Panobinostat

Panobinostat: First Global Approval

Karly P. Garnock-Jones1

© Springer International Publishing Switzerland 2015

Abstract Novartis has developed oral and intravenous formulations of panobinostat (Farydak®), a histone deacetylase (HDAC) inhibitor, for the treatment of cancer. HDACs have important roles in maintaining chromatin structure and in regulating gene expression, including that
of tumour suppressor genes, and thus represent valid tar- gets in the search for cancer therapeutics. Oral panobinostat is approved in the US, as combination therapy with bortezomib and dexamethasone in patients with recurrent multiple myeloma who have received at least two prior treatment regimens, including bortezomib and an im- munomodulatory agent. Regulatory submissions have been made for the use of combination therapy with panobinostat in patients with recurrent multiple myeloma in the EU and Japan. Panobinostat is in various stages of clinical devel- opment worldwide for a range of haematological and solid tumours. This article summarizes the milestones in the development of panobinostat leading to this first approval for multiple myeloma.
1 Introduction

Histone deacetylase (HDAC) enzymes, along with histone acetylase (HAT), control the changes to core histone acetylation [1]. The removal of acetyl groups from histones by HDACs prevents transcription of genes encoding pro- teins that are involved with cell cycle regulation, cell dif- ferentiation, and apoptosis. Higher levels of HDAC activity are associated with the silencing of differentiation and tu- mour suppressor genes, leading to oncogenesis [1]. In- creased HDAC levels have been reported in several human tumours and cancer cell lines [2–4], including multiple
myeloma [5]. Panobinostat (Farydak®) is a nonselective
HDAC inhibitor [6], a relatively new class of anticancer agents.
In February 2015 [7], the US FDA approved oral panobinostat in combination with bortezomib and dexam- ethasone for the treatment of patients with multiple myeloma who have received at least two prior treatment regimens, including bortezomib and an immunomodulatory agent [6]. The approval, granted under the accelerated ap- proval program, was based on progression-free survival (PFS) [6] in a pre-specified subgroup analysis of the PANORAMA-1 trial [8]. The FDA accepted the company’s NDA in May 2014 and granted priority review [9]. Prior to

this, in November 2014, Novartis announced that the FDA’s

This profile has been extracted and modified from the Adis R&D Insight drug pipeline database. Adis R&D Insight tracks drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch.

& Karly P. Garnock-Jones [email protected]

1 Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland, New Zealand
Oncologic Drugs Advisory Committee (ODAC) did not recommend the approval of panobinostat for the treatment of relapsed multiple myeloma, as, based on the data re- viewed, the drug’s benefits did not outweigh its risks in these patients [7, 10]. Following the negative opinion, the company submitted additional data supporting the use of panobinostat in patients with multiple myeloma who have received at least two prior standard therapies, including bortezomib and an immunomodulatory agent [7], and the

Features and properties of panobinostat
Alternative names Farydak®; LBH 589; LBH 589A; LBH-589; LBH-589A; LBH589; LBH589A Class Hydroxamic-acids, Indoles, Small-molecules
Mechanism of action Histone deacetylase inhibitor
Route of administration PO, IV
Pharmacodynamics Potently and nonselectively inhibits HDAC enzyme activity, resulting in increased acetylation of
histones and other proteins, ultimately leading to activation of transcription
Associated with accumulation of acetylated histones and other proteins, leading to cell cycle arrest and/ or apoptosis of cancer cells from cell lines across multiple cancer types
Acts synergistically with other chemotherapeutic drugs (e.g. dexamethasone and bortezomib)
Pharmacokinetics
Time to peak concentration Within 2 h
Absolute oral bioavailability &21 %
Bound to plasma protein &90 %
Oral clearance &160 L/h Terminal elimination half-life &37 h
Special patient populations Hepatic impairment can increase panobinostat exposure
Potential drug interactions Strong CYP3A inhibitors, strong CYP3A inducers, sensitive CYP2D6 substrates Adverse events (incidence)
General (C20 %) Diarrhoea, fatigue, nausea, peripheral oedema, decreased appetite, pyrexia, vomiting

