Belinostat (PXD-101) is a class I/II intravenous histone deacetylase (HDAC) inhibitor. HDAC plays an important role in the epigenetic silencing of tumor suppressor genes. The overall response rate was 25% following a median of 2 cycles of belinostat in 24 patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) in a multinational, 2-cohort, phase II trial. In July 2014, belinostat (Beleodaq) was approved by the FDA for the treatment of relapsed or refractory PTCL. It was an accelerated approval based on tumor response rate and duration of response; however, continued approval may be dependent upon verification and description of clinical benefit in confirmatory trials.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
-Low
-Administer prn antiemetics as necessary.
Route-Specific Administration
Injectable Administration
Intravenous Administration
Reconstitution:
-Add 9 mL of Sterile Water for Injection, USP to each 500 mg vial of belinostat. Swirl the contents of the vial until there are no visible particles in the solution. The reconstituted solution will contain belinostat 50 mg/mL.
-The reconstituted solution is stable at ambient room temperature for up to 12 hours.
-Aseptically withdraw the appropriate amount of belinostat from the reconstituted vial and further dilute in 250 mL 0.9% Sodium Chloride for Injection, USP.
-The final solution is stable at room temperature for up to 36 hours, including infusion time.
Intermittent Infusion:
-Visually inspect the solution for particulate matter. Do not administer if cloudiness or particulates are observed.
-Connect to an infusion set with a 0.22 micron in-line filter.
-Administer belinostat as an intravenous infusion over 30 minutes. If infusion site pain or other symptoms that may be attributable to the infusion occur, extend the infusion time to 45 minutes.
In a safety analysis of an open-label, single-arm, non-randomized, multicenter trial, constipation was reported in 23% (grade 3 or 4, 1%), anorexia in 15% (grade 3 or 4, 2%) and abdominal pain in 11% (grade 3 or 4, 1%) of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) treated with belinostat monotherapy (n = 129). Nausea (all grade, 42%; grade 3 or 4, 1%), vomiting (all grade, 29%; grade 3 or 4, 1%), and diarrhea (all grade, 23%; grade 3 or 4, 2%) have also occurred with belinostat and may require the use of antiemetic and antidiarrheal medications.
In a safety analysis of an open-label, single-arm, non-randomized, multicenter trial, anemia was reported in 32% (grade 3 or 4, 11%) and thrombocytopenia in 16% (grade 3 or 4, 7%) of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) treated with belinostat monotherapy (n = 129). Neutropenia has also been reported. Blood counts should be monitored weekly during treatment; dose modifications or treatment discontinuation may be necessary.
In a safety analysis of an open-label, single-arm, non-randomized, multicenter trial of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) treated with belinostat monotherapy (n = 129), the following general adverse reactions were reported: fatigue (all grade, 37%; grade 3 or 4, 5%), headache (all grade, 15%), infusion site pain (all grade, 14%), and dizziness (all grade, 10%). Additionally, 16% of patients who received belinostat monotherapy had increased levels of lactate dehydrogenase (grade 3 or 4, 2%).
In a safety analysis of an open-label, single-arm, non-randomized, multicenter trial, peripheral edema was reported in 20%, hypokalemia in 12% (grade 3 or 4, 4%), and hypotension in 10% (grade 3 or 4, 3%) of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) treated with belinostat monotherapy (n = 129). In the same study, QT prolongation occurred in 11% of patients (grade 3 or 4, 4%). A treatment-related death from ventricular fibrillation was reported in another monotherapy trial with belinostat; however, ECG analysis did not identify QTc prolongation. In multiple clinical trials with belinostat, analysis of clinical ECG and plasma concentration data did not demonstrate a meaningful effect of belinostat on cardiac repolarization.
In a safety analysis of an open-label, single-arm, non-randomized, multicenter trial, rash (unspecified) was reported in 20% (grade 3 or 4, 1%) and pruritus in 16% (grade 3 or 4, 3%) of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) (n = 129) treated with belinostat monotherapy.
In a safety analysis of an open-label, single-arm, non-randomized, multicenter trial, phlebitis occurred in 10% (grade 3 or 4, 1%) of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) treated with belinostat monotherapy (n = 129).
