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  • CLASSES

    Histone Deacetylase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    IV histone deacetylase inhibitor for patients with relapsed or refractory peripheral T-cell lymphoma (PTCL)
    Accelerated FDA-approval based on tumor response rate and duration of response; no improvement in survival has been found
    Myelosuppression, an increased risk of serious infections, and fatal hepatotoxicity have been reported

    COMMON BRAND NAMES

    Beleodaq

    HOW SUPPLIED

    Beleodaq Intravenous Inj Pwd F/Sol: 500mg

    DOSAGE & INDICATIONS

    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).

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    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.

    ADMINISTRATION

    Belinostat is a cytotoxic anticancer agent. Use caution when handling, preparing, or administering the solution. The use of protective gloves and other protective clothing is recommended.

    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.

    STORAGE

    Beleodaq:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original package until time of use
    - Use within 12 hours after reconstitution

    CONTRAINDICATIONS / PRECAUTIONS

    Anemia, bone marrow suppression, leukopenia, neutropenia, thrombocytopenia

    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.

    Chemotherapy, infection, sepsis

    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.

    Hepatic disease

    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)

    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.

    Breast-feeding

    It is not known whether belinostat is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from this drug, a decision should be made whether to discontinue breast-feeding or to discontinue belinostat, taking into account the importance of belinostat to the mother.

    Children, infants, neonates

    The safety and efficacy of belinostat have not been established in adolescents, children, infants, or neonates.

    Infertility, pregnancy

    Belinostat can cause fetal harm when administered to a woman during pregnancy. Belinostat is classified as FDA pregnancy risk category D. Reproductive and developmental animal toxicology studies have not been conducted with belinostat; however, it is a genotoxic drug that actively targets dividing cells. Teratogenicity and/or embryo-fetal death may occur. Women of childbearing potential should avoid becoming pregnant during treatment with belinostat. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Belinostat may impair male fertility (infertility). In a 24-week repeat-dose toxicology study in dogs, a delay in testicular maturation was correlated to reduced weight of the testes/epididymides after exposure to belinostat.

    Asian patients, Black patients, Caucasian patients

    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 caucasian 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.

    ADVERSE REACTIONS

    Severe

    anemia / Delayed / 11.0-11.0
    thrombocytopenia / Delayed / 7.0-7.0
    dyspnea / Early / 6.0-6.0
    fatigue / Early / 5.0-5.0
    QT prolongation / Rapid / 4.0-4.0
    hypokalemia / Delayed / 4.0-4.0
    hypotension / Rapid / 3.0-3.0
    pruritus / Rapid / 3.0-3.0
    anorexia / Delayed / 2.0-2.0
    diarrhea / Early / 2.0-2.0
    fever / Early / 2.0-2.0
    vomiting / Early / 1.0-1.0
    abdominal pain / Early / 1.0-1.0
    nausea / Early / 1.0-1.0
    constipation / Delayed / 1.0-1.0
    ventricular fibrillation / Early / 0-1.0
    rash (unspecified) / Early / 1.0-1.0
    phlebitis / Rapid / 1.0-1.0
    chills / Rapid / 1.0-1.0
    hepatic failure / Delayed / 0-1.0
    tumor lysis syndrome (TLS) / Delayed / 0-1.0
    renal failure (unspecified) / Delayed / 2.0

    Moderate

    peripheral edema / Delayed / 20.0-20.0
    neutropenia / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0

    Mild

    cough / Delayed / 19.0-19.0
    headache / Early / 15.0-15.0
    dizziness / Early / 10.0-10.0
    infection / Delayed / 1.0-10.0

    DRUG INTERACTIONS

    Atazanavir: (Severe) 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: (Severe) 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.
    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.
    Erlotinib: (Moderate) Erlotinib inhibits UGT1A1 in vitro; belinostat is primarily metabolized by UGT1A1. Use caution if coadministration of belinostat with erlotinib is necessary, as increased belinostat concentrations and toxicities may occur.
    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.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Sorafenib: (Moderate) Sorafenib inhibits UGT1A1 in vitro; belinostat is primarily metabolized by UGT1A1. Use caution if coadministration of belinostat with sorafenib is necessary, as increased belinostat concentrations and toxicities may occur.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    Belinostat can cause fetal harm when administered to a woman during pregnancy. Belinostat is classified as FDA pregnancy risk category D. Reproductive and developmental animal toxicology studies have not been conducted with belinostat; however, it is a genotoxic drug that actively targets dividing cells. Teratogenicity and/or embryo-fetal death may occur. Women of childbearing potential should avoid becoming pregnant during treatment with belinostat. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Belinostat may impair male fertility (infertility). In a 24-week repeat-dose toxicology study in dogs, a delay in testicular maturation was correlated to reduced weight of the testes/epididymides after exposure to belinostat.

    MECHANISM OF ACTION

    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).

    PHARMACOKINETICS

    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.