Haematological laboratory abnormalities (C60 %)
Other laboratory abnormalities (C40 %)
ATC codes
Thrombocytopenia, lymphopenia, leukopenia, neutropenia, anaemia Hypophosphataemia, hypokalaemia, hyponatraemia, increased creatinine

WHO ATC code L01X-X42 (Panobinostat)
EphMRA ATC code L1X9 (All other antineoplastics)
Chemical Name 3- [4- [2-(2-Methyl-1H-indol-3-yl)ethylaminomethyl] phenyl] -2(E)-propenohydroxamic acid

review period was extended by up to 3 months [9]. Regulatory applications were also filed in the EU and Japan in May and September of 2015, respectively [11]. Panobi- nostat has been granted orphan drug designation for mul- tiple myeloma in the USA [7], the EU [12] and Japan [11].
The recommended starting dosage of oral panobinostat is 20 mg on days 1, 3 and 5 of weeks 1 and 2 in a 3-week cycle, for up to 8 cycles, with or without food [6]. Treat- ment may be continued for an additional 8 cycles if the patient shows clinical benefit and does not experience un- resolved severe or medically significant adverse events, making the maximum total treatment duration 16 cycles, or 48 weeks. Panobinostat must be coadministered with bortezomib given as an injection at a recommended dosage of 1.3 mg/m2 (days 1 and 4 of weeks 1 and 2 of the first 8 cycles and day 1 of weeks 1 and 2 of cycles 9–16) and oral dexamethasone at a recommended dosage of 20 mg (days 1, 2, 4 and 5 of weeks 1 and 2 of the first 8 cycles and days
⦁ and 2 of weeks 1 and 2 of cycles 9–16) [6].
Patients should be regularly monitored (complete blood count, ECG and serum electrolytes) for toxicities [6]. Panobinostat or bortezomib dosage adjustments may be required if toxicities occur; panobinostat dose should be
reduced in increments of 5 mg, and if the dosage is
\10 mg three times a week panobinostat should be dis- continued. Patients with mild or moderate hepatic impair- ment should have a lower starting panobinostat dosage (15 or 10 mg, respectively), and patients with severe hepatic impairment should not receive panobinostat [6]. The starting panobinostat dosage should also be reduced to 10 mg in patients receiving concomitant strong cy- tochrome P450 (CYP)3A inhibitors.

O
OH
NH

Chemical structure of panobinostat

The US prescribing information for panobinostat has a boxed warning for risks of severe diarrhoea and severe and fatal cardiac ischaemic events, severe arrhythmias, and

ECG changes with panobinostat treatment [6]. Thus, panobinostat has been approved with a risk evaluation and mitigation strategy (REMS), to apprise healthcare provi- ders of these risks and how to minimize them [8].
Panobinostat is also currently under development for the treatment of multiple other haematological malignancies (including chronic myeloid leukaemia, acute myeloid leukaemia, chronic lymphocytic leukaemia, mantle- cell lymphoma, myelofibrosis, and Waldenstro¨m’s macroglobulinaemia) and solid tumours (including col- orectal cancer, neuroendocrine tumours, prostate cancer, and renal cancer), as well as myelodysplastic syndromes, graft-versus-host disease and HIV-1 infections, in several countries worldwide. Development has ceased for the use of oral panobinostat as a single agent in multiple myeloma, Hodgkin’s disease and cutaneous T-cell lymphoma, and for intravenous panobinostat in any indication.

