Belinostat, a histone deacetylase (HDAC) inhibitor, is an antineoplastic agent.1
Belinostat is used for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL);1, 2, 3, 10 the drug is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this cancer.4 The current indication is based on overall response rate and duration of response; there currently are no controlled trials demonstrating a clinical benefit (e.g., improvement in disease-related symptoms, increased survival).1
The current indication for belinostat is based principally on the results of an open-label, noncomparative, nonrandomized study (BELIEF) in 129 patients with relapsed or refractory PTCL.1, 2 The primary measure of efficacy was overall response rate (complete plus partial responses) as assessed by an independent review committee using the International Workshop Criteria (IWC).1, 2 The median age of patients was 64 years; the patients had received a median of 2 prior therapies for their disease.1 In this study, all patients received belinostat (1 g/m2 IV daily on days 1-5 every 3 weeks) until disease progression or unacceptable toxicity occurred.1, 2 The overall response rate was 25.8%; 10.8% of patients receiving the drug achieved a complete response.1 At the time of analysis, the median duration of response for all responders was 5.6 weeks (range: 4.3-50.4 weeks); the median duration of response based on the first date of response to disease progression or death was 8.4 months.1 Following therapy with belinostat, 7.5% of patients underwent stem cell transplantation.1
Complete blood cell counts (CBCs) should be obtained prior to initiation of belinostat therapy and monitored weekly during therapy.1 In addition, serum chemistry tests, including hepatic and renal function tests, should be performed before administration of the first belinostat dose of each treatment cycle.1
Procedures for proper handling (e.g., use of gloves or protective clothing) and disposal of antineoplastic agents should be followed.1
Belinostat is administered by IV infusion over 30 minutes.1 If infusion site reactions (e.g., pain) occur, the infusion time may be extended to 45 minutes.1
Prior to administration, commercially available belinostat powder for injection must be reconstituted and diluted using proper aseptic technique.1 The lyophilized powder is reconstituted by adding 9 mL of sterile water for injection to a vial labeled as containing 500 mg of the drug to provide a solution containing 50 mg/mL.1 The vial should be swirled until complete dissolution of the powder occurs.1 The solution should be inspected visually for particulate matter and discoloration prior to dilution and administration.1 The reconstituted belinostat solution may be stored at 15-25°C for up to 12 hours.1
For preparation of the final diluted belinostat solution for infusion, the required dose of reconstituted belinostat solution should be injected into an infusion bag containing 250 mL of 0.9% sodium chloride injection.1 The final diluted solution may be stored at 15-25°C for up to 36 hours (including infusion time).1 Belinostat should be administered through a 0.22-µm inline filter.1
For the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL), the recommended adult dosage of belinostat is 1 g/m2 administered as a 30-minute IV infusion daily on days 1-5 of each 21-day cycle.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Dosage adjustments for thrombocytopenia or neutropenia should be based on nadir blood cell counts during the previous treatment cycle.1
If the absolute neutrophil count (ANC) decreases to no less than 500/mm3 and platelet counts decrease to no less than 25,000/mm3, belinostat therapy should be withheld until ANC reaches or exceeds 1000/mm3 and platelet counts reach or exceed 50,000/mm3.1 Therapy may then be resumed at the same dosage.1
If ANC decreases to less than 500/mm3 with any platelet count, belinostat therapy should be withheld until ANC reaches or exceeds 1000/mm3 and platelet counts reach or exceed 50,000/mm3.1 Upon resumption of therapy, the belinostat dosage should be reduced by 25%.1
If platelet counts decrease to less than 25,000/mm3 with any ANC, belinostat therapy should be withheld until ANC reaches or exceeds 1000/mm3 and platelet counts reach or exceed 50,000/mm3.1 Upon resumption of therapy, the belinostat dosage should be reduced by 25%.1
If ANC less than 500/mm3 and/or platelet count less than 25,000/mm3 recurs following 2 dosage reductions, belinostat therapy should be discontinued.1
If prolonged grade 3 or 4 nausea, vomiting, and/or diarrhea (i.e., lasting more than 7 days despite initiation of supportive management) or if other grade 3 or 4 nonhematologic toxicity occurs, belinostat therapy should be withheld until the toxicity resolves to grade 2 or less.1 Upon resumption of therapy, the belinostat dosage should be reduced by 25%.1
If grade 3 or 4 nonhematologic toxicity recurs following 2 dosage reductions, belinostat therapy should be discontinued.1
Reduced Uridine Diphosphate-glucuronosyltransferase (UGT) 1A1 Activity
In patients who are homozygous for the UGT1A1*28 allele, the initial dose of belinostat should be reduced to 750 mg/m2.1 (See Description.)
