2.1 Recommended Dosage

The recommended dosage of Beleodaq is 1,000 mg/m2 administered over 30 minutes by intravenous infusion once daily on Days 1 through 5 of a 21-day cycle. Cycles can be repeated every 21 days until disease progression or unacceptable toxicity.

2.2 Dosage Modification for Hematologic and Non-Hematologic Toxicities

Table 1  displays the recommended Beleodaq dosage modifications for hematologic and non-hematologic toxicities. Base dosage adjustments for thrombocytopenia and neutropenia on platelet and absolute neutrophil nadir (lowest value) counts in the preceding cycle of  therapy.

•

Absolute neutrophil count (ANC) should be greater than or equal to 1 x 109/L and the platelet count should be greater than or equal to 50 x 109/L prior to the start of each cycle and prior to resuming treatment following toxicity. Resume subsequent treatment with Beleodaq according to the guidelines described in Table 1 below. Discontinue Beleodaq in patients who have recurrent ANC nadirs less than 0.5 x 109/L and/or recurrent platelet count nadirs less than 25 x 109/L after two dosage reductions.

•

Other toxicities must be NCI-CTCAE Grade 2 or less prior to re-treatment.

Monitor complete blood counts at baseline and weekly. Perform serum chemistry tests, including renal and hepatic functions prior to the start of the first dose of each cycle.

ªFor nausea, vomiting, and diarrhea, dose modification may not be necessary if the duration is less than 7 days with supportive management

2.3 Recommended Dosage in Patients with Hepatic Impairment

Beleodaq dosage in patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 x ULN, any aspartate aminotransferase (AST)) is 500 mg/m2 administered over 30 minutes by intravenous infusion once daily on Days 1 through 5 of a 21-day cycle. Avoid use of Beleodaq in patients with severe hepatic impairment (total bilirubin > 3 x ULN, any AST). No dosage adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ 1.5 x ULN, any AST). Hepatic impairment is defined per the National Cancer Institute Organ Dysfunction Working Group.

2.4 Recommended Dosage in Patients with Renal Impairment

Beleodaq dosage in patients with moderate renal impairment (creatinine clearance [CLcr] 30 to <60 mL/min) is 500 mg/m2 administered over 30 minutes by intravenous infusion once daily on Days 1 through 5 of a 21-day cycle. Avoid use of Beleodaq in patients with severe renal impairment (CLcr < 30 mL/min). No dosage adjustment is recommended for patients with mild renal impairment (CLcr 60 to < 90 mL/min).

2.5 Dosage Modification for Patients with Reduced UGT1A1 Activity

Reduce the starting dose of Beleodaq to 750 mg/m2 in patients known to be homozygous for the UGT1A1*28 allele [see Clinical Pharmacology (12.5)].

2.6 Dosage Modification for Concomitant Use with UGT1A1 Inhibitors

Avoid concomitant use of Beleodaq with UGT1A1 inhibitors. If concomitant use of a UGT1A1 inhibitor is unavoidable, reduce the Beleodaq dosage by 25% as shown in Table 2.

2.7 Preparation and Administration

Beleodaq is a hazardous drug. Follow applicable special handling and disposal procedures.1

Preparation:

• Aseptically reconstitute each vial of Beleodaq by adding 9 mL of Sterile Water for Injection into the Beleodaq vial with a suitable syringe to achieve a concentration of 50 mg of belinostat per mL. Swirl the contents of the vial until there are no visible particles in the resulting solution. If not used immediately, the reconstituted product may be stored for up to 12 hours at room temperature (15°C to 25°C; 59°F to 77°F).
  
  
• Aseptically withdraw the volume needed for the required dosage (based on the 50 mg/mL concentration and the patient’s BSA [m2]) and transfer to an infusion bag containing 250 mL of 0.9 % Sodium Chloride Injection. If not used immediately, the infusion bag with drug solution may be stored at room temperature (15°C to 25°C; 59°F to 77°F) for up to 36 hours including infusion time.
  
  
• Visually inspect the solution for particulate matter. Do not use if cloudiness or particulates are observed.

Administration:

• Connect the infusion bag containing drug solution to an infusion set with a 0.22 micron in-line filter for administration.
  