⦁ Scientific Summary

⦁ Pharmacodynamics

As an HDAC inhibitor, panobinostat (at nanomolar con- centrations) inhibits HDAC enzymes’ removal of acetyl groups from lysine residues of histones and some non- histone proteins, thus resulting in increased acetylation of these proteins [6]. This leads to relaxation of chromatin, which leads to activation of transcription [6]. This inhibi- tion is potent across all Class I, II and IV purified recom- binant HDAC enzymes, and half maximal inhibitory panobinostat concentrations were consistently lower than those for fellow nonspecific HDAC inhibitors vorinostat and belinostat in vitro [2].
Panobinostat is more cytotoxic towards tumour cells that normal cells [6]. In vitro, panobinostat is associated with accumulation of acetylated histones and other proteins, leading to cell cycle arrest and/or apoptosis of cancer cells from cell lines across multiple cancer types [2, 6]. Tumour xenografts in mice treated with panobinostat had increased levels of acetylated histones [2, 6, 13], and showed a rapid response to treatment (tumour regression, apoptosis, and decreased cell proliferation) [2, 13].
Panobinostat is also associated with a synergistic effi- cacy when coadministered with other chemotherapeutic drugs. For example, the addition of panobinostat to dex- amethasone and bortezomib or lenalidomide led to a clear additive effect with regard to antitumour activity in mul- tiple myeloma cell lines and murine models of multiple myeloma [14].
A non-histone-related effect of panobinostat involves the ubiquitin-proteasome system [15]; in an in vitro study
in multiple myeloma cells, panobinostat treatment was associated with hyperacetylation of a-tubulin and disrup- tion of the interaction between HDAC6 and dynein (in- volved with the transportation of misfolded protein aggregates to the autophagosome, where they are degraded by lysosomes), thus resulting in increased levels of ubiq- uitinated protein and apoptosis [16]. This effect was sig- nificantly augmented in the presence of bortezomib (a proteasome inhibitor) [16].
In clinical trials, panobinostat was associated with in- creased histone acetylation in CD19? and CD34? cells and apoptosis in CD14? cells in patients with refractory haematological malignancies [17], and (in combination with azacitidine) decreased levels of tumour necrosis fac- tor-positive regulatory T cells in patients with acute mye- loid leukaemia [18].

⦁ Pharmacokinetics

Oral panobinostat is rapidly absorbed in patients with ad- vanced cancer, with peak concentrations reached within 2 h [6]. Panobinostat exposure is approximately dose pro- portional over the dosing range, and it has an absolute oral bioavailability of 21 % [6]. Following a high-fat meal in patients with advanced cancer, panobinostat exposure was decreased slightly compared with fasting conditions, and the time to Cmax (tmax) was increased by 2.5 h [19]. With chronic oral dosing, up to 2-fold accumulation was ob- served in patients with advanced cancer [6].
Panobinostat is moderately bound to plasma protein in vitro (&90 %), independently of concentration [6]. Extensive metabolism of panobinostat occurs, involving reduction, hydrolysis, oxidation and glucuronidation; CYP3A metabolism accounts for &40 % of the total hepatic panobinostat elimination. It is also a P-glycoprotein substrate and a CYP2D6 inhibitor [6].
Following a single radiolabelled dose of oral panobi- nostat in patients with advanced cancer, 29–51 % of the dose was excreted in urine and 44–77 % in the faeces;\2.5 and \3.5 % of the dose, respectively, was unchanged panobinostat [6, 20]. Panobinostat has an oral clearance of &160 L/h (with high inter-subject variability) and a ter- minal elimination half-life of &37 h, according to a population-based pharmacokinetic model in patients with advanced cancer.
Hepatic impairment is associated with increased panobinostat exposure [6, 21]. In patients with advanced cancer, those with mild and moderate hepatic impairment had areas under the panobinostat concentration-time curve (AUC) from time zero to infinity (AUC?) that were 43 and 105 % higher than those with normal hepatic function [6, 21], and dosage modification is recommended in these

patients [6]. The effect of severe hepatic impairment on panobinostat pharmacokinetics has not been determined; therefore, panobinostat should not be administered in these patients. Mild to severe renal impairment did not impact plasma panobinostat exposure [6, 22]; panobinostat has not been investigated in patients with end-stage renal disease or those undergoing dialysis [6].

