trations increasedproportionally with dose over the dose range of 0.01 to 1.0 mg/kg (0.01 to 1 times the approvedrecommended dosage).
Following repeated dosing of the approved recommended dosage, steady state concentrationswere reached after 8 doses (12 weeks), and the systemic accumulation was 1.6-fold.
At steadystate, the peak concentration (Cmax,ss) is 32 (68%) µg/mL, the trough concentration (Cmin,ss) is 11(239%) µg/mL, and AUCss is 5577 (125%) µg•hr/mL.
Distribution
The central volume of distribution is 3.6 L (20%).
Elimination
The terminal half-life is 17 days (66%), and the clearance is 12 mL/h (84%).
Specific Populations:
No clinically significant changes in the PK of mogamulizumab-kpkc were observed based on age(range: 22 to 101 years), sex, ethnicity, renal impairment (creatinine clearance <90 mL/min,estimated by Cockcroft-Gault), mild (total bilirubin ≤ ULN and AST <ULN, or total bilirubin <1to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST)hepatic impairment, disease subtype (MF or SS), degree of CCR4 expression, or ECOG status.
The effect of severe hepatic impairment (total bilirubin >3 times ULN and any AST) onmogamulizumab-kpkc PK is unknown.
Drug Interaction Studies No drug interaction studies have been conducted with POTELIGEO.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
No carcinogenicity or genotoxicity studies have been conducted with POTELIGEO.
No specific studies have been conducted to eva luate potential effects of POTELIGEO onfertility. No mogamulizumab-kpkc -related toxic effects in the male and female reproductiveorgans were observed in sexually mature monkeys in repeat-dose toxicology studies up to 26weeks in duration.
14 CLINICAL STUDIES
Trial 1
A randomized, open-label, multicenter trial (Study 0761-010; NCT01728805) eva luated the
efficacy of POTELIGEO in adult patients with MF or SS after at least one prior systemic therapy. The trial randomized 372 patients 1:1 to either POTELIGEO (186 patients; 56% with MF, 44% with SS) or vorinostat (186 patients; 53% with MF, 47% with SS).
The trial includedpatients regardless of tumor CCR4 expression status and excluded patients with histologictransformation, prior allogeneic HSCT, autologous HSCT within 90 days, active autoimmunedisease, or active infection. The trial required patients to have ANC ≥1500/µL (≥1000/µL ifbone marrow was involved), platelet count ≥100,000/µL (≥75,000/µL if bone marrow wasinvolved), creatinine clearance >50 mL/min or serum creatinine ≤1.5 mg/dL and hepatictransaminases ≤2.5 times ULN (≤5 times ULN if lymphomatous liver infiltration).
The dose of POTELIGEO was 1 mg/kg administered intravenously over at least 60 minutes ondays 1, 8, 15, and 22 of the first 28-day cycle and on days 1 and 15 of each subsequent cycle.
Vorinostat was dosed at 400 mg orally once daily, continuously for 28-day cycles. Treatmentcontinued until disease progression or unacceptable toxicity. Vorinostat-treated patients withdisease progression or unacceptable toxicities were permitted to cross over to POTELIGEO.
The median age was 64 years (range: 25 to 101), 58% of patients were male, and 70% werewhite. At study baseline, 38% had stage IB-II disease, 10% stage III, and 52% stage IV. Themedian number of prior systemic therapies was 3. In the POTELIG |
