of therapeutics for treating multiple myeloma. Ricolinostat (ACY-1215) is the ﬁrst oral selective HDAC6 inhibitor with reduced class I HDAC activity to be studied clinically. Motivated by ﬁndings from preclinical studies showing potent synergistic activity with ricolinostat and lenalidomide, our goal was to assess the safety and preliminary activity of the combination of ricolinostat with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma.
Methods In this multicentre phase 1b trial, we recruited patients aged 18 years or older with previously treated relapsed or refractory multiple myeloma from ﬁve cancer centres in the USA. Inclusion criteria included a Karnofsky Performance Status score of at least 70, measureable disease, adequate bone marrow reserve, adequate hepatic function, and a creatinine clearance of at least 50 mL per min. Exclusion criteria included previous exposure to HDAC inhibitors; previous allogeneic stem-cell transplantation; previous autologous stem-cell transplantation within 12 weeks of baseline; active systemic infection; malignancy within the last 5 years; known or suspected HIV, hepatitis B, or hepatitis C infection; a QTc Fridericia of more than 480 ms; and substantial cardiovascular, gastrointestinal, psychiatric, or other medical disorders. We gave escalating doses (from 40–240 mg once daily to 160 mg twice daily) of oral ricolinostat according to a standard 3 + 3 design according to three diﬀerent regimens on days 1–21 with a conventional 28 day schedule of oral lenalidomide (from 15 mg [in one cohort] to 25 mg [in all other cohorts] once daily) and oral dexamethasone (40 mg weekly). Primary outcomes were dose-limiting toxicities, the maximum tolerated dose of ricolinostat in this combination, and the dose and schedule of ricolinostat recommended for further phase 2 investigation. Secondary outcomes were the pharmacokinetics and pharmacodynamics of ricolinostat in this combination and the preliminary anti-tumour activity of this treatment. The trial is closed to accrual and is registered at ClinicalTrials.gov, number NCT01583283.
Findings Between July 12, 2012, and Aug 20, 2015, we enrolled 38 patients. We observed two dose-limiting toxicities with ricolinostat 160 mg twice daily: one (2%) grade 3 syncope and one (2%) grade 3 myalgia event in diﬀerent cohorts. A maximum tolerated dose was not reached. We chose ricolinostat 160 mg once daily on days 1–21 of a 28 day cycle as the recommended dose for future phase 2 studies in combination with lenalidomide 25 mg and dexamethasone 40 mg. The most common adverse events were fatigue (grade 1–2 in 14 [37%] patients; grade 3 in seven [18%]) and diarrhoea (grade 1–2 in 15 [39%] patients; grade 3 in two [5%]). Our pharmacodynamic studies showed that at clinically relevant doses, ricolinostat selectively inhibits HDAC6 while retaining a low and tolerable level of class I HDAC inhibition. The pharmacokinetics of ricolinostat and lenalidomide were not aﬀected by co-administration. In a preliminary assessment of antitumour activity, 21 (55% [95% CI 38–71]) of 38 patients had an overall response.
Interpretation The ﬁndings from this study provide preliminary evidence that ricolinostat is a safe and well tolerated selective HDAC6 inhibitor, which might partner well with lenalidomide and dexamethasone to enhance their eﬃcacy in relapsed or refractory multiple myeloma.
Funding Acetylon Pharmaceuticals.
Lancet Oncol 2016
Published Online September 16, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30375-8
See Online/Comment http://dx.doi.org/10.1016/ S1470-2045(16)30407-7
Massachusetts General Hospital Cancer Center,
Harvard Medical School, Boston, MA, USA (A J Yee MD, J G Supko PhD, E E Wallace BA,
N E Birrer BA, J N Burke MSN, N S Raje MD); University of
Washington, Seattle, WA, USA
(W I Bensinger MD,
E N Libby MD); University of North Carolina, Chapel Hill, NC,
USA (P M Voorhees MD); Sarah Cannon Research
Institute, Nashville, TN, USA (J G Berdeja MD); Dana-Farber Cancer Institute, Harvard
Medical School, Boston, MA, USA (Prof P G Richardson MD); and Acetylon Pharmaceuticals,
Boston, MA, USA
(D L Tamang PhD, M Yang PhD, S S Jones PhD, C A Wheeler MD, R J Markelewicz MD)
Dr Noopur S Raje, Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA
The past decade has witnessed substantial improve- ments in treatment of multiple myeloma with the introduction and widespread adoption of immuno- modulatory drugs, proteasome inhibitors, and recently, monoclonal antibodies. However, multiple myeloma remains incurable in almost all patients who will eventually relapse. As a result, an ongoing need exists for agents with new mechanisms of action for this
disease. Histone deacetylase (HDAC) inhibitors, such as vorinostat and panobinostat, are an important new class of cancer therapeutics.1 They modulate the transcriptional proﬁle of cells and other nuclear events by increasing histone acetylation. Several classes of these inhibitors exist, and substrates of HDACs unrelated to histones reside in the cytoplasm through which HDAC inhibitors aﬀect protein degradation via the aggresome and protein–protein interactions.