⦁ Drug Interactions

Strong CYP3A inhibitors increase and strong CYP3A in- ducers decrease panobinostat exposure; starting dosage modification (for the former) or avoidance of coadminis- tration (for the latter) is recommended [6]. Coadministra- tion of multiple doses of the strong CYP3A inhibitor ketoconazole 400 mg/day with a single dose of panobi- nostat 20 mg in patients with advanced solid tumours led to an increase in panobinostat Cmax and AUC? of 62 and 73 %, respectively; tmax was unchanged [6]. Physio- logically based pharmacokinetic models predict a &70 % decrease in systemic panobinostat exposure in the presence of strong CYP3A inducers [6].
Coadministration of panobinostat with sensitive CYP2D6 substrates or CYP2D6 substrates with a narrow therapeutic index should be avoided; if concomitant use of CYP2D6 substrates is unavoidable, monitor patients fre- quently for adverse reactions [6]. When multiple doses of panobinostat 20 mg and a single dose of dextromethorphan 60 mg were coadministered, dextromethorphan Cmax and AUC? increased by 20–200 and 20–130 %, in patients with advanced cancer [6]. Simulations predict that if panobinostat is coadministered with the sensitive CYP3A substrate midazolam, midazolam exposure is likely to in- crease by \10 %, with unknown clinical implications [6]. In vitro, panobinostat inhibits CYP2D6, CYP2C19, CYP3A4, organic anion transporter (OAT)3, organic cation transporter (OCT)1, OCT2, organic anion-transporting polypeptide (OATP)1B1 and OATP1B3, but not CYP1A2, CYP2C8, CYP2C9, CYP2E, OAT1, P-glycoprotein, or breast-cancer resistant protein [6]. It does not induce CYP1A1/2, CYP2B6, CYP2C8/9/19, CYP3A, uridine
diphosphate glucuronosyltransferase (UGT)1A1, P-glyco- protein, or multidrug resistance protein 2 transporters.

⦁ Therapeutic Trials

While efficacy results from phase I or I/II trials investi- gating the use of panobinostat (both alone and in combi- nation with other treatments) in patients with multiple myeloma, other haematological malignancies, solid tu- mours, and graft-versus-host disease are available [23–43], this section focuses on trials that were phase II or higher.
⦁ Multiple Myeloma

Oral panobinostat plus bortezomib and dexamethasone was more effective than placebo plus bortezomib and dexam- ethasone in previously treated (1–3 treatments) patients with relapsed or relapsed and refractory multiple myeloma (phase III PANORAMA-1 trial; NCT01023308) [44].
Median PFS (primary endpoint) was significantly (p \ 0.0001) longer with panobinostat than placebo [11.99 versus 8.08 months; hazard ratio (HR) 0.63 (95 % CI 0.52–0.76)]. While overall survival data were not mature, at the time of analysis median overall survival was 33.64 versus 30.39 months [HR 0.87 (95 % CI 0.69–1.10)], re- spectively; at data cut-off, 35 and 40 % of patients had died. Overall response rates did not significantly differ between groups (60.7 versus 54.6 %); however, the com- plete or near complete response rate was significantly higher with panobinostat than placebo (27.6 versus 15.7 %; p \ 0001). Median duration of partial or better response was 13.14 versus 10.87 months and median time to partial or better response was 1.51 versus 2.00 months. PANOR- AMA-1 is a randomized, double-blind, multicentre, ongo- ing trial involving 387 recipients of panobinostat 20 mg (on days 1, 3, 5, 8, 10 and 12 for eight 21-day cycles
followed by days 1, 3, 5, 8, 10, 12, 22, 24, 26, 29, 31 and 33 for four 42-day cycles) and 381 placebo recipients; all patients received intravenous bortezomib 1.3 mg/m2 (on days 1, 4, 8 and 11 of the first 8 cycles and days 1, 8 22 and 29 of the remaining cycles) and oral dexamethasone 20 mg (on days 1, 2, 4, 5, 8, 9, 11 and 12 of the first 8 cycles and
days 1, 2, 8, 9, 22, 23, 29 and 30 of the remaining cycles). At the time of analysis, the median follow-up was 6.47 and
5.59 months in panobinostat and placebo recipients, re- spectively [44].
In the phase II PANORAMA-2 trial (NCT01083602), patients with relapsed and bortezomib-refractory multiple myeloma with C2 prior treatments who received panobi- nostat plus bortezomib and dexamethasone had an overall response rate (primary endpoint) of 34.5 % and a clinical benefit rate of 52.7 % [45]. Median PFS was 5.4 months. Median time to response was 1.4 months and median du- ration of response was 6.0 months. PANORAMA-2 was a noncomparative trial involving 55 patients who received oral panobinostat 20 mg (on days 1, 3, 5, 8, 10 and 12 for
eight 21-day cycles followed by days 1, 3, 5, 8, 10, 12, 22,
24, 26, 29, 31 and 33 for the remaining, 42-day, cycles)
plus intravenous bortezomib 1.3 mg/m2 (on days 1, 4, 8
and 11 of the first 8 cycles and days 1, 8 22 and 29 of the remaining cycles) and oral dexamethasone 20 mg (on days 1, 2, 4, 5, 8, 9, 11 and 12 of the first 8 cycles and
days 1, 2, 8, 9, 22, 23, 29 and 30 of the remaining cycles).
Median exposure was 4.6 months [45].

