Beleodaq

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/m²administered over 30 minutes via IV infusion once daily on Days 1 through 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 4summarizes the baseline demographic and disease characteristics of the study population, who were evaluable for efficacy.

Table 4 Baseline Patient Characteristics (PTCL Population)

Characteristics	Evaluable Patients (N=120)
Age (years) Median (range)	64 (29-81)
Sex, % Male Female	52 48
Race, % White Black Asian Latin Other	88 6 3 3 2
PTCL Subtype Based on Central Diagnosis, % PTCL Unspecified (NOS) Angioimmunoblastic T-cell lymphoma (AITL) ALK-1 negative anaplastic large cell lymphoma (ALCL) Other	64 18 11 7
Baseline Platelet Count, % ≥100,000/μL <100,000/μL	83 17
ECOG Performance Status, % 0 1 2 3	34 43 22 1
Median Time (months) from Initial PTCL Diagnosis (Range)	12 (2.6 - 266.4)
Median Number of Prior Systemic Therapies (Range)	2 (1-8)

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

CR+PRCRPR

Table 5: Response Analysis per Central Assessment Using IWC in Patients with Relapsed or Refractory PTCL

	Evaluable Patients (N=120)
Response Rate	N (%)	(95% CI)
31 (25.8)	18.3-34.6
13 (10.8)	5.9-17.8
18 (15.0)	9.1-22.7

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.

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).

The mean belinostat volume of distribution approaches total body water, indicating that belinostat has limited body tissue distribution.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.

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).

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

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%.

Belinostat steady state clearance decreased and AUC increased as a function of the degree of liver dysfunction, but were unchanged for C_max, 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.

Belinostat C_maxincreased by 1.7-fold, AUC_0-∞by 1.3-fold and CL_totwas unchanged in patients with mild renal impairment (CLcr 60 to <90 ml/min). Belinostat C_maxand AUC_0-∞increased by 1.7-fold and CL_totdecreased 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.

Clinical Studies and Model-Informed Approaches

: Belinostat t_1/2increased by 1.5-fold, AUC_0-infincreased by 1.4-fold, C_maxdecreased 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 C_max, AUC_0-24; however, belinostat glucuronide excretion decreased by 48%.

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

: Belinostat and its metabolites are CYP2C8 and CYP2C9 inhibitors.

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

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).

The mean belinostat volume of distribution approaches total body water, indicating that belinostat has limited body tissue distribution.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.

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).

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

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%.

Belinostat steady state clearance decreased and AUC increased as a function of the degree of liver dysfunction, but were unchanged for C_max, 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.

Belinostat C_maxincreased by 1.7-fold, AUC_0-∞by 1.3-fold and CL_totwas unchanged in patients with mild renal impairment (CLcr 60 to <90 ml/min). Belinostat C_maxand AUC_0-∞increased by 1.7-fold and CL_totdecreased 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.

Clinical Studies and Model-Informed Approaches

: Belinostat t_1/2increased by 1.5-fold, AUC_0-infincreased by 1.4-fold, C_maxdecreased 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 C_max, AUC_0-24; however, belinostat glucuronide excretion decreased by 48%.

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

: Belinostat and its metabolites are CYP2C8 and CYP2C9 inhibitors.

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