Belinostat – Uses, Dosage, Side Effects, Interactions

Beleodaq is a histone deacetylase (HDAC) inhibitor that exhibits pan-HDAC inhibition and potent growth inhibitory and pro-apoptotic activities in a variety of tumor cells, including PTCL cells, at nanomolar concentrations. None of the trials show any clinically relevant changes caused by Beleodaq on heart rate, PR duration, or QRS duration as measures of autonomic state, atrioventricular conduction or depolarization; there were no cases of Torsades de Pointes.

Use in Cancer

Belinostat is approved to treat:

• Peripheral T-cell lymphoma in patients whose disease has recurred (come back) or is refractory (does not respond to treatment).

This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, a confirmatory trial(s) must show that belinostat provides a clinical? benefit in these patients.

Belinostat is also being studied in the treatment of other types of cancer.

Contraindications

• 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.

Dosage?

Strengths: 500 mg

Lymphoma

• 1,000 mg/m2 IV over 30 minutes once daily on days 1 to 5 of a 21-day cycle
• Duration of therapy: Repeat the cycle every 21 days until disease progression? or unacceptable toxicity.
• Dose reduction, discontinuation, or interruption of therapy may be needed to manage adverse reactions.

Dose Adjustments

Hematologic toxicities:

• Nadir absolute neutrophil count less than 0.5 x 10(9)/L or platelet count less than 25 x 10(9)/L: Decrease dose by 25% (750 mg/m2)

Non-hematologic toxicities:

• Any Grade 3 or 4 adverse reaction: Decrease dose by 25% (750 mg/m2)
• Recurrence? of Grade 3 or 4 adverse reaction after 2 dose reductions: Discontinue treatment

Patients with Reduced UGT1A1 Activity:

• Reduce the starting dose to 750 mg/m2 in patients known to be homozygous for the UGT1A1*28 allele.

Side Effects

The Most Common

• nausea?
• diarrhea?
• vomiting?
• constipation
• headache
• tiredness
• decreased appetite
• pain at the injection site
• swelling of the hands, feet, or ankles
• rash
• fever, cough, chills, muscle aches, worsening skin problems, flu-like symptoms, or other signs of infection
• painful, frequent, burning or difficult urination
• unusual bleeding or bruising
• dizziness, weakness, excessive tiredness, pale skin, or shortness of breath
• yellowing of the skin or eyes, pain in the right upper stomach area, dark urine, or itching

More Common

• severe ongoing nausea, vomiting, or diarrhea;
• a fever, chills, muscle aches, flu-like symptoms,
• cough with mucus, chest pain, fast heartbeats, rapid breathing or shortness of breath;
• easy bruising, unusual bleeding, purple or red spots under your skin;
• pain or burning when you urinate;
• confusion, severe drowsiness, feeling very ill;
• liver problems–loss of appetite, stomach pain (upper right side), tiredness, itching, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
• low red blood cells (anemia)–pale skin, unusual tiredness, feeling light-headed or short of breath, cold hands and feet; or
• signs of tumor cell breakdown–tiredness, weakness, muscle cramps, nausea, vomiting, diarrhea, fast or slow heart rate, tingling in your hands and feet or around your mouth.

Rare

• chest pain
• confusion
• cough
• decreased urine
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry mouth
• fainting
• fast heartbeat
• fever or chills
• increased thirst
• irregular heartbeat
• loss of appetite
• mood changes
• muscle pain or cramps
• nausea or vomiting
• numbness or tingling in the hands, feet, or lips
• pale skin
• pinpoint red spots on the skin
• rapid, shallow breathing
• sore throat
• sweating
• tenderness
• tightness in the chest
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness
• unusual weight gain or loss

Drug Interaction

Pregnancy and Lactation

Pregnancy

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.

Breast-feeding

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, breastfeeding is not recommended during therapy or for 2 weeks after the last belinostat dose.

References