Key clinical trials of panobinostat (Novartis)

Drug(s) Indication Phase Status Location(s) Identifier
Panobinostat ? bortezomib ? Multiple myeloma III Ongoing Worldwide PANORAMA-1; NCT01023308;
dexamethasone CLBH589D2308; 2009-015507-52
Panobinostat ? bortezomib ? Multiple myeloma dexamethasone III Ongoing Worldwide 2014-003239-21; CLBH589D2001X
Panobinostat ? bortezomib ? Multiple myeloma II Completed USA PANORAMA-2; NCT01083602;

dexamethasone
Panobinostat ? lenalidomide ?
dexamethasone Panobinostat ? bortezomib ?
dexamethasone
CLBH589DUS71
Multiple myeloma II Recruiting USA NCT01651039;
GCO 12-0469; CLBH589DUS85T
Multiple myeloma II Planned Japan NCT02290431; CLBH589D1201

Panobinostat Chronic myeloid leukaemia
Panobinostat Chronic myeloid leukaemia
II/III Completed USA,
Germany II/III Completed Belgium,
Germany
NCT00449761; CLBH589B2211 NCT00451035; CLBH589B2202

Panobinostat Cutaneous T-cell lymphoma
Panobinostat Cutaneous T-cell lymphoma
II/III Completed USA NCT00490776; CLBH589B2212

II/III Completed Worldwide NCT00425555; CLBH589B2201;
2006-000880-27

Panobinostat Hodgkin’s lymphoma III Completed Worldwide NCT01034163; CLBH589E2301;
2009-014846-26
Panobinostat Hodgkin’s lymphoma II Completed Worldwide NCT00742027; CLBH589E2214;
2008-003016-35
Panobinostat ? lenalidomide Hodgkin’s lymphoma II Recruiting USA NCT01460940; OSU-10049;
NCI-2011-03323

Panobinostat Non-Hodgkin’s lymphoma
Panobinostat ? rituximab Diffuse large B-cell
lymphoma Panobinostat ? rituximab Diffuse large B-cell
lymphoma
Panobinostat versus RAD001 Diffuse large B-cell
lymphoma
II Recruiting USA NCT01261247; MC0986; NCI-2010-02326;
10-004705; CLBH589BUS59T; MC0986
II Ongoing USA NCT01282476; 10-441

II Ongoing Canada NCT01238692; Q-CROC-02 II Recruiting USA NCT00978432; Pro00012947

Panobinostat ? bortezomib T-cell or NK/T-cell
lymphoma
II Completed Republic of
Korea, Malaysia, Singapore
NCT00901147; SGH651; SHF/CTG023/2008

Panobinostat Acute myelogenous leukaemia
Panobinostat Waldenstro¨m’s macroglobulinaemia
II Completed Worldwide NCT00880269; CLBH589B2213;
2008-002983-32
II Ongoing USA NCT00936611; 09-071; CLBH589CUS56T