  
• Infuse intravenously over 30 minutes. If infusion site pain or other symptoms potentially attributable to the infusion occur, the infusion time may be extended to 45 minutes.

5.1 Hematologic Toxicity

Beleodaq can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia; monitor blood counts weekly during treatment, and modify dosage as necessary [see Dosage and Administration (2.2) and Adverse Reactions(6.1)].

5.2 Infections

Serious and sometimes fatal infections, including pneumonia and sepsis, have occurred with Beleodaq. Do not administer Beleodaq to patients with an active infection. Patients with a history of extensive or intensive chemotherapy may be at higher risk of life threatening infections [see Adverse Reactions (6.1)].

5.3 Hepatotoxicity

Beleodaq can cause fatal hepatotoxicity and liver function test abnormalities [see Adverse Reactions (6.1)]. Monitor liver function tests before treatment and before the start of each cycle. Interrupt or adjust dosage until recovery, or permanently discontinue Beleodaq based on the severity of the hepatic toxicity[see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

5.4 Tumor Lysis Syndrome

Tumor lysis syndrome has occurred in Beleodaq-treated patients in the clinical trial of patients with relapsed or refractory PTCL [see Clinical Studies (14)]. Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions [see Adverse Reactions (6.1)].

5.5 Gastrointestinal Toxicity

Nausea, vomiting and diarrhea occur with Beleodaq [see Adverse Reactions (6.1)] and may require the use of antiemetic and antidiarrheal medications.

5.6 Embryo-fetal Toxicity

Based on its mechanism of action and findings of genotoxicity, Beleodaq can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. Advise pregnant women of the risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with Beleodaq and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3). Advise males with female partners of reproductive potential to use effective contraception during treatment with Beleodaq and for 3 months after the last dose.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Beleodaq may not reflect the rates observed in practice.

Adverse Reactions in Patients with Peripheral T-Cell Lymphoma

The safety of Beleodaq was evaluated in 129 patients with relapsed or refractory PTCL in the single arm clinical trial in which patients were administered Beleodaq at a dosage of 1,000 mg/m2 administered over 30 minutes by IV infusion once daily on Days 1 through 5 of a 21-day cycle [see Clinical Studies (14)]. The median duration of treatment was 2 cycles (range 1 – 33 cycles).

The most common adverse reactions observed in the trial of patients with relapsed or refractory PTCL treated with Beleodaq were nausea, fatigue, pyrexia, anemia, and vomiting [see Clinical Studies (14)]. Table 3 summarizes the adverse reactions regardless of causality from the trial in patients with relapsed or refractory PTCL.

Note: Adverse reactions are listed by order of incidence in the “All Grades” category first, then by incidence in “the Grade 3 or 4” category; Measured by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0

Serious Adverse Reactions

Sixty-one patients (47.3%) experienced serious adverse reactions while taking Beleodaq or within 30 days after their last dose of Beleodaq. The most common serious adverse reactions (> 2%) were pneumonia, pyrexia, infection, anemia, increased creatinine, thrombocytopenia, and multi-organ failure. One treatment-related death associated with hepatic failure was reported in the trial.

One patient with baseline hyperuricemia and bulky disease experienced Grade 4 tumor lysis syndrome during the first cycle of treatment and died due to multi-organ failure. A treatment-related death from ventricular fibrillation was reported in another monotherapy clinical trial with Beleodaq. ECG analysis did not identify QTc prolongation.

Discontinuations due to Adverse Reactions

Twenty-five patients (19.4%) discontinued treatment with Beleodaq due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment included anemia, febrile neutropenia, fatigue, and multi-organ failure.

Dosage Modifications due to Adverse Reactions

In the trial, dosage adjustments due to adverse reactions occurred in 12% of Beleodaq-treated patients.

7.1 UGT1A1 Inhibitors

Avoid concomitant administration of Beleodaq with UGT1A1inhibitors. If concomitant use of a UGT1A1 inhibitor is unavoidable, modify the Beleodaq dose [see Dosage and Administration (2.6)].

Belinostat is primarily metabolized by UGT1A1. Concomitant use with a UGT1A1 inhibitor increases belinostat exposure [see Clinical Pharmacology (12.3)], which may increase the risk of Beleodaq adverse reactions.

