Mechanism Of Action
Ofatumumab binds specifically to both the small and large extracellular loops of the CD20 molecule. The CD20
molecule is expressed on normal B lymphocytes (pre–B- to mature B-lymphocyte) and on B-cell CLL. The
CD20 molecule is not shed from the cell surface and is not internalized following antibody binding.
The Fab domain of ofatumumab binds to the CD20 molecule and the Fc domain mediates immune effector
functions to result in B-cell lysis in vitro. Data suggest that possible mechanisms of cell lysis include
complement-dependent cytotoxicity and antibody-dependent, cell-mediated cytotoxicity.
In patients with previously untreated CLL, at 6 months after the last dose, the median
reductions in CD19-positive B cells were >99% (n = 155) for ARZERRA in combination with chlorambucil
and 94% (n = 121) for chlorambucil alone.
In patients with relapsed CLL, the proportion of responders in the ofatumumab in combination with fludarabine
and cyclophosphamide (O+FC) arm who showed complete or near complete B cell depletion was 39% (n = 59)
and 82% (n = 126) , respectively. The proportion of responders in the fludarabine and cyclophosphamide (FC)
arm with complete or near complete B cell depletion was 4% (n = 5) and 23% (n = 28), respectively.
In patients treated with extended treatment for CLL after response to therapy for their recurrent or progressive
disease, the median decreases in B-cell counts were 61% (n = 168) after the first infusion and 80% (n = 114)
prior to the sixth infusion; in the observation arm, the median changes in B-cell counts at the same time points
were increases of 32% (n = 148) and 1,328% (n = 95).
In patients with CLL refractory to fludarabine and alemtuzumab, the median decrease in circulating
CD19-positive B cells was 91% (n = 50) with the 8th infusion and 85% (n = 32) with the 12th infusion. The time
to recovery of lymphocytes, including CD19-positive B cells, to normal levels has not been determined.
Although the depletion of B-cells in the peripheral blood is a measurable pharmacodynamic effect, it is not
directly correlated with the depletion of B cells in solid organs or in malignant deposits. B-cell depletion has not
been shown to be directly correlated to clinical response.
The effect of multiple doses of ARZERRA on the QTc interval was evaluated in a
pooled analysis of 3 open-label studies in patients with CLL (N = 85). Patients received ARZERRA 300 mg on
Day 1 followed by either 1,000 mg or 2,000 mg for subsequent doses. No large changes in the mean QTc
interval (i.e., >20 milliseconds) were detected in the pooled analysis.
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.
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.
Coadministration of ARZERRA did not result in clinically relevant effects on the
pharmacokinetics of fludarabine, cyclophosphamide, chlorambucil, or its active metabolite, phenylacetic acid
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)
|Primary and Key Secondary Endpoints
||ARZERRA plus Chlorambucil
(N = 221)
(N = 226)
Progression-free survival (PFS)||
Hazard ratiob (95% CI)||
0.57 (0.45, 0.72)|
Stratified log rank P value||
Overall response, %||
P = 0.001
Complete response, %||
Duration of response||
|IRC = Independent Review Committee; ITT = Intention to treat; CI = Confidence interval.
a Intention-to-treat population includes all 447 randomized patients.
b Pike Estimator.
Figure 1. Kaplan-Meier Estimates of IRC-assessed Progression-free Survival
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)
|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
Hazard ratiob (95% CI)
Stratified log rank P value
28.9 (22.8, 35.9)||
18.8 (14.4, 25.8)|
0.67 (0.51, 0.88)
P = 0.0032
Overall response, % (95% CI)|
Complete response with incomplete bone marrow recovery
84 (77, 89)||
68 (60, 74)|
P = 0.0003
|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.
Figure 2. Kaplan-Meier Estimates of IRC-assessed Progression-free Survival
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.
Extended Treatment In CLL
The efficacy of ARZERRA as extended treatment in CLL was evaluated in a randomized, parallel arm, openlabel
trial. In this trial, 474 patients who were in complete or partial response after at least two lines of prior
therapy, were randomized to receive ARZERRA as intravenous infusions (300 mg on Day 1 followed 1 week
later by 1,000 mg on Day 8 followed 7 weeks later by 1,000 mg and every 8 weeks thereafter for up to a
maximum of 2 years) or observation.
In the overall trial population, the median age was 65 years (range: 33 to 87 years), 68% were male, and 96%
were white. Most patients were in partial remission (81%), had two prior treatments (70%), and had received
chemoimmunotherapy (80%) as prior therapy. The main efficacy outcome was progression-free survival (PFS)
as assessed by the investigator.
At the time of the efficacy analysis, the median follow-up was 19.4 months with the ARZERRA arm and
18.7 months with the observation arm. The event rate (progressed or died) was 33% in the ARZERRA arm and
51% in the observation arm. The investigator-assessed median PFS was 29.4 months in the ARZERRA arm and
15.2 months in the observation arm (hazard ratio: 0.50 with 95% confidence interval [0.38, 0.66]; P <0.0001).
Figure 3. Kaplan-Meier Estimates of Investigator-assessed Progression-free Survival
Study 4 was a single-arm, multicenter trial in 154 patients with relapsed or refractory CLL. ARZERRA was
administered by intravenous infusion according to the following schedule: 300 mg (Week 0), 2,000 mg weekly
for 7 infusions (Weeks 1 through 7), and 2,000 mg every 4 weeks for 4 infusions (Weeks 12 through 24).
Patients with CLL refractory to fludarabine and alemtuzumab (n = 59) comprised the efficacy population. Drug
refractoriness was defined as failure to achieve at least a partial response to, or disease progression within
6 months of, the last dose of fludarabine or alemtuzumab. The main efficacy outcome was durable objective
tumor response rate. Objective tumor responses were determined using the 1996 NCI-WG Guidelines for CLL.
In patients with CLL refractory to fludarabine and alemtuzumab, the median age was 64 years (range: 41 to
86 years), 75% were male, and 95% were white. The median number of prior therapies was 5; 93% received
prior alkylating agents, 59% received prior rituximab, and all received prior fludarabine and alemtuzumab.
Eighty-eight percent of patients received at least 8 infusions of ARZERRA and 54% received 12 infusions.
The investigator-determined overall response rate in patients with CLL refractory to fludarabine and
alemtuzumab was 42% (99% CI: 26, 60) with a median duration of response of 6.5 months (95% CI: 5.8, 8.3).
There were no complete responses. Anti-tumor activity was also observed in additional patients in Study 4 and
in a multicenter, open-label, dose-escalation study (Study 5) conducted in patients with relapsed or refractory