Panobinostat Primary myelofibrosis II Completed USA NCT00931762; CLBH589BUS58

Panobinostat Haematological neoplasms
II Ongoing USA, Israel,
Netherlands, Spain
NCT01802879; CLBH589B2402B; 2012-005252-41

Panobinostat Prostate cancer II Completed USA NCT00667862; CLBH589C2208 Panobinostat Colorectal cancer II Completed USA NCT00690677; CLBH589BUS19T;
CRC GOLP CNOV 0823
Panobinostat Renal carcinoma II Completed USA NCT00550277; SCRI GU 49

Panobinostat Small-cell lung cancer
II Completed Germany, Italy NCT01222936; S075LBH501

Panobinostat Soft tissue sarcoma II Completed France NCT01136499; ESTIM-LBH;
2009-011280-37

Panobinostat Thyroid cancer II Ongoing USA NCT01013597; H-2009-0173; CO 08322
Panobinostat Breast cancer II Ongoing USA NCT00777049; TRIO 017

continued
Drug(s) Indication Phase Status Location(s) Identifier
Panobinostat Neuroendocrine tumours II Ongoing USA NCT00985946; 2010-0050 (CO08209); CLBH589BUS38T
Panobinostat ? erythropoietin- stimulating agents Myelodysplastic syndrome IV Completed Germany GEPARD; NCT01034657; CLBH589BDE04; EudraCT 2009-010403-84;
2009-010403-84
Panobinostat Myelodysplastic syndrome II Completed USA NCT00594230; SCRI MDS 07

Another noncomparative, phase II trial investigating oral panobinostat plus melphalan, prednisone and thalido- mide in 31 patients with relapsed/refractory multiple myeloma found that an at least partial response occurred in
38.5 % of patients and a complete response in 6.5 % [46]. The median PFS was 14 months at a median follow-up of 12 months; the 1-year PFS rate was 59 % and the 1-year overall survival rate was 63 %. Patients received six 28-day cycles of panobinostat 10–20 mg (on days 1, 3, 5, 8, 10, 12, 15, 17 and 19), oral melphalan 0.18 mg/kg (on days 1–4), prednisone 1.5 mg/kg (on days 1–4), and thalidomide 50 mg/day (continuous).

⦁ Other Haematological Malignancies

Oral panobinostat, as a single agent, was associated with a 47 % overall response rate in patients with relapsed/re- fractory Waldenstro¨m’s macroglobulinaemia, in a non- comparative, phase II trial (NCT00936611) [47]. The median time to first response was 1.8 months, and the median PFS was 6.6 months. Thirty-six patients received panobinostat 30 mg 3 days a week in 28-day cycles (B6 cycles).
A phase II trial (NCT00931762) investigating oral panobinostat as a single agent in patients with primary myelofibrosis, post-essential thrombocythaemia, or post- polycythaemia vera myelofibrosis found that 1 of 35 patients achieved an International Working Group for Myelofibrosis Research and Treatment response (C50 % reduction in spleen size lasting C8 weeks), and only 16 patients completed C2 cycles of treatment (as a result of poor tolerability) [48]. Panobinostat 40 mg was ad- ministered once daily three times weekly in 28-day cycles.
Preliminary data from a noncomparative, phase II study (NCT01523834) in 23 patients with relapsed or refractory diffuse large B-cell lymphoma indicate that oral panobi- nostat as a single agent may be an effective salvage therapy in this indication [49]. A total of 22 % of patients achieved an overall response (13 % complete response and 9 % partial response). Time to response was 2.5 months, and
1-year PFS and overall survival rates were 22 and 28 %, respectively. Patients received panobinostat 40 mg three times weekly in a 28-day cycle.

⦁ Solid Tumours

Several noncomparative, phase II studies (n = 7–47) of single-agent [50–53] or combination treatment [54, 55]
with oral [50, 52–55] or intravenous [51] panobinostat in solid tumours (previously treated, extensive- or limited- stage small-cell lung cancer [50], previously treated, cas- tration-resistant prostate cancer [51], previously gemcita- bine-treated, progressing, advanced pancreatic cancer [54], refractory metastatic renal cell carcinoma [52], advanced, pretreated soft-tissue sarcoma [53], and recurrent glioblastoma [55]) indicate that it is unlikely to be effective in these indications.