In a safety analysis of an open-label, single-arm, non-randomized, multicenter trial, fever was reported in 35% (grade 3 or 4, 2%) and chills in 16% (grade 3 or 4, 1%) of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) treated with belinostat monotherapy (n = 129). Dyspnea and cough were reported in 22% (grade 3 or 4, 6%) and 19% of patients, respectively. Serious and sometimes fatal infections, including pneumonia (> 2%) and sepsis, have also occurred. Patients with active infection should not be treated with belinostat.
Belinostat can cause hepatotoxicity and elevated hepatic enzymes. In clinical trials, one treatment-related death associated with hepatic failure was reported. Monitor liver function tests before the start of each cycle; interruption of therapy, dose adjustment, or discontinuation may be necessary. Increased serum creatinine (renal failure (unspecified)) has also been reported in > 2% of patients treated with belinostat monotherapy.
In clinical trials, one patient treated with belinostat monotherapy who had baseline hyperuricemia and bulky disease, developed grade 4 tumor lysis syndrome (TLS) during the first treatment cycle and died due to multi-organ failure. Multi-organ failure has been reported in > 2% of patients. Closely monitor patients with advanced stage disease and/or high tumor burden; take appropriate precautions and institute treatment as appropriate.
Hematologic toxicity, including thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia have been reported with belinostat therapy. Monitor complete blood cell counts prior to starting therapy and then weekly. Dose modifications may be necessary in patients with bone marrow suppression and should be determined by the absolute neutrophil count (ANC) and platelet count nadirs of the previous cycle of therapy. Platelet counts should be >= 50,000/mm3 and ANC > 1000/mm3 before starting each cycle.
Serious infections, including pneumonia and sepsis, have occurred during treatment with belinostat; some occurrences have been fatal. Do not administer belinostat to patients with an active infection. Use caution in patients with a history of extensive or intensive chemotherapy, as they may be at higher risk of life-threatening infections.
Abnormal liver function tests and fatal hepatic toxicity have been observed in patients receiving belinostat. Monitor liver function tests prior to the start of each cycle of therapy. Patients with signs of hepatic impairment or hepatic disease may require dose modification or discontinuation.
Tumor lysis syndrome (TLS) has occurred in patients treated with belinostat. Patients with high tumor burden or advanced stage disease are at greater risk for developing TLS; consider tumor lysis prophylaxis with anti-hyperuricemic agents and hydration beginning 12-24 hours prior to treatment with belinostat in these patients. For TLS treatment, administer aggressive intravenous hydration and antihyperuricemic agents, correct electrolyte abnormalities, and monitor renal function.
Belinostat is primarily metabolized by UGT1A1. Patients with reduced UGT1A1 activity, including patients with the UGT1A1*28 allele, could have decreased drug clearance. Approximately 20% of Black patients, 10% of White patients, and 2% of Asian patients are homozygous for the UGT1A1*28 allele. Reduce the starting dose of belinostat to 750 mg/m2 in patients who are homozygous for the UGT1A1*28 allele.
Belinostat can cause fetal harm including teratogenicity and/or embryo-fetal death if administered during pregnancy, based on its mechanism of action. Reproductive animal studies have not been conducted with belinostat and there is no data in pregnant humans; however, it is a genotoxic drug that actively targets dividing cells. Women of childbearing potential should avoid becoming pregnant during treatment with belinostat. Advise pregnant women of the potential hazard to the fetus.
Counsel patients about the reproductive risk and contraception requirements during belinostat treatment. Pregnancy testing should be performed prior to starting belinostat in female patients of reproductive potential. These patients should use effective contraception and avoid pregnancy during and for 6 months after belinostat therapy. Women who become pregnant while receiving belinostat should be apprised of the potential hazard to the fetus. Additionally, male patients with a female partner of reproductive potential should use effective contraception during therapy and for 3 months after the last dose due to the risk of male-mediated teratogenicity. Belinostat may cause male infertility, based on data from animal studies. It is not known if infertility is reversible.
No information is available regarding the presence of belinostat in human milk, the effects on the breastfed child, or the effects on milk production. Due to the potential for serious adverse reactions in the nursing child, breast-feeding is not recommended during therapy or for 2 weeks after the last belinostat dose.
For the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL):
The FDA has designated belinostat as an orphan drug for the treatment of PTCL.
