cellular-mediated lysis following cell surface binding of Campath to the leukemic cells.
12.3 Pharmacokinetics
Campath pharmacokinetics were characterized in a study of 30 previously treated B-CLL patients in whom Campath was administered at the recommended dose and schedule. Campath pharmacokinetics displayed nonlinear elimination kinetics. After the last 30 mg dose, the mean volume of distribution at steady-state was 0.18 L/kg (range 0.1 to 0.4 L/kg). Systemic clearance decreased with repeated administration due to decreased receptor-mediated clearance (i.e., loss of CD52 receptors in the periphery). After 12 weeks of dosing, patients exhibited a seven-fold increase in mean AUC. Mean half-life was 11 hours (range 2 to 32 hours) after the first 30 mg dose and was 6 days (range 1 to 14 days) after the last 30 mg dose.
Comparisons of AUC in patients ≥ 65 years (n=6) versus patients < 65 years (n=15) suggested that no dose adjustments are necessary for age. Comparisons of AUC in female patients (n=4) versus male patients (n=17) suggested that no dose adjustments are necessary for gender.
The pharmacokinetics of Campath in pediatric patients have not been studied. The effects of renal or hepatic impairment on the pharmacokinetics of Campath have not been studied.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to establish the carcinogenic or mutagenic potential of Campath, or to determine its effects on fertility in males or females.
14 CLINICAL STUDIES
14.1 Previously Untreated B-CLL Patients
Campath was eva luated in an open-label, randomized (1:1) active-controlled study in previously untreated patients with B-CLL, Rai Stage I-IV, with evidence of progressive disease requiring therapy. Patients received either Campath 30 mg IV 3 times/week for a maximum of 12 weeks or chlorambucil 40 mg/m2 PO once every 28 days, for a maximum of 12 cycles.
Of the 297 patients randomized, the median age was 60 years, 72% were male, 99% were Caucasian, 96% had a WHO performance status 0-1, 23% had maximum lymph node diameter ≥ 5cm, 34% were Rai Stage III/IV, and 8% were treated in the U.S.
Patients randomized to receive Campath experienced longer progression free survival (PFS) compared to those randomized to receive chlorambucil (median PFS 14.6 months vs. 11.7 months, respectively). The overall response rates were 83% and 55% (p < 0.0001) and the complete response rates were 24% and 2% (p < 0.0001) for Campath and chlorambucil arms, respectively. The Kaplan-Meier curve for PFS is shown in Figure 1.
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