⦁ Other Diseases

Two phase II studies of oral panobinostat [one noncom- parative as a single-agent (n = 13) [56] and one random- ized with/without concomitant erythropoietin (n = 34) [57]] in patients with low or intermediate-1 risk myelodysplastic syndrome indicate that it is unlikely to be effective in these patients.

⦁ Adverse Events

Panobinostat has a generally acceptable tolerability profile [6, 44]. In PANORAMA-1, grade 3–4 adverse events oc- curred in 96 and 82 % of panobinostat- and placebo-based regimen recipients, respectively; the most common were thrombocytopenia (67 versus 31 %), lymphopenia (53
versus 40 %), diarrhoea (26 versus 8 %), asthenia/fatigue
(24 versus 12 %) and peripheral neuropathy (18 versus 15 %) [44]. Serious adverse events occurred in 60 and 42 % of recipients, respectively [6, 44]; the most common serious adverse events in panobinostat recipients were pneumonia (18 %), diarrhoea (11 %), thrombocytopenia (7 %), fatigue (6 %) and sepsis (6 %) [6]. A total of 36

versus 20 % of panobinostat- and placebo-based regimen recipients discontinued treatment as a result of adverse events [6, 44]; 24 and 12 % as a result of grade 3–4 adverse events [44]. The most common adverse events leading to discontinuation of panobinostat-based treatment were di- arrhoea, peripheral neuropathy, asthenia/fatigue, thrombo- cytopenia and pneumonia [44]. A total of 8 versus 5 % of patients died while on treatment, respectively (30 versus 18 patients); 4 versus 6 deaths were as a result of pro- gressive disease, and 11 versus 7 deaths were considered to be related to treatment [haemorrhage (2 patients), infection (7), myocardial infarction (1) and cerebrovascular accident
(1) in the panobinostat group and infection (4), haemor- rhage (1), pulmonary embolism (1) and cardiac arrest (1) in the placebo group] [44].
The US prescribing information contains a boxed warning regarding the risk of diarrhoea with panobinostat treatment [6]. In PANORAMA-1, diarrhoea of any grade occurred in 68 versus 42 % of panobinostat- and placebo- based regimen recipients, respectively; severe diarrhoea occurred in 25 versus 8 %. Patients should be monitored for diarrhoea symptoms, and treatment should be inter- rupted at the onset of moderate diarrhoea [6].
There is also a boxed warning regarding the increased risk of cardiac toxicities [6]. Some recipients of panobi- nostat have had severe and fatal cardiac ischaemic events, severe arrhythmias, and ECG changes. Cardiac ischaemic events occurred in 4 versus 1 % of panobinostat versus placebo recipients, arrhythmias in 12 versus 5 %, ST-seg- ment depression in 22 versus 4 %, and T-wave abnor- malities in 40 versus 18 %. QT interval may be prolonged by panobinostat; in PANORAMA-1, a maximum increase in corrected QT (QTc) interval from baseline of [30 ms occurred in &15 % of panobinostat recipients (no QTc interval was [500 ms; 11 % of recipients had a QTc in- terval of 451–480 ms and 1 % had 481–500 ms) [6]. Panobinostat treatment should not be initiated in patients with a recent history of myocardial infarction, unstable angina, a QTc interval of [450 ms, or clinically significant ST-segment or T-wave abnormalities, and monitoring is necessary in all patients [6]. Concomitant use of panobi- nostat with drugs known to prolong the QT interval is not recommended [6].
Severe and fatal haemorrhage and localized and sys-
temic infections have occurred during panobinostat treat- ment [6]. In PANORAMA-1, grade 3/4 haemorrhage occurred in 4 versus 2 % of panobinostat and placebo re- cipients [6]. A total of 31 and 24 % of patients had severe infections.
Panobinostat is associated with myelosuppression, in- cluding severe thrombocytopenia, neutropenia and anaemia [6]. Grade 3–4 thrombocytopenia occurred in 67 versus 31 % of panobinostat versus placebo recipients in
PANORAMA-1, and thrombocytopenia led to treatment interruption or dosage modification in 31 versus 11 %. Severe neutropenia occurred in 34 versus 11 %, and neu- tropenia led to discontinuation or dosage modification in 10 % of panobinostat recipients. Hepatic dysfunction (e.g. aminotransferase or total bilirubin elevations) has occurred in patients receiving panobinostat [6].
Asthenic adverse events (fatigue, malaise, asthenia or lethargy) of any grade occurred in 60 versus 42 % of panobinostat versus placebo recipients in PANORAMA-1 and led to discontinuation of treatment in 6 versus 3 %; grade 3 or greater events occurred in 25 versus 12 %.
Panobinostat was teratogenic in preclinical animal trials, and can cause fetal harm when administered to pregnant women [6]. Patients aged [65 years had a greater fre- quency of certain adverse events and treatment discon- tinuation than those aged B65 years; the incidence of death in panobinostat recipients was 9 and 5 %, respec- tively [6].

