BELEODAQ Powder for solution for injection Ref.[9943] Active ingredients: Belinostat

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.

The pharmacokinetic characteristics of belinostat were analyzed from pooled data from phase ½ clinical studies that used doses of belinostat ranging from 150 to 1,200 mg/m². The total mean plasma clearance and elimination half-life were 1240 mL/min and 1.1 hours, respectively. The total clearance approximates average hepatic blood flow (1500 mL/min), suggesting high hepatic extraction (clearance being flow dependent).

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

Metabolism

Belinostat is primarily metabolized by hepatic UGT1A1. Strong UGT1A1 inhibitors are expected to increase exposure to belinostat. Belinostat also undergoes hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 enzymes to form belinostat amide and belinostat acid. The enzymes responsible for the formation of methyl belinostat and 3-(anilinosulfonyl)-benzenecarboxylic acid, (3-ASBA) are not known.

Excretion

Following a single dose of [¹⁴C]-labelled belinostat (100 μCi, 1500 mg) administered as a 30-minute intravenous infusion in patients with recurrent or progressive malignancy (N=6), 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%.

Drug Interaction Studies

In vitro studies showed belinostat and its metabolites (including belinostat glucuronide, belinostat amide, methyl belinostat) inhibited metabolic activities of CYP2C8 and CYP2C9. Other metabolites (3-ASBA and belinostat acid) inhibited CYP2C8.

In cancer patients, co-administration of Beleodaq (1,000 mg/m²) and warfarin (5 mg), a known CYP2C9 substrate, did not increase the AUC or C_max of either R- or S-warfarin.

Belinostat is likely a glycoprotein (P-gp) substrate but is unlikely to inhibit P-gp.

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.

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.

Relapsed or Refractory Peripheral T-cell Lymphoma (PTCL)

In an open-label, single-arm, non-randomized international trial conducted at 62 centers, 129 patients with relapsed or refractory PTCL were treated with Beleodaq 1,000 mg/m ² administered over 30 minutes via IV infusion once daily on Days 1-5 of a 21-day cycle. There were 120 patients who had histologically confirmed PTCL by central review evaluable for efficacy. Patients were treated with repeat cycles every three weeks until disease progression or unacceptable toxicity.

Efficacy was evaluated using response rate (complete response and partial response) as assessed by an independent review committee (IRC) using the International Workshop Criteria (IWC) (Cheson 2007). Response assessments were evaluated every 6 weeks for the first 12 months and then every 12 weeks until 2 years from the start of study treatment. Duration of response was measured from the first day of documented response to disease progression or death. Response and progression of disease were evaluated by the IRC using the IWC.

Table 3 summarizes the baseline demographic and disease characteristics of the study population, who were evaluable for efficacy.

Table 3. Baseline Patient Characteristics (PTCL Population):

In all evaluable patients (N=120) treated with Beleodaq, the overall response rate per central review using IWC was 25.8% (n=31) (Table 4) with rates of 23.4% for PTCL, NOS and 45.5% for AITL, the two largest subtypes enrolled.

Table 4. Response Analysis per Central Assessment Using IWC in Patients with Relapsed or Refractory PTCL:

CI=confidence interval, CR=complete response, PR=partial response

The median duration of response based on the first date of response to disease progression or death was 8.4 months (95% CI: 4.5–29.4). Of the responders, the median time to response was 5.6 weeks (range 4.3-50.4 weeks). Nine patients (7.5%) were able to proceed to a stem cell transplant after treatment with Beleodaq.