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Zydelig is being granted traditional approval to treat patients whose chronic lymphocytic leukemia (CLL) has retu"...
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 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, 8, or 12 infusions) of 1,000 mg or 2,000 mg doses in 598 patients with CLL (Studies 1, 2, 3, and 4). The geometric mean (%CV) values for clearance, volume of distribution at steady state (Vss), and half-life for ofatumumab in these patients were 11.6 mL/hour (74%), 5.8 L (53%), and 17.1 days (82%). 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.
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 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.
The primary endpoint was 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 8; 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 8).
Table 8: 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)|
|Median, months (95% CI)||22.4 (19.0, 25.2)||13.1 (10.6, 13.8)|
|Hazard ratiob (95% CI)||0.57 (0.45, 0.72)|
|Stratified log rank P value||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)|
|IRC = Independent Review
Committee; ITT = Intention to treat; CI = Confidence interval.
aIntention-to-treat population includes all 447 randomized patients.
Figure 1: Kaplan-Meier
Estimates of IRC-assessed Progression-free Survival
Extended Treatment In CLL
The efficacy of ARZERRA as extended treatment in CLL was evaluated in a randomized, parallel arm, open-label 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 2: Kaplan-Meier
Estimates of Investigator-assessed Progression-free Survival
Study 3 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 3 and in a multicenter, open-label, dose-escalation study (Study 4) conducted in patients with relapsed or refractory CLL.
Last reviewed on RxList: 1/27/2016
This monograph has been modified to include the generic and brand name in many instances.
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