ARZERRA (Page 5 of 6)

12.3 Pharmacokinetics

Ofatumumab is eliminated through both a target-independent route and a B cell-mediated route. Ofatumumab exhibited dose-dependent clearance in the dose range of 100 to 2,000 mg. Due to the depletion of B cells, the clearance of ofatumumab decreased substantially after subsequent infusions compared with the first infusion.

Pharmacokinetic data were obtained after repeated administration (4, 5, 6, 8, or 12 infusions) of 1,000 mg or 2,000 mg doses in 774 patients with CLL (Studies 1, 2, 3, 4 and 5). The geometric mean (% CV) values for clearance, volume of distribution at steady state (Vss), and half-life for ofatumumab in these patients were 9.3 mL/hour (91%), 6.1 L (52%), and 17.6 days (83%). The pharmacokinetic profile was similar across doses in patients with CLL.

Specific Populations: The following population characteristics do not have a clinically meaningful effect on the pharmacokinetics of ofatumumab: body size, gender, age, and renal impairment (evaluated in patients with a calculated creatinine clearance ≥30 mL/min).

No formal studies of ARZERRA in patients with hepatic impairment have been conducted. The effect of a calculated CrCL < 30 mL/min on the pharmacokinetics of ARZERRA has not been evaluated.

Drug Interactions: Coadministration of ARZERRA did not result in clinically relevant effects on the pharmacokinetics of fludarabine, cyclophosphamide, chlorambucil, or its active metabolite, phenylacetic acid mustard.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the maximum human dose (2,000 mg) of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies.

14 CLINICAL STUDIES

14.1 Previously Untreated CLL

The efficacy of ARZERRA was evaluated in a randomized, open-label, parallel-arm study; 447 patients previously untreated for CLL were randomized to receive either ARZERRA as monthly intravenous infusions (Cycle 1: 300 mg on Day 1 and 1,000 mg on Day 8; subsequent cycles: 1,000 mg on Day 1 every 28 days) in combination with chlorambucil (10 mg/m2 orally on Days 1 to 7 every 28 days) or chlorambucil alone (10 mg/m2 orally on Days 1 to 7 every 28 days). Patients received treatment for a minimum of 3 cycles. Treatment was continued for 3 cycles beyond maximal response (2 consecutive response assessments of stable disease, partial response, or complete response) for up to 12 cycles. Approximately 60% of patients received 3 to 6 cycles of ARZERRA and 30% received 7 to 12 cycles.

This trial enrolled patients for whom fludarabine-based therapy was considered to be inappropriate by the investigator for reasons that included advanced age or presence of co-morbidities. In the overall trial population, the median age was 69 years (range: 35 to 92 years) and 69% of patients in both arms were at least 65 years of age. In the overall trial population, 72% of patients had 2 or more co-morbidities and 48% of patients had a creatinine clearance of less than 70 mL/min. Sixty-three percent (63%) of patients were male and 89% were white. Elevated beta-2 microglobulin (β2m) >3,500 mcg/L was present in 72% of patients at baseline.

Efficacy was evaluated by progression-free-survival (PFS) as assessed by a blinded Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008). ARZERRA plus chlorambucil resulted in statistically significant improvement in IRC-assessed median PFS compared with chlorambucil alone (22.4 months versus 13.1 months; hazard ratio: 0.57 [0.45, 0.72]) (Table 9; Figure 1).

Secondary efficacy endpoints, including overall response (OR), complete response (CR), and duration of response, were also assessed by the IRC using the 2008 IWCLL Guidelines (Table 9).

Table 9. IRC-assessed Efficacy Results in Previously Untreated CLL (ITT Populationa)

IRC = Independent Review Committee; ITT = Intention to treat; CI = Confidence interval.

a Intention-to-treat population includes all 447 randomized patients.

b Pike Estimator.

Primary and Key Secondary Endpoints

ARZERRA plus Chlorambucil

(N = 221)

Chlorambucil

(N = 226)

Progression-free survival (PFS)

Median, months
(95% CI)

22.4

(19.0, 25.2)

13.1

(10.6, 13.8)

Hazard ratiob (95% CI)

Stratified log rank P value

0.57 (0.45, 0.72)

P <0.001

Overall response, %
(95% CI)

82.4

(76.7, 87.1)

68.6

(62.1, 74.6)

P
value

P = 0.001

Complete response, %

12

1

Duration of response
Median, months
(95% CI)

22.1

(19.1, 24.6)

13.2

(10.8, 16.4)

Figure 1. Kaplan-Meier Estimates of IRC-assessed Progression-free Survival

Figure 1
(click image for full-size original)

14.2 Relapsed CLL

Study 2 (randomized, open-label, parallel-arm, multicenter trial) evaluated the efficacy of ARZERRA in combination with fludarabine and cyclophosphamide compared with fludarabine and cyclophosphamide in 365 patients with relapsed CLL. Baseline disease characteristics and prognostic markers were balanced between treatment arms. Patient median age was 61 years (range: 32 to 90 years), 60% were male and 55% and 28% of patients were Binet stage B and C, respectively. Eighty one percent (81%) of patients received 1-2 prior treatments and 21% of patients had received prior rituximab.

Patients received ARZERRA as intravenous infusions (Cycle 1: 300 mg on Day 1 and 1,000 mg on Day 8; followed by 1,000 mg on Day 1 of subsequent cycles). Approximately 90% of patients received 3-6 cycles of ARZERRA and 66% completed all 6 cycles.

Efficacy was evaluated by progression-free survival (PFS), as assessed by an independent review committee (IRC). PFS was prolonged in the ARZERRA plus fludarabine and cyclophosphamide (O+FC) arm compared to the fludarabine and cyclophosphamide (FC) arm (Table 10) resulting in a 10 months improvement in median PFS (mPFS) (see Figure 2).

Table 10. IRC-assessed Efficacy Results in relapsed CLL (ITT Population)

a Confidence intervals were obtained using the Brookmeyer-Crowley method.

b Hazard ratios were obtained using the Pike estimator. A hazard ratio<1 indicates a lower risk with O+FC compared with FC. The hazard ratio and p-value from the stratified log-rank test are adjusted for Binet stage and number of prior therapies.

c Cochran-Mantel-Haenzel test, adjusting for stratification factors: Binet stage and number of prior therapies.

Primary and Key Secondary Endpoints

ARZERRA plus Fludarabine and Cyclophosphamide

(N = 183)

Fludarabine and Cyclophosphamide

(N = 182)

Progression-free survival (PFS)

Median, months (95% CI)a

28.9 (22.8, 35.9)

18.8 (14.4, 25.8)

Hazard ratiob (95% CI)

Stratified log rank P value

0.67 (0.51, 0.88)

P = 0.0032

Overall response, % (95% CI)

84 (77, 89)

68 (60, 74)

P
valuec

P = 0.0003

Complete response

27%

7%

Complete response with incomplete bone marrow recovery

2%

1%

Figure 2. Kaplan-Meier Estimates of IRC-assessed Progression-free Survival

Figure 2
(click image for full-size original)

With a median follow-up of approximately 34 months, overall survival results showed a HR of 0.78 [95% CI: 0.56-1.09]. The median overall survival was 56.4 months [95% CI: 44.2, NC] in the O+FC arm and was 45.8 months [95% CI: 37.3, NC] in the FC arm.

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