Research in context
Evidence before this study Added value of this study
We searched PubMed using the key terms “HDAC inhibitor”, Ricolinostat is an oral, selective inhibitor of HDAC6, with reduced “vorinostat”, “panobinostat”, and “multiple myeloma” and class I HDAC activity. This trial is the ﬁrst of ricolinostat in focused on clinical trials published up to March 1, 2016, in English. combination with lenalidomide and dexamethasone in relapsed We identiﬁed two large randomised trials that assessed use of a or refractory multiple myeloma. This regimen has a favourable histone deacetylase (HDAC) inhibitor in multiple myeloma, side-eﬀect proﬁle and shows promising activity, with an overall speciﬁcally the pan-HDAC inhibitors vorinostat and panobinostat. response of 55% and a median progression-free survival of Although ﬁndings from the trial of vorinostat did not show a 20·7 months, which is similar to ﬁndings from trials combining clinically meaningful beneﬁt when combined with bortezomib new agents with lenalidomide and dexamethasone. The
and dexamethasone, ﬁndings from the trial of panobinostat improved tolerability of ricolinostat suggests a beneﬁt of selective showed a signiﬁcant improvement in progression-free survival inhibition of HDAC6 compared with pan-HDAC inhibition.
when given with bortezomib and dexamethasone compared with Implications of all the available evidence
the control group of bortezomib and dexamethasone alone. This HDAC inhibition is a new strategy in treatment of multiple
ﬁnding led to US Food and Drug Administration (FDA) approval myeloma. Selective inhibition of HDAC6 might enhance the
of panobinostat in combination with bortezomib in multiple eﬃcacy of HDAC inhibition while minimising the side-eﬀects
myeloma for patients with two or more previous lines of of pan-HDAC inhibition. On the basis of the ﬁndings of this treatment. However, use of panobinostat is limited by some of its study and previous trials, we established the dose of ricolinostat toxicities, such as diarrhoea and arrhythmias, which are both FDA for future studies with lenalidomide and dexamethasone.
black box warnings.
Multiple HDACs exist, which are divided into several classes on the basis of homology to yeast proteins: class I (HDAC1, 2, 3, and 8), IIA (HDAC4, 5, 7, and 9), IIB
(HDAC6 and 10), III (sirtuins), and IV (HDAC11).1,2 Preclinical work in multiple myeloma targeting both proteasomal protein degradation with proteasome inhibitors and aggresomal protein degradation pathways with HDAC inhibitors has shown accumulation of polyubiquitinated proteins followed by activation of apoptotic cascades and synergistic cytotoxicity.3,4 These ﬁndings prompted clinical development of HDAC inhibitors in multiple myeloma in combination therapy, beginning with the pan-HDAC inhibitors vorinostat and then panobinostat. On the basis of the phase 3 PANORAMA1 trial,5 panobinostat received accelerated approval in patients who received at least two previous lines of therapy, including bortezomib and an immunomodulatory drug. However, the US Food and Drug Administration (FDA) has issued black box warnings for panobinostat for diarrhoea and cardiac events, such as ischaemic events and arrhythmias, given its association with QT prolongation. These toxicities therefore drive the need for a more tolerable HDAC inhibitor than panobinostat.
HDAC6 regulates acetylation of α tubulin and the aggresome degradation pathway, an alternative to the proteasome degradation pathway, which removes misfolded and polyubiquitinated proteins. Multiple myeloma cells are susceptible to HDAC6 inhibition.4 Speciﬁc inhibition of HDAC6 does not, however, substantially aﬀect gene expression or cell cycle progression.6 For example, mice with a genetic knockout of Hdac6 survive normally without a substantial phenotype, suggesting that Hdac6 function is not
essential for normal development or function.7 By contrast, pan-HDAC inhibition has profound eﬀects on gene transcription and thus might contribute to an increased toxicity. Therefore, selective targeting of HDAC6 might result in an improved safety proﬁle compared with inhibition across all HDAC members, while retaining a low and potentially relevant biological level of class I HDAC inhibition.8,9
Ricolinostat (ACY-1215) is an oral, ﬁrst-in-class, selective inhibitor of HDAC6 that is tolerated well as monotherapy.10 However, it has minimal clinical activity as a single agent, similar to the pan-HDAC inhibitors vorinostat11 and panobinostat.12 When used in combination with bortezomib, ricolinostat shows synergistic activity in vitro, with increased endoplasmic reticulum stress and apoptosis via activation of caspases 3, 8, and 9, and poly (ADP) ribosome polymerase.13 When combined with immunomodulatory drugs, ricolinostat also shows synergistic activity. Such immunomodulatory drugs (eg, lenalidomide) target cereblon, a component of the E3 ubiquitin ligase complex, which leads to destruction of IKAROS family zinc ﬁnger 1 or 3 and downregulation of interferon regulatory factor 4 (IRF4), transcription factors that are crucial to multiple myeloma proliferation.14,15 Similarly, HDAC inhibitors can also downregulate MYC in other cell types16,17 via class I inhibition.9 Although ricolinostat is mainly HDAC6 selective, it has some class I inhibitory activity. Decreases in MYC and IRF4 mRNA as well as decreases in their protein concentration are seen in multiple myeloma cell lines treated with ricolinostat.8 Findings from additional in-vitro studies suggest that as single agents, the anti-multiple myeloma eﬀect of HDAC inhibition is mediated in part through
class I inhibition.18 However, emerging work shows that, pan-HDAC inhibitors such as panobinostat might lead to downregulation of cereblon and thereby antagonise the eﬀect of lenalidomide, as seen in vitro with the class I HDAC inhibitor entinostat (MS-275).9 By contrast, in preclinical models, ricolinostat in combination with lenalidomide did not show this potential counterproductive eﬀect on cereblon as the decrease in expression of MYC and IRF4 transcription factors occurred without aﬀecting cereblon expression.9 These unique characteristics of ricolinostat, primarily HDAC6 selectivity with some class I inhibition, serve as the basis for it being partnered with lenalidomide.