8.1 Pregnancy

Risk Summary

Based on its mechanism of action, Beleodaq can cause teratogenicity and/or embryo-fetal lethality because it is genotoxic and targets actively dividing cells [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)].  There are no available data on Beleodaq use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. No animal reproduction studies were conducted with Beleodaq. Advise pregnant women of the potential risk to a fetus. 

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk Summary

There are no data on the presence of belinostat in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with Beleodaq, and for 2 weeks after the last dose 

8.3 Females and Males of Reproductive Potential

Beleodaq can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing
Pregnancy testing is recommended for females of reproductive potential prior to initiating Beleodaq.

Contraception

Females
Advise females of reproductive potential to use effective contraception during treatment with Beleodaq and for 6 months after the last dose.
 
Males
Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with Beleodaq and for 3 months after the last dose [see Nonclinical Toxicology (13.1)]. 

Infertility

Males
Based on findings from animal studies, Beleodaq may impair male fertility. The reversibility of the effect on fertility is unknown [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of Beleodaq in pediatric patients have not been established.

8.5 Geriatric Use

In the single-arm trial, 48% of patients (N = 62) were ≥ 65 years of age and 10% of patients (N=13) were ≥ 75 years of age [see Clinical Studies (14)]. The median age of the trial population was 63 years. Patients ≥ 65 years of age had a higher response rate to Beleodaq treatment than patients < 65 years of age (36% versus 16%) while no meaningful differences in response rate were observed between patients ≥ 75 years of age and those < 75 years of age. No clinically meaningful differences in serious adverse reactions were observed in patients based on age (< 65 years compared with ≥ 65 years or < 75 years of age compared with ≥ 75 years of age).

8.6 Use in Patients with Hepatic Impairment

No dosage adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ 1.5 x ULN, any AST). Reduce the Beleodaq dosage in patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 x ULN, any AST) [see Dosage and Administration (2.3)]. Avoid use of Beleodaq in patients with severe hepatic impairment (total bilirubin > 3 x ULN, any AST) [see Clinical Pharmacology (12.3)].

Belinostat is metabolized in the liver, moderate hepatic impairment (total bilirubin > 1.5 to 3 x ULN, any AST) and severe hepatic impairment (total bilirubin > 3 x ULN, any AST) increases belinostat exposure [see Clinical Pharmacology (12.3)], which may increase the risk of Beleodaq adverse reactions.

8.7 Use in Patients with Renal Impairment

No dosage adjustment is recommended for patients with mild renal impairment (CLcr 60 to < 90 mL/min). Reduce the Beleodaq dosage in patients with moderate renal impairment (CLcr 30 to <60 mL/min) [see Dosage and Administration (2.4)]. Avoid use of Beleodaq in patients with severe renal impairment (CLcr < 30 mL/min).

Moderate renal impairment (CLcr 30 to <60 mL/min) increases belinostat exposure [see Clinical Pharmacology (12.3)], which may increase the risk of Beleodaq adverse reactions. The effect of severe renal impairment (CLcr < 30 mL/min) on belinostat pharmacokinetics is unknown [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Beleodaq is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. In vitro, belinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Belinostat shows preferential cytotoxicity towards tumor cells compared to normal cells. Belinostat inhibited the enzymatic activity of histone deacetylases at nanomolar concentrations (<250 nM).

12.2 Pharmacodynamics

Belinostat exposure-response relationships and the time course of pharmacodynamic response are not fully characterized.

Cardiac Electrophysiology

Multiple clinical trials have been conducted with Beleodaq, in many of which ECG data were collected and analyzed by a central laboratory. Analysis of clinical ECG and belinostat plasma concentration data demonstrated no meaningful effect of Beleodaq on cardiac repolarization. None of the trials showed any clinically relevant changes caused by Beleodaq on heart rate, PR duration or QRS duration as measures of autonomic state, atrio-ventricular conduction or depolarization; there were no cases of Torsades de Pointes.

12.3 Pharmacokinetics

The pharmacokinetic characteristics of belinostat were analyzed from pooled data from phase 1/2 clinical studies that used doses of belinostat ranging from 150 to 1200 mg/m2 (0.15 to 1.2 times the approved recommended dosage).