⦁ Ongoing Clinical Trials

Many phase I or phase I/II trials of panobinostat as a single agent or in combination with other drugs are currently ongoing in several indications, including multiple myeloma (NCT01440582, NCT01549431, NCT01301807, NCT0196 5353, NCT02145715, NCT02057640, NCT00918333),
other haematological malignancies (NCT01321346, NCT 00918333, NCT01451268, NCT01169636, NCT01693601, NCT00840346, NCT01884428, NCT01032148), solid tu- mours (NCT00925132, NCT02032810, NCT01005797, NCT01582009, NCT00878436, NCT00907179, NCT0154
3763), and other diseases (NCT01451268, NCT01463046, NCT01245179, NCT01672229). Ongoing phase II and over studies are outlined below.

⦁ Multiple Myeloma

Novartis, in December 2014, initiated an expanded treat- ment protocol of panobinostat in combination with borte- zomib and dexamethasone in patients with relapsed/ refractory multiple myeloma (CLBH589D2001X; Eu- draCT2014-003239-21). The phase III study is being con- ducted with an aim to provide an early access to treatment to this patient population. The primary endpoint of the study will be the incidence of adverse events, treatment discontinuations or death. A total of 314 adult and elderly subjects will be enrolled in several countries.
Novartis is planning a phase II study to evaluate the safety and efficacy of panobinostat plus bortezomib plus dexamethasone in Japanese patients with relapsed or re- fractory multiple myeloma (CLBH589D1201; NCT022 90431). The primary endpoint will be the 24-week near

complete response plus complete response rate. Ap- proximately 33 patients will be enrolled in Japan.
A phase II trial is currently recruiting, investigating the efficacy of panobinostat plus lenalidomide and dexam- ethasone in patients with multiple myeloma (NCT0165 1039). A total of 27 patients will be enrolled in the USA. The primary endpoint is overall response rate at B4 years.

⦁ Other Haematological Malignancies

The efficacy of panobinostat versus RAD001 in patients with relapsed/refractory diffuse large B-cell lymphoma is being investigated in a phase II trial (NCT00978432). The primary endpoint is the overall response rate at B2 years. A total of 75 patients will be enrolled in the USA.
A phase II trial of panobinostat in patients with relapsed or refractory non-Hodgkin lymphoma is currently recruit- ing (NCT01261247). The primary endpoint is the propor- tion of confirmed complete or partial response, and 37 patients will be enrolled in the USA.
A total of 25 patients with relapsed or refractory Hodgkin’s lymphoma are expected to be enrolled in the USA in a phase II trial investigating the efficacy of panobinostat plus lenalidomide (NCT01460940). The pri- mary endpoint is the overall response rate.

⦁ Current Status

Panobinostat received its first global approval on 23 Fe- bruary 2015 [7] for combination therapy with bortezomib and dexamethasone in patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an immunomodulatory agent, in the US [6].

Disclosure The preparation of this review was not supported by any external funding. During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. K. P. Garnock-Jones is a salaried employee of Adis, Springer SBM.

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