Motivated by preclinical studies of ricolinostat in combination with immunomodulatory drugs,8 we aimed to explore the activity of ricolinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma.
Study design and participants
In this multicentre phase 1b trial, we recruited patients aged 18 years or older with relapsed or relapsed and refractory multiple myeloma according to International Myeloma Working Group (IMWG) criteria19 who had had one or more previous lines of therapy from ﬁve cancer centres in the USA (appendix p 1). We deﬁned relapsed and refractory as progressing within 60 days of the most recent line of therapy.
Inclusion criteria included a Karnofsky Performance Status score of at least 70; measurable disease (serum monoclonal protein concentration ≥0·5 g/dL or urine monoclonal protein concentration ≥200 mg for 24 h; we permitted patients with disease measureable by an involved serum free light chain concentration ≥100 mg/L and an abnormal ratio to enrol until Aug 19, 2014; we changed this criterion to harmonise with eligiblity citeria in other trials; adequate bone marrow reserve (absolute neutrophil count >1000 cells per μL and platelet count >50 000 platelets per μL); adequate hepatic function (serum bilirubin concentration <2 mg/dL and alanine transaminase and aspartate aminotransferase concentration less than three times the upper limit of normal); and a creatinine clearance of at least
50 mL per min. Patients who had previously had treatment with lenalidomide were allowed, including those who were refractory to lenalidomide.
Exclusion criteria included previous exposure to HDAC inhibitors; previous allogeneic stem-cell transplantation; previous autologous stem-cell transplantation within 12 weeks of baseline; radiotherapy or standard systemic therapy within 2 weeks of baseline; active systemic infection; recent malignancy within the past 5 years; known or suspected HIV or hepatitis B or C infection; a QTc Fridericia of more than 480 ms; and substantial cardiovascular, gastrointestinal, psychiatric, or other medical disorders. All patients provided written informed
Day 1 8 15 22 28 1 8 15 22 28 1 8 15 22 28
1 40 mg once daily A: days 1–5 and 8–12 15 mg 3
2 40 mg once daily A: days 1–5 and 8–12 25 mg 3
3 80 mg once daily A: days 1–5 and 8–12 25 mg 4
4 160 mg once daily A: days 1–5 and 8–12 25 mg 3
5 240 mg once daily A: days 1–5 and 8–12 25 mg 3
6 160 mg once daily B: days 1–5, 8–12, and 15–19 25 mg 3
7 160 mg twice daily B: days 1–5, 8–12, and 15–19 25 mg 6 One grade 3 syncope
8 160 mg twice daily C: days 1–21 25 mg 6 One grade 3 myalgia
Expansion 160 mg once daily Days 1–21 25 mg 7
Figure 1: Dose escalation schema
Each dosing cycle was 28 days. There were three dosing regimens for ricolinostat for the dose escalation
(A, B, and C). Lenalidomide was given daily (15 mg or 25 mg) on days 1–21 with dexamethasone 40 mg weekly. One dose-limiting toxicity occurred in cohort 7 and cohort 8, leading to expansion of the cohort. No maximum tolerated dose was reached. The expansion cohort dosing for ricolinostat was 160 mg daily on days 1–21.
consent. Institutional review boards at all participating institutions approved the study. The study was done in accordance with the Declaration of Helsinki and International Conference on Harmonisation for Good Clinical Practice.
Patients received ricolinostat orally (ranging from 40–240 mg once daily to 160 mg twice daily) as a solution combined with lenalidomide (15 mg or 25 mg) orally on days 1–21 and dexamethasone 40 mg orally weekly on a 28 day cycle (ﬁgure 1). In the dose-escalation design, in regimen A, patients were given ricolinostat daily on days 1–5 and 8–12. In regimen B, ricolinostat was additionally given on days 15–19 (daily or twice daily). In regimen C, ricolinostat was given twice daily on days 1–21. We gave patients treatment until disease progression according to IMWG criteria, unacceptable toxicity, withdrawal of consent, or investigator decision. We gave patients aspirin or equivalent (low-molecular- weight heparin or warfarin) for deep-vein thrombosis prophylaxis.
Dose escalation proceeded via a standard 3 + 3 schema. We based dose escalation decisions on occurrence of dose- limiting toxicities in cycle 1. We deﬁned these dose-limiting toxicities as adverse events occurring during cycle 1 that were judged to be related to ricolinostat: grade 4 neutropenia for more than 5 days; febrile neutropenia; grade 4 thrombocytopenia on two separate occasions unresponsive to transfusion support; grade 3 thrombocytopenia with at least grade 2 bleeding; any grade 4 nausea, vomiting, or diarrhoea; grade 3 nausea or vomiting persisting for more than 72 h despite maximal medical intervention; grade 3 diarrhoea persisting for more than 48 h despite maximal medical intervention; and any other grade 3 or higher non-haematological toxicity if clinically signiﬁcant. We reviewed laboratory-only, asymptomatic adverse events
See Online for appendix
<65 63 (57–71)
65–74 11 (29%)
≥75 7 (18%)
Male 30 (79%)
Female 8 (21%)
ISS stage at diagnosis
I 16 (42%)
II 7 (18%)
III 14 (37%)
Unknown 1 (3%)
Total 4 (11%)
Deletion 17p 3 (8%)
t(4;14) 1 (3%)
Number of previous regimens
Median 2 (1–3)
Bortezomib 32 (84%)
Lenalidomide* 26 (68%)
Thalidomide 11 (29%)
Previous refractory regimen
Lenalidomide† 12 (32%)
Bortezomib 11 (29%)
Thalidomide 4 (11%)
Cyclophosphamide 3 (8%)
Melphalan 3 (8%)
None 14 (37%)
without clinical correlation on a case-by-case basis. We deﬁned the maximum tolerated dose as the highest dose level with no more than one patient having dose-limiting toxicities during cycle 1.