The manufacturer states that insufficient data are available to provide dosage recommendations for patients with moderate or severe hepatic impairment or for patients with a creatinine clearance of 39 mL/minute or less.1 The manufacturer makes no specific dosage recommendations for geriatric patients.1 (See Specific Populations under Cautions: Warnings/Precautions.)
The manufacturer states there are no known contraindications to the use of belinostat.1
Thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia may occur.1 In the principal efficacy study of belinostat in patients with peripheral T-cell lymphoma (PTCL), thrombocytopenia or anemia occurred in 16 or 32% of patients, respectively; grade 3 or 4 thrombocytopenia occurred in 7% of patients, and grade 3 or 4 anemia occurred in 11% of patients.1 Complete blood cell counts (CBCs) should be monitored weekly during therapy and the dosage of belinostat should be adjusted if necessary.1 (See Hematologic Toxicity under Dosage: Dosage Modification, in Dosage and Administration.)
Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in patients receiving belinostat.1 Patients with a history of extensive or intensive chemotherapy may be at greater risk for life-threatening infections.1 Belinostat should not be administered to patients with an active infection.1
Fatal hepatotoxicity and liver function test abnormalities may occur.1 In the principal efficacy study of belinostat in patients with PTCL, fatal hepatic failure was reported in one patient.1 Liver function tests should be performed prior to initiation of belinostat therapy and prior to each treatment cycle.1 In patients who develop hepatotoxicity, temporary interruption of therapy, dosage reduction, or drug discontinuance may be required.1 (See Nonhematologic Toxicity under Dosage: Dosage Modification, in Dosage and Administration.)
Tumor lysis syndrome has been reported in patients receiving belinostat for the treatment of relapsed or refractory PTCL.1 In the principal efficacy study of belinostat in patients with PTCL, grade 4 tumor lysis syndrome resulting in death occurred in one patient with baseline hyperuricemia and bulky disease during the first cycle of therapy.1 The risk of tumor lysis syndrome is increased in patients with advanced stage disease and/or a large tumor burden; such patients should be monitored closely and appropriate precautions should be taken.1
Nausea, vomiting, and diarrhea occur frequently in patients receiving belinostat.1 In the principal efficacy study of belinostat in patients with PTCL, nausea, vomiting, and diarrhea were reported in 42, 29, and 23% of patients, respectively.1 Antiemetic and antidiarrheal therapy may be necessary in patients receiving belinostat therapy.1
Fetal/Neonatal Morbidity and Mortality
Belinostat may cause fetal harm if administered to pregnant women.1 Based on its mechanism of action, teratogenicity and embryo and fetal lethality may occur.1 Pregnancy should be avoided during belinostat therapy.1 If belinostat is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
Results of animal studies suggest that belinostat may impair male fertility.1 The effect of belinostat on fertility in humans is not known.1
Category D.1 (See Users Guide and see Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)
It is not known whether belinostat is distributed into milk in humans; because of the potential for serious adverse reactions to belinostat in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1
Safety and efficacy of belinostat have not been established in pediatric patients.1
In the principal efficacy study evaluating belinostat in patients with PTCL, 48% of patients were 65 years of age or older and 10% were 75 years of age or older.1 In patients with PTCL, the overall response rate was 36% in those 65 years of age and older compared with 16% in those younger than 65 years of age.1 No meaningful differences in overall response rate were observed between patients 75 years of age and older and those younger than 75 years of age.1 No clinically important differences in safety were observed between geriatric patients and younger adults.1 (See Dosage and Administration: Special Populations.)