Intravenous dosage:
Adults: 1,000 mg/m2 IV over 30 minutes once daily on days 1, 2, 3, 4, and 5 repeated every 21 days until disease progression or unacceptable toxicity. The initial belinostat starting dose is 750 mg/m2 in patients who are homozygous for the UGT1A1*28 allele. Interruption, dose reduction, or discontinuation of therapy may be necessary in patients who develop toxicities. The absolute neutrophil count should be 1,000 cells/mm3 or greater and the platelet count should be 50,000 cells/mm3 or greater before the start of each new cycle. The overall response rate (ORR) (primary end point) assessed by an independent review committee was 25.8% following treatment with belinostat in patients with relapsed or refractory PTCL in a multinational, single-arm, phase II trial (n = 129; the BELIEF trial). The complete response (CR) was 10.8% and the median duration of response (DOR) was 8.4 months. Additionally, the median progression-free survival and overall survival times were 1.6 months and 7.9 months, respectively. In this trial, the median number of prior therapies was 2 (range, 1 to 8 therapies); 20.8% of patients had previously had a hematopoietic stem-cell transplant. The ORR was 25% in patients with relapsed or refractory PTCL who received belinostat (median of 2 cycles of therapy; range 1 to 9 cycles) in another multinational, phase II trial (n = 24); 8.3% of these patients achieved a CR. The median DOR was 109 days, and the median time to progression was 82 days. Patients in this study had received a median of 3 prior therapies (range, 1 to 9 therapies).
Therapeutic Drug Monitoring:
Dose Adjustments due to Treatment-Related Toxicity:
Hematologic Toxicities: Dose adjustments for thrombocytopenia and neutropenia should be based on the platelet and absolute neutrophil count (ANC) nadirs in the preceding cycle of therapy. Do not begin the next cycle of treatment until the ANC is 1,000 cells/mm3 or greater and the platelet count is 50,000 cells/mm3 or greater.
-ANC nadir 500 cells/mm3 or greater AND platelet count nadir 25,000 cells/mm3 or greater: No dose adjustment needed.
-ANC nadir less than 500 cells/mm3 (any platelet count): Begin next cycle of treatment at a reduced dose of 750 mg/m2 IV. For the second occurrence of an ANC nadir less than 500 cells/mm3, reduce the dose of the next cycle to 500 mg/m2 IV. If the ANC nadir is less than 500 cells/mm3 after 2 dose reductions, discontinue belinostat therapy.
-Platelet nadir less than 25,000 cells/mm3 (any ANC): Begin next cycle of treatment at a reduced dose of 750 mg/m2 IV. For the second occurrence of a platelet nadir less than 25,000 cells/mm3, reduce the dose of the next cycle to 500 mg/m2 IV. If the platelet nadir is less than 25,000 cells/mm3 after 2 dose reductions, discontinue belinostat therapy.
Non-Hematologic Toxicities:
-Grade 3 or 4 nausea, vomiting or diarrhea for greater than 7 days with supportive management, or other grade 3 or 4 toxicity of any duration: Hold belinostat treatment. When toxicity resolves to grade 2 or less, restart the next cycle at a reduced dose of 750 mg/m2 IV. For the second occurrence of grade 3 or 4 toxicity (for a duration of greater than 7 days with supportive management for gastrointestinal toxicities), resume therapy at 500 mg/m2 IV upon resolution to grade 2 toxicity or less. If the grade 3 or 4 toxicity recurs after 2 dose reductions, discontinue belinostat therapy.
Maximum Dosage Limits:
-Adults
1,000 mg/m2 IV daily for 5 consecutive days per cycle.
-Geriatric
1,000 mg/m2 IV daily for 5 consecutive days per cycle.
Patients with Hepatic Impairment Dosing
Baseline hepatic impairment: Specific guidelines for initial dosage adjustment of belinostat in patients with hepatic impairment are not available; however, belinostat is metabolized in the liver and hepatic impairment is expected to increase drug exposure. Patients with a total bilirubin levels greater than 1.5-times the upper limit of normal were excluded from clinical trials.
Grade 3 or 4 treatment-related hepatotoxicity: Hold therapy until the toxicity resolves to grade 2 or less; decrease the belinostat dose by 25% (e.g., from 1,000 mg/m2 to 750 mg/m2). Discontinue therapy in patients who have a recurrence of grade 3 or 4 toxicity following 2 dose reductions.
Patients with Renal Impairment Dosing
No initial dosage adjustment of belinostat is necessary in patients with a creatinine clearance (CrCl) greater than 39 mL/min. There is insufficient data to recommend a dose in patients with a CrCl of 39 mL/min or less.