We permitted dose delays of up to 2 weeks and dose reductions for management of toxicities. We held dosing of ricolinostat for grade 3 non-haematological or grade 4 haematological toxicity (except for grade 3 thrombo- cytopenia with grade 2 or higher bleeding), which could be resumed at one dose level lower when toxicity resolved to grade 1 or better. We permitted dose reductions for ricolinostat for grade 3 non-haematological toxicity and grade 4 haematological toxicity, after resolution of toxicity to grade 1. We held lenalidomide dosing for grade 3 neutropenia with fever or grade 4 neutropenia, grade 3
thrombocytopenia, or other grade 3 adverse events. Lenalidomide could be resumed when haematological toxicity resolved to grade 2 or better with a dose level reduction. For grade 3 or higher non-haematological toxicity, lenalidomide could be resumed with a dose level reduction when toxicity resolved to grade 2 or better. We held dexamethasone and reduced its dose for grade 3 non-haematological toxicity. We held it and reduced its dose for grade 2 confusion, mood alteration, or muscle weakness.
We graded adverse events using the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4. We collected reports of adverse events up to 30 days after the last study drug dose. We also recorded serious adverse events occurring more than 30 days after the last study drug dose that were judged to be treatment related. The treating investigator attributed adverse events, which were reviewed by a scientiﬁc review committee.
Assessments consisted of physical examination and laboratory testing (consisting of a complete blood count and metabolic proﬁle) on days 1, 2 (cycle 1 only), 8, 15, and 21 of the ﬁrst two cycles and then days 1 and 15 thereafter, and serum protein electrophoresis, serum free light chains assessment, and 24 h urine protein electrophoresis on day 1. We assessed disease response on day 1 of each cycle according to the IMWG uniform criteria,19 with the additional category of minimal response according to the European Bone Marrow Transplant criteria.20 We did skeletal surveys at screening and other radiographic assessments, such as CT and MRI, as clinically indicated. Individual investigators did response assessments. We obtained blood samples for pharmacokinetic and pharmacodynamic analyses before study drug administration and at 0·25 h, 0·5 h, 1 h, 2 h, 4 h, 6 h, and 24 h after the initial dose was given in cycle 1 and according to the same schedule on day 8 or day 15 of cycle 1, or both, with the exception of the 24 h sample (appendix p 2). We measured plasma concentrations of acetylated tubulin (a marker of HDAC6 inhibition) and acetylated histone (a marker of class I HDAC inhibition) as previously described.21
Primary outcomes were the dose-limiting toxicities and the maximum tolerated dose of ricolinostat in combination with lenalidomide and dexamethasone, as well as ascertainment of the recommended dose and schedule for future phase 2 studies. Secondary outcomes were the safety of ricolinostat in this combination and the preliminary anti-tumour activity of the treatment regimen (ie, change from baseline in monoclonal protein component, overall response, and disease control rate), as well as the pharmacokinetics, and pharmacodynamics, of ricolinostat in combination with lenalidomide and dexamethasone. Additional phase 2 secondary outcomes related to preliminary anti-tumour activity that we report in this study (because we opted for a phase 1 expansion
Total (n=38) Grade 1–2 Grade 3 Grade 4 Total (n=38) Grade 1–2 Grade 3 Grade 4
Fatigue 21 (55%) 14 (37%) 7 (18%) 0 (Continued from previous page)
Diarrhoea 17 (45%) 15 (39%) 2 (5%) 0 Deep vein 4 (11%) 4 (11%) 0 0
Neutropenia 16 (42%) 3 (8%) 10 (26%) 3 (8%) thrombosis
Upper respiratory 14 (37%) 14 (37%) 0 0 Dyspepsia 4 (11%) 4 (11%) 0 0
tract infection Dyspnoea 4 (11%) 4 (11%) 0 0
Anaemia 13 (34%) 11 (29%) 2 (5%) 0 Peripheral 4 (11%) 3 (8%) 1 (3%) 0
Thrombocytopenia 13 (34%) 11 (29%) 2 (5%) 0 neuropathy
concentration 11 (29%) 10 (26%) 1 (3%) 0 Cerebrovascular 2 (5%)
accident 0 2 (5%) 0
increased Pneumonia 2 (5%) 0 2 (5%) 0
Muscle spasms 11 (29%) 11 (29%) 0 0 Atrial ﬁbrillation 1 (3%) 0 1 (3%) 0
Nausea 11 (29%) 10 (26%) 1 (3%) 0 Biliary dilatation 1 (3%) 0 1 (3%) 0
Constipation 10 (26%) 9 (24%) 1 (3%) 0 Constipation 1 (3%) 0 1 (3%) 0
Leucopenia 10 (26%) 9 (24%) 1 (3%) 0 Gastroenteritis 1 (3%) 0 0 1 (3%)
Hypophosphataemia 9 (24%) 7 (18%) 2 (5%) 0 Hypercalcaemia 1 (3%) 0 0 1 (3%)
Dysgeusia 8 (21%) 8 (21%) 0 0 Inﬂuenza A 1 (3%) 0 1 (3%) 0
Headache 8 (21%) 8 (21%) 0 0 Myelodysplastic 1 (3%) 0 1 (3%) 0
Peripheral oedema 8 (21%) 8 (21%) 0 0 syndrome
Rash 8 (21%) 8 (21%) 0 0 Sciatica 1 (3%) 0 1 (3%) 0
Back pain 7 (18%) 7 (18%) 0 0 Stent graft endoleak 1 (3%) 0 0 1 (3%)
Hyperglycaemia 7 (18%) 7 (18%) 0 0 Stomatitis 1 (3%) 0 1 (3%) 0
Hyponatraemia 5 (13%) 5 (13%) 0 0
Insomnia 5 (13%) 5 (13%) 0 0
Pain in extremity 5 (13%) 5 (13%) 0 0
Vomiting 5 (13%) 3 (8%) 2 (5%) 0
Hyperbilirubinaemia 4 (11%) 4 (11%) 0 0
Blood creatinine concentration
increased 4 (11%) 4 (11%) 0 0
rather than opening a phase 2 portion of the trial) are duration of response and progression-free survival, which are of key interest for assessment of this treatment regimen.