Data are lacking on use of belinostat in patients with moderate or severe hepatic impairment (total bilirubin concentrations exceeding 1.5 times the upper limit of normal [ULN]); however, since belinostat is eliminated principally by hepatic metabolism, hepatic impairment may result in increased plasma belinostat concentrations.1 (See Dosage and Administration: Special Populations.)
Systemic exposure to belinostat was not altered in patients with creatinine clearance exceeding 39 mL/minute.1 Data are lacking on use of belinostat in patients with creatinine clearance of 39 mL/minute or less.1 (See Dosage and Administration: Special Populations.)
Adverse effects reported in 10% or more of patients receiving belinostat include nausea,1, 3 fatigue,1 pyrexia,1 vomiting,1, 3 constipation,1 diarrhea,1 dyspnea,1 rash,1 peripheral edema,1 cough,1 pruritus,1 chills,1 decreased appetite,1 headache,1 infusion site pain,1, 3 prolonged QT interval,1 abdominal pain,1 hypotension,1 phlebitis,1 and dizziness.1, 3 Laboratory abnormalities reported in 10% or more of patients receiving belinostat include anemia,1 thrombocytopenia,1 elevated serum LDH concentrations,1 and hypokalemia.1
Belinostat is metabolized principally (80-90%) by uridine diphosphate-glucuronosyltransferase (UGT) 1A1.1 In vitro studies indicate that belinostat and its metabolites, including belinostat glucuronide, belinostat amide, and methyl belinostat, are inhibitors of cytochrome P-450 (CYP) isoenzymes 2C8 and 2C9; other metabolites, including 3-(anilinosulfonyl)-benzenecarboxylic acid (3-ASBA) and belinostat acid, are inhibitors of CYP2C8 in vitro.1
Belinostat is a likely substrate, but an unlikely inhibitor, of P-glycoprotein (P-gp).1
Drugs Affecting Uridine Diphosphate-glucuronosyltransferase (UGT)
Concomitant use of belinostat with potent inhibitors of UGT1A1 may result in increased systemic exposure to belinostat.1 Concomitant use of belinostat with potent UGT1A1 inhibitors should be avoided.1
In cancer patients receiving warfarin sodium (5 mg), a CYP2C9 substrate, concomitantly with belinostat (1 g/m2), the area under the concentration-time curve (AUC) and peak plasma concentrations of the R - and S -enantiomers of warfarin were not substantially altered.1
Belinostat, a histone deacetylase (HDAC) inhibitor, is an antineoplastic agent.1 HDAC enzymes catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors.1, 5, 6, 7, 8 Overexpression of HDAC enzymes or aberrant recruitment of HDAC enzymes to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones has been observed in some cancer cells.7, 8 Hypoacetylation of histones is associated with a condensed chromatin structure and repression of gene transcription.6, 7, 8 Inhibition of HDAC activity allows for the accumulation of acetyl groups on the histone lysine residues, resulting in an open chromatin structure and transcriptional activation.7, 8 In vitro, belinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells.1 Belinostat inhibits the enzymatic activity of histone deacetylases and exhibits cytotoxic activity and induces apoptosis in various tumor cell lines at nanomolar concentrations.1, 5, 9
Belinostat is metabolized principally (80-90%) by uridine diphosphate-glucuronosyltransferase (UGT) 1A1; the drug also is metabolized by cytochrome P-450 (CYP) isoenzymes 2A6, 2C9, and 3A4 to form the metabolites belinostat amide and belinostat acid.1 Other metabolites of the drug include methyl belinostat and 3-(anilinosulfonyl)-benzenecarboxylic acid (3-ASBA); the enzymes responsible for the formation of these metabolites have not been determined.1 Belinostat is a likely substrate, but an unlikely inhibitor, of P-glycoprotein (P-gp).1 The main circulating metabolites are excreted in urine, with 2 metabolites predominating (3-ASBA and belinostat glucuronide, which account for 4.61 and 30.5%, respectively, of an administered dose); only a small portion (less than 2%) of a dose is excreted in urine as unchanged drug.1 Belinostat is 92.9-95.8% bound to plasma proteins.1 Following administration of belinostat (150-1200 mg/m2), the elimination half-life of the drug was 1.1 hours.1