*non-FDA-approved indication
Atazanavir: (Contraindicated) Avoid concomitant administration of belinostat with strong UGT1A1 inhibitors such as atazanavir, as belinostat is primarily metabolized by UGT1A1. Coadministration with strong UGT1A1 inhibitors may increase belinostat exposure and result in increased toxicities.
Atazanavir; Cobicistat: (Contraindicated) Avoid concomitant administration of belinostat with strong UGT1A1 inhibitors such as atazanavir, as belinostat is primarily metabolized by UGT1A1. Coadministration with strong UGT1A1 inhibitors may increase belinostat exposure and result in increased toxicities.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Gemfibrozil: (Moderate) Gemfibrozil may inhibit UGT1A1 in vitro; belinostat is primarily metabolized by UGT1A1. Use caution if coadministration of belinostat with gemfibrozil is necessary, as increased belinostat concentrations and toxicities may occur.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Sodium Phenylbutyrate: (Major) Avoid coadministration of sodium phenylbutyrate and belinostat. Concomitant use may result in unpredictable effects, resulting in increased toxicities or a reduction in efficacy. Sodium phenylbutyrate and belinostat are inhibitors of histone deacetylase (HDAC).
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate and belinostat. Concomitant use may result in unpredictable effects, resulting in increased toxicities or a reduction in efficacy. Sodium phenylbutyrate and belinostat are inhibitors of histone deacetylase (HDAC).
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Belinostat is a class I and II inhibitor of the histone deacetylase (HDAC) family of enzymes. HDACs are enzymes that catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. Overexpression of HDACs or an abnormal recruitment of HDACs to oncogenic transcription factors is present in some cancer cells. This causes hypoacetylation of core nucleosomal histones resulting in a condensed chromatin structure and repression of gene transcription. Inhibition of HDAC activity produces an accumulation of acetyl groups on the histone lysine residues resulting in an open chromatin structure and transcriptional activation. In many different malignant cell lines, HDAC inhibitors have been shown to activate differentiation, inhibit the cell cycle, and induce apoptosis. In vivo, HDAC inhibitors have exhibited stimulation of the immune system and blockage of angiogenesis. In vitro, belinostat has shown preferential cytotoxicity towards tumor cells compared to normal cells, inducing cell cycle arrest and/or apoptosis of some transformed cells at nanomolar concentrations (< 250 nanomolar).
Belinostat is administered intravenously. It has limited tissue distribution, with 92.9% to 95.8% of drug bound to plasma proteins. In pooled data from a phase I/II trial, the total mean plasma clearance was 1,240 mL/min and the elimination half-life was 1.1 hours following belinostat doses ranging from 150 to 1,200 mg/m2. The total clearance approximates average hepatic blood flow (1,500 mL/min), suggesting high hepatic extraction. Belinostat is primarily metabolized in the liver via UGT1A1. Identified metabolites include belinostat amide and belinostat acid, methyl belinostat, and 3-(anilinosulfonyl)-benzenecarboxylic acid (3-ASBA). Following a single, radiolabeled 1,500-mg dose of belinostat IV given over 30 minutes in 6 patients with recurrent or progressive malignancy, the mean percent of radioactivity recovered over 168 hours were 9.7% +/- 6.5% and 84.8% +/- 9.8% in the feces and urine, respectively. Unchanged belinostat accounted for 1.7% of the radioactivity recurred in the urine.
Affected cytochrome P450 isoenzymes or transporters: UGT1A1, P-gp
Belinostat is primarily metabolized by UGT1A1; avoid concomitant administration with strong UGT1A1 inhibitors. In vitro studies have demonstrated it also undergoes hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 and that belinostat and its metabolites inhibit CYP2C8 and CYP2C9. Belinostat is a P-glycoprotein (P-gp) substrate; it is unlikely to inhibit P-gp.
-Special Populations
Hepatic Impairment
Belinostat is metabolized in the liver. Hepatic impairment is expected to increase belinostat exposure, although patients with moderate and severe hepatic impairment (total bilirubin level greater than 1.5-times the upper limit of normal) were excluded from clinical trials.
Renal Impairment
Belinostat exposure is not altered in patients with creatinine clearance (CrCL) greater than 39 mL/min; there is insufficient data in patients with a CrCL of 39 mL/min or less.