The size of the dose escalation cohort is based on the conventional 3 + 3 dose escalation design for phase 1 trials; consequently, we did not do a formal sample size estimation. We planned to treat a minimum of one patient and a maximum of six patients at each dose level. We considered all patients assessable for toxicity. We considered patients who discontinued the study before the ﬁrst response assessment at the beginning of cycle 2 unassessable for response. We summarised data using
descriptive statistics. We used the Kaplan-Meier method for time-to-event analysis, including progression-free survival. We established 95% CIs for overall response with the Clopper-Pearson exact method. We used SAS version 9.3 and R version 3.2.3 for analyses.
This trial is registered with ClinicalTrials.gov, number NCT01583283.
Role of the funding source
The trial was initially designed by the corresponding author and funder. The data were collected, analysed, and interpreted by the investigators and the funder. All authors had full access to all the data in the study on request. The corresponding author wrote the initial draft of the manuscript in collaboration with the funder. The corresponding author had ﬁnal responsibility for the decision to submit for publication.
Between July 12, 2012, and Aug 20, 2015, we enrolled
38 patients. The baseline characteristics of the participants are summarised in table 1. Median follow-up was 5·9 months (IQR 2·8–19·0). At data cutoﬀ (Jan 21, 2016), nine (24%) patients remained on treatment. 16 (42%) discontinued treatment for progressive disease, seven (18%) discontinued because
Day 1 3 117 (41) 268 (88) NC NC 75 years: four (57%) of the seven patients aged 75 years
Day 8 3 87 (67) 284 (143)* NC NC or older had grade 3 fatigue compared with three (10%)
Cohort 3: ricolinostat 80 mg of the 31 patients aged younger than 75 years. In the
Day 1 4 364 (184) 861 (465) 1593 (942)* 61 (36)* older patients, we attributed the fatigue to lenalidomide
Day 8 4 424 (108) 897 (502) NC NC in all four cases, with one case also attributed to
Cohorts 4 and 6: ricolinostat 160 mg† ricolinostat. In the younger patients, the fatigue was
Day 1 6 668 (345) 1201 (510)‡ 1510 (219)§ 106 (15)§ also thought to be treatment related. No cases of febrile
Day 8 or 15 6 752 (334) 1349 (475)‡ NC NC neutropenia or QT prolongation were recorded. Dose
Table 2 summarises the most common adverse events. We assessed all 38 patients for toxicity. Fatigue and diarrhoea were the most common adverse events. Common haematological adverse events included neutropenia, anaemia, and thrombocytopenia. In a post-hoc analysis, patients aged 75 years or older had fatigue more frequently than patients younger than
reductions of ricolinostat and lenalidomide did not
Day 1 3 618 (190) 1489 (477) 1767 (546) 136 (45) occur. Six (16%) patients discontinued treatment
Day 8 3 550 (48) 1477 (344)* NC NC because of adverse events, but only two (33%) attributed
Cohort 7: ricolinostat 160 mg¶
Day 1 6 821 (54) 1489 (254) NC NC
Day 8 or 15 6 782 (232) 1471 (273) NC NC
Cohort 8: ricolinostat 160 mg¶
Day 1 6 397 (286) 1008 (520) NC NC
Day 15 6 362 (246) 919 (405) NC NC
Expansion cohort: ricolinostat 160 mg to ricolinostat (diarrhoea in one patient and fatigue, weight loss, and anorexia in the other). We did not observe cumulative toxicities, and as a result, long-term toxicities could not be correlated with dose. No patients died during the study.
Mean pharmacokinetic variables for ricolinostat for cycle 1 day 1 and subsequent dosing on cycle 1 days 8 or 15
Day 1 7 469 (247) 1148 (422) 1420 (508)|| 113 (37)|| coadministered with lenalidomide (15 mg or 25 mg), are
Day 15 6** 712 (206) 1305 (273) NC NC presented in table 3. Ricolinostat was absorbed rapidly
after oral administration, with the maximum observed
concentration in plasma (C ) occurring at a mean of
of withdrawal by the patient or the investigator, and six (16%) discontinued because of adverse events. We observed two dose-limiting toxicities in patients receiving ricolinostat 160 mg twice daily in combination with lenalidomide 25 mg and dexamethasone 40 mg. One grade 3 syncope adverse event occurred in cohort 7 (regimen B; ricolinosat 160 mg twice daily on days 1–5, 8–12, and 15–19), which did not recur with rechallenge and the patient continued on treatment, and one grade 3 myalgia adverse event occurred in cohort 8 (regimen C; ricolinostat 160 mg twice daily on days 1–21); this patient left the study without receiving additional treatment and made a full recovery. We expanded both these cohorts to six patients each after the adverse events occurred. A maximum tolerated dose was not reached. On the basis of these ﬁndings and similar observations of better tolerability with once-daily dosing than with twice-daily dosing in combination studies with bortezomib22 and pomalidomide,23 we chose ricolinostat 160 mg once daily on days 1–21 as the recommended phase 2 dose (in combination with lenalidomide 25 mg and dexamethasone 40 mg).