In patients with genetic polymorphisms associated with reduced UGT1A1 activity (e.g., individuals who are homozygous for the UGT1A1*28 allele), clearance of belinostat may be reduced and dosage adjustment may be required.1 (See Reduced Uridine Diphosphate-glucuronosyltransferase [UGT] 1A1 Activity under Dosage: Dosage Modification, in Dosage and Administration.)
Importance of instructing patients to read the manufacturer's patient information carefully before starting belinostat therapy and to reread it before each treatment.1
Importance of informing patients that nausea, vomiting, and diarrhea occur frequently with belinostat therapy and that treatment with antiemetic and/or antidiarrheal agents may be necessary.1 Importance of informing clinicians if nausea, vomiting, or diarrhea occurs.1
Risk of cytopenias.1 Importance of informing clinician immediately if unusual bleeding or bruising, tiredness, pallor, shortness of breath, or infection occurs.1
Risk of infections.1 Importance of informing clinician if fever, flu-like symptoms, cough, shortness of breath, burning on urination, muscle aches, or worsening skin problems occur.1
Risk of fetal harm.1 Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Apprise patient of potential hazard to the fetus if used during pregnancy; women of childbearing potential should avoid becoming pregnant.1
Risk of hepatotoxicity and importance of liver function test monitoring.1 Importance of informing clinician if icteric changes, dark urine, pruritus, or abdominal pain (particularly in the right upper quadrant) occurs.1
Risk of tumor lysis syndrome.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., hepatic impairment).1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions August 10, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Spectrum Pharmaceuticals, Inc. Beleodaq® (belinostat) for injection prescribing information. Irvine, CA; 2014 Jul.
2. O'Connor OW, Masszi T, Savage KJ et al. Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL): results from the BELIEF trial. J Clin Oncol . 2013; 31 (suppl): Abstract No. 8507 (presented at the 48th Annual ASCO Meeting. Chicago, IL: 2013 Jun 1).
3. Foss F, Advani R, Duvic M et al. A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma. Br J Haematol . 2014; :. [PubMed 25404094]
4. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2014 Jul 15. [Web]
5. Steele NL, Plumb JA, Vidal L et al. A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors. Clin Cancer Res . 2008; 14:804-10. [PubMed 18245542]
6. Howman RA, Prince HM. New drug therapies in peripheral T-cell lymphoma. Expert Rev Anticancer Ther . 2011; 11:457-72. [PubMed 21417858]
7. Merck & Co., Inc. Zolinza® (vorinostat) capsules prescribing information. Whitehouse Station, NJ; 2013 Apr.
8. Richon VM. Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor. Br J Cancer . 2006; 95:S2-6: [Web][PubMedCentral]
9. Plumb JA, Finn PW, Williams RJ et al. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol Cancer Ther . 2003; 2:721-8. [PubMed 12939461]
10. Reimer P, Chawla S. Long-term complete remission with belinostat in a patient with chemotherapy refractory peripheral T-cell lymphoma. J Hematol Oncol . 2013; 6:69. [PubMedCentral][PubMed 24020452]