Distribution
The mean belinostat volume of distribution approaches total body water, indicating that belinostat has limited body tissue distribution. In vitro plasma studies have shown that between 92.9% and 95.8% of belinostat is bound to protein in an equilibrium dialysis assay, and was independent of belinostat plasma concentrations from 500 to 25,000 ng/mL.

Elimination
Belinostat elimination half-life is 1.1 hours with a total mean plasma clearance of 1240 mL/min. The total clearance approximates average hepatic blood flow (1500 mL/min), suggesting high hepatic extraction (clearance being flow dependent).

Metabolism
Belinostat is primarily metabolized by hepatic UGT1A1. Belinostat also undergoes hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 enzymes.

Excretion
Following a single dose of radiolabeled belinostat (100 μCi, 1500 mg) administered as a 30-minute intravenous infusion in patients with recurrent or progressive malignancy, fecal excretion accounted for a mean (± SD) of 9.7% (± 6.5%) of the administered radioactive belinostat dose over 168 hours. The mean (± SD) of the administered radioactive belinostat dose that was excreted in urine over 168 hours was 84.8% (± 9.8%), of which unchanged belinostat accounted for only 1.7%.

Specific Populations
Hepatic Impairment
Belinostat steady state clearance decreased and AUC increased as a function of the degree of liver dysfunction, but were unchanged for Cmax, half‐life and apparent volume of distribution. Mean belinostat clearance was reduced by 18% in mild (total bilirubin ≤ ULN and AST >ULN, or total bilirubin ˃1 to 1.5 x ULN), 24% in moderate (total bilirubin ˃ 1.5 to 3 times ULN and any value for AST) and 33% in severe hepatic impairment (total bilirubin ˃ 3 to 10 times ULN and any value for AST). Increases in belinostat exposure were correlated with worsening liver function, but there was no obvious relationship between exposure and DLTs during the first cycle of therapy.

Renal Impairment
Belinostat Cmax increased by 1.7-fold, AUC0-∞ by 1.3-fold and CLtot was unchanged in patients with mild renal impairment (CLcr 60 to <90 ml/min). Belinostat Cmax and AUC0-∞ increased by 1.7-fold and CLtot decreased by 26% in patients with moderate renal impairment (CLcr 30 < 60 ml/min). The effect of severe renal impairment (CLcr < 30 mL/min) on belinostat pharmacokinetics is unknown.

Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
UGT1A1 inhibitors: Belinostat t1/2 increased by 1.5-fold, AUC0-inf increased by 1.4-fold, Cmax decreased by 33%, and renal excretion increased by 2.5-fold following concomitant administration with atazanavir (UGT1A1 inhibitor), but there was minimal change in steady state clearance. There was minimal change in belinostat glucuronide Cmax, AUC0-24; however, belinostat glucuronide excretion decreased by 48%. 

Warfarin: No clinically significant differences in the pharmacokinetics of R- or S-warfarin were observed when used concomitantly with belinostat.

In Vitro Studies 
CYP450 Enzymes: Belinostat and its metabolites are CYP2C8 and CYP2C9 inhibitors.

Transporter Systems: Belinostat is a glycoprotein (P-gp) substrate but is not a P-gp inhibitor.

12.5 Pharmacogenomics

UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism. Approximately 20% of the Black population, 10% of the White population, and 2% of the Asian population are homozygous for the UGT1A1*28 allele. Additional reduced function alleles may be more prevalent in specific populations.

Because belinostat is primarily (80 -90%) metabolized by UGT1A1, the clearance of belinostat could be decreased in patients with reduced UGT1A1 activity (e.g., patients with UGT1A1*28 allele). Reduce the starting dose of Beleodaq to 750 mg/m2 in patients known to be homozygous for the UGT1A1*28 allele to minimize dose limiting toxicities. [see Dosage and Administration (2.5)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with belinostat.

Belinostat was genotoxic in a bacterial reverse mutation test (AMES assay), an in vitro mouse lymphoma cell mutagenesis assay, and an in vivo rat micronucleus assay.

Beleodaq may impair male fertility. Fertility studies using belinostat were not conducted. However, belinostat effects on male reproductive organs observed during the 24-week repeat-dose dog toxicology study included reduced organ weights of the testes/epididymides that correlated with a delay in testicular maturation.