0·98 h (SD 0·38) for the initial dose and 0·98 h (0·70) for the dose given on days 8 or 15. The drug was eliminated rapidly from systemic circulation, with plasma concentrations below the lower limit of quantiﬁcation (0·50 ng/mL) 24 h after the dose was received at doses of 80 mg or less. Ricolinostat plasma concentrations were measureable at 24 h in nine (69%) of 13 patients receiving 160 mg once daily and 11 (92%) of 12 patients receiving
160 mg twice daily. Overall mean values of the pharmacokinetic variables for the initial 160 mg once daily dose of ricolinostat in nine (24%) patients were as follows: Cmax 569 ng/mL (SD 288), apparent elimination half-life 2·88 h (0·33), apparent oral clearance 110 L/h (30), and apparent oral total-body volume of distribution 459 L (160). Above a dose of 80 mg of ricolinostat, we noted a less than proportionate increase by either Cmax (table 3), drug concentration in plasma 1 h after dosing (ﬁgure 2A), or area under the plasma concentration–time curve from 0 h to 6 h (AUC0–6; table 3) compared with the initial 40 mg dose of ricolinostat. Saturable absorption was also supported by the increase in mean apparent oral clearance for the groups of patients receiving doses of 80 mg, 160 mg, and 240 mg (table 3). In the expansion cohort, when ricolinostat 160 mg was given once daily for 21 days, the mean AUC0–6 did not increase substantially from days 1 to 15 and the accumulation factor for repeated administration was negligible (1·1 [SD 0·2]). Mean values of the ricolinostat AUC0–6 were similar on day 1
Tubulin acetylation fold change
and day 8 or 15 at each dose level (table 3), suggesting that daily administration of lenalidomide did not have a clinically signiﬁcant eﬀect on the pharmacokinetics of ricolinostat.
Ricolinostat plasma concentration (ng/mL)
Overall mean values of the pharmacokinetic variables for the initial dose of lenalidomide (25 mg) were as follows: time taken to reach maximum concentration in plasma (tmax) 1·7 h (SD 0·9; n=34); Cmax 301 ng/mL (101; n=34); apparent elimination half-life 4·01 h (0·64; n=30); apparent oral clearance 13·8 L/h (3·6; n=30); apparent oral total-body volume of distribution 79·6 L (19·6; n=30; appendix p 5). Concurrent administration of ricolinostat did not have an eﬀect on the plasma pharmacokinetics of lenalidomide as indicated by similar values for tmax (1·7 h [SD 0·9] for day 1 vs 2·0 h [1·3] for day 8 or 15; n=34; p=0·22), Cmax (301 ng/mL  vs 312 ng/mL ; n=34; p=0·43), and AUC0–6
(1095 ng × h/mL  vs 1158 ng × h/mL ; n=31;
Histone acetylation fold change
With increasing ricolinostat dose, we observed a corresponding increase in tubulin acetylation, a marker of HDAC inhibition, in CD3-positive lymphocytes, and the diﬀerences between the lowest dose level (40 mg) and the cohorts receiving 80 mg and 160 mg were both signiﬁcant (ﬁgure 2B). However, histone acetylation, a marker of class I HDAC inhibition, was near background levels at doses lower than 160 mg, suggesting that ricolinostat has a selectivity window of 160 mg or less, with modest histone acetylation occurring at the high end of the dose range (ﬁgure 2C). Consistent with the observed plateau in drug concentration in plasma 1 h after dosing with increases in the dose of ricolinostat, acetylated tubulin and acetylated histone concentrations did not increase as the dose was increased above 160 mg. Finally, tubulin acetylation levels decreased in parallel with the decline in concentration of ricolinostat in plasma (ﬁgure 2D).
All 38 patients were assessable for response. 21 (55% [95% CI 38–71]) of 38 patients had an overall response (table 4). In the 26 (68%) patients who were not refractory to lenalidomide, overall response was higher (18 [69%, 95% CI 48–86]) than in all patients overall. In the 12 (32%) patients who were only refractory to lenalidomide, three (25% [95% CI 6–57]) had an overall response, and in the ﬁve (13%) who were refractory to both lenalidomide and bortezomib, two (40% [5–85]) had an overall response. In patients achieving a partial response or better, median time to response was 7 weeks (95% CI 4–8), the median number of cycles given was 14 (range 9–22), and the median duration of response was 23·5 months (95% CI 17·8–38·7). 19 (50%) patients had disease progression at data cutoﬀ; no deaths occurred. Median progression-free survival was 20·7 months (4·9–40·3; ﬁgure 3). Change from baseline in monoclonal protein component is not reported because these numbers are used to calculate overall response, which is reported.
Ricolinostat plasma concentration (ng/mL)
Acetylation fold change
Figure 2: Pharmacokinetics and pharmacodynamics of ricolinostat
(A) Concentration of ricolinostat in plasma 1 h after dosing. (B) Tubulin acetylation and (C) histone acetylation in CD3-positive lymphocytes from patient peripheral blood 1 h after dosing. (D) Acetylation of tubulin and histones in cohort 6. We used cohort 6 because the dose is the recommended phase 2 dose. Error bars represent the SEM. Plotted marker shapes represent values in individual patients and horizontal bars are the arithmetic mean for each cohort. To increase robustness of the data for comparing diﬀerent doses, where possible on the basis of sample availability, we plotted data for both days 1 and 8 because plasma concentrations for ricolinostat were undetectable immediately before dosing on day 8. p values for all comparisons are available in the appendix. Pc=plasma concentration. *Outlier identiﬁed by Grubbs’ test excluded.
Results from this phase 1b trial of the combination of the HDAC6 selective inhibitor ricolinostat with lenalidomide and dexamethasone showed encouraging early indications of eﬃcacy and tolerability in relapsed or refractory multiple myeloma.
The combination of ricolinostat with lenalidomide and dexamethasone was well tolerated. A maximum tolerated dose was not reached, and dose reductions in ricolinostat and lenalidomide did not occur. Adverse events observed in this study were generally mild and similar to those
All patients (n=38) Lenalidomide refractory Bortezomib refractory (n=10) Lenalidomide and bortezomib Previous ASCT (n=19) Lenalidomide as last line (n=14) Previous lenalidomide, not No previous lenalidomide
(n=12) refractory (n=5) refractory (n=14) (n=12)
response 2 (5%) 0 0 0 2 (11%) 2 (14%) 2 (14%) 0
Complete response 2 (5%) 0 1 (10%) 0 0 1 (7%) 1 (7%) 1 (8%)
Very good partial
response 7 (18%) 1 (8%) 2 (20%) 0 2 (11%) 1 (7%) 2 (14%) 4 (33%)
Partial response 10 (26%) 2 (17%) 2 (20%) 2 (40%) 8 (42%) 3 (21%) 7 (50%) 1 (8%)
Minimal response 3 (8%) 1 (8%) 0 0 1 (5%) 2 (14%) 1 (7%) 1 (8%)
Stable disease 7 (18%) 5 (42%) 4 (40%) 2 (40%) 3 (16%) 4 (29%) 0 2 (17%)
Progressive disease 7 (18%) 3 (25%) 1 (10%) 1 (20%) 3 (16%) 1 (7%) 1 (7%) 3 (25%)
Overall response 21 (55%) 3 (25%) 5 (50%) 2 (40%) 12 (63%) 7 (50%) 12 (86%) 6 (50%)
Clinical beneﬁt rate* 24 (63%) 4 (33%) 5 (50%) 2 (40%) 13 (68%) 9 (64%) 13 (93%) 7 (58%)
Disease control rate† 31 (82%) 9 (75%) 9 (90%) 4 (80%) 16 (84%) 13 (93%) 13 (93%) 9 (75%)
ASCT=autologous stem-cell transplantation. *Patients achieving minimal response or better. †Patients achieving stable disease or better.
Table 4: Best responses to ricolinostat plus lenalidomide and dexamethasone
Time (months) 30 40
16 (7) 8 (15) 2 (18) 1 (19)
Progression-free survival (%)
Figure 3: Progression-free survival
often recorded with the lenalidomide–dexamethasone doublet in relapsed multiple myeloma.24–26 These adverse events suggest that addition of ricolinostat does not substantially magnify the side-eﬀect proﬁle of the standard combination of lenalidomide and dexamethasone. Furthermore, patients were able to tolerate this combination for extended periods of time, and the proportion of patients discontinuing treatment due to adverse events was low. Moreover, at the recommended phase 2 dose of 160 mg once daily, we found that ricolinostat attains suﬃcient exposure to selectively inhibit HDAC6 on the basis of concentrations of acetylated tubulin while retaining a low level of class I HDAC inhibition on the basis of concentrations of acetylated histones. Furthermore, in previous studies, we have observed that in combination with bortezomib22 or
pomalidomide,23 higher doses of ricolinostat (160 mg twice daily) than the recommended phase 2 dose from this study were associated with increased diarrhoea and required dose reductions, further supporting the phase 2 dose of 160 mg once daily.
Substantial adverse events with pan-HDAC inhibitors such as vorinostat27 and panobinostat5 include diarrhoea and thrombocytopenia, which might limit dosing exposure to HDAC inhibition and thus its activity. Vorinostat has been combined with lenalidomide and dexamethasone in a phase 1 study.28 However, the proportion of patients discontinuing from this vorinostat combination because of a drug-related adverse event was high (32%). In the PANORAMA1 trial5 of panobinostat given with bortezomib and dexamethasone, the frequency of grade 3–4 diarrhoea was 25% and thrombocytopenia 68%. The proportion of patients discontinuing because of adverse events was 36%—nearly double that of the bortezomib and dexamethasone control group (20%). Some of these adverse events might have been compounded by use of a proteasome inhibitor in the traditional twice-weekly schedule. By contrast, these types of adverse events were less frequent with the ricolinostat and lenalidomide and dexamethasone combination than with the panobinostat and bortezomib and dexamethasone combination. Additionally, in the accelerated approval of panobinostat (approved on Feb 23, 2015), the US FDA noted arrhythmias and electrocardiogram changes such as QT prolongation with the panobinostat combination.29 We did not observe QT prolongation with ricolinostat in our trial. Overall, the favourable toxicity proﬁle of ricolinostat might reﬂect the more favourable ratio of HDAC6 to class I HDAC inhibition rather than pan- HDAC inhibition. Moreover, the use of ricolinostat with lenalidomide rather than bortezomib in this trial might have mitigated these side-eﬀects. Notably, panobinostat, at a lower dose than in the PANORAMA1 trial,5 is being studied with lenalidomide and dexamethasone in a
phase 2 trial,30 and this regimen seems to be better tolerated, with less grade 3–4 diarrhoea (12%) than reported with the bortezomib-based combination.
The pharmacokinetics of ricolinostat are characterised by rapid absorption after oral administration; a short terminal-phase half-life, resulting in negligible drug accumulation with repeated daily dosing; and saturable absorption. At doses above 160 mg, we noted a plateau in the pharmacokinetic data. The pharmacokinetics of ricolinostat and lenalidomide were not aﬀected by their coadministration. Ricolinostat given with lenalidomide and dexamethasone showed encouraging preliminary activity in this relapsed or refractory population. These patients had received a median of two previous lines of treatment, and 55% of patients achieved an overall response. The addition of ricolinostat might enhance the activity of lenalidomide and dexamethasone, reﬂecting the cooperativity seen in vitro, and ricolinostat might salvage responses in patients who are refractory to lenalidomide, with 25% of these patients having an overall response in this study; in patients who were double refractory to both lenalidomide and bortezomib, 40% of patients had an overall response (although the number of patients who were double refractory was smaller than that of those who were refractory to lenalidomide alone).
Our study has several limitations, including the small number of patients inherent to a phase 1 trial. We excluded patients with moderate renal dysfunction given the lenalidomide combination. Additionally, the median age of 63 years in our study population was younger than that of the multiple myeloma population overall (69 years),31 but was similar to the age of patients in trials of panobinostat5 and carﬁlzomib.26 With these considerations and the limitations of cross-trial comparisons in mind—given, for example, that the populations in these trials are not evenly matched—the median progression-free survival of 20·7 months recorded in this trial is encouraging and might be similar to that in other studies in relapsed multiple myeloma of lenalidomide and dexamethasone in combination with approved agents such as carﬁlzomib,26 elotuzumab,25 or ixazomib.24 Furthermore, the responses in this trial are notable because 68% of patients had previous treatment with lenalidomide and 32% were refractory to previous lenalidomide therapy. By contrast, in these lenalidomide-based triplet trials, patients refractory to lenalidomide were excluded, and few had previous lenalidomide exposure (10–20%). Finally, responses in this study were durable: patients who were responding to treatment were able to continue on treatment for a median of nearly 2 years, consistent with the tolerability of this regimen, which allows for long treatment exposure.
HDAC inhibition has been previously validated as a therapeutic approach in relapsed multiple myeloma on the basis of results of the pan-HDAC inhibitor panobinostat with bortezomib and dexamethasone.5 Although the complexity of HDAC biology is noted, taken
together, the ﬁndings from this trial suggest that selective targeting of HDAC6 with a reduced level of class I HDAC inhibition with ricolinostat in combination with lenalidomide and dexamethasone might be an eﬀective and better tolerated approach than is pan-HDAC inhibition. Both the encouraging activity and safety proﬁle of ricolinostat might be due to its unique mechanisms of synergy with immunomodulatory drugs. Additional studies of ricolinostat in multiple myeloma include combinations with bortezomib22 or pomalidomide.23 Although the results from this phase 1 study are preliminary, they are promising and require substantiation with larger studies than this one. They set the stage for another agent, ACY-241, a selective HDAC6 inhibitor that is structurally similar to ricolinostat but administered as a tablet rather than an oral solution. ACY-241 is being assessed in an ongoing phase 1b trial in combination with pomalidomide and dexamethasone (NCT02400242) with the goal of development of a larger randomised trial than the phase 1b trial. Findings from these studies will better deﬁne the role of selective and pan-HDAC inhibition in treatment of multiple myeloma than at present.
AJY, WIB, JGS, PMV, JGB, PGR, ENL, EEW, NEB, JNB, and NSR
recruited and cared for patients and collected data. AJY, SSJ, CAW, RJM, and NSR designed the study developed the protocol. AJY, JGS, SSJ, DLT, CAW, RJM, NSR, and MY analysed and interpreted data. AJY, DLT, JGS, SSJ, and NSR wrote the manuscript. All authors reviewed and edited the manuscript and approved the ﬁnal version of the manuscript before submission.
Declaration of interests
WIB has received funding from and consulted for Acetylon Pharmaceuticals and Celgene. PMV has served on the advisory board for Celgene, Takeda, Novartis, Janssen, and Bristol-Myers Squibb, and has received research funding from Celgene, Acetylon, Oncopeptides, Merck, Amgen, and GlaxoSmithKline. He also chaired the Independent Review Committee for Takeda and Novartis. JGB has received grants from Bristol-Myers Squibb, Amgen, Janssen, Novartis, Abbvie, Curis, Array BioPharma, Constellation, and Bluebird Bio. PGR has served on advisory committees for Novartis, Takeda, Johnson & Johnson, and Celgene, and has received research funding from Celgene and Takeda. DLT, MY, SSJ, CAW, and RJM are employed by Acetylon Pharmaceuticals, the funder of this study. NSR has served on the advisory board for Celgene, received research funding from Acetylon Pharmaceuticals, and consulted for Novartis, Amgen, Takeda, Roche, and Eli Lilly. All other authors declare no competing interests.
This study was supported by Acetylon Pharmaceuticals. The authors thank all the patients and their family members and caregivers who participated in the study. We also would like to thank the physicians, research nurses, study coordinators, and research staﬀ for their time and eﬀort.
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