On April 17, 2014, the U. S. Food and Drug Administration approved ofatumumab (Arzerra Injection, for intravenous infusion; GlaxoSmithKline) in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL), for whom fludarabine-based therapy is considered inappropriate.
The approval was based on the results of a multi-center, randomized, open-label trial comparing ofatumumab in combination with chlorambucil to single agent chlorambucil. The trial enrolled 447 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). Seventy-two percent of patients had two or more co-morbidities and 48% of patients had a creatinine clearance of <70 mL/min. Patients received ofatumumab as an intravenous infusion according to the following schedule: 300 mg administered on cycle 1 day 1, 1000 mg administered on cycle 1 day 8 and 1000 mg administered on day 1 of all subsequent 28 day cycles. In both arms, chlorambucil was given at a dose of 10 mg/m2 orally on days 1 to 7 every 28 days. Prior to each infusion of ofatumumab, patients received pre-medication with acetaminophen, an antihistamine, and a glucocorticoid.
The primary endpoint of the trial was progression free survival (PFS) as assessed by a blinded Independent Review Committee (IRC) using the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) update of the National Cancer Institute Working Group (NCI-WG) guidelines. Median PFS was 22.4 months (95% CI: 19.0, 25.2 months) for patients receiving Arzerra in combination with chlorambucil compared to 13.1 months (95% CI: 10.6, 13.8 months) for patients receiving single-agent chlorambucil [hazard ratio 0.57 (95% CI: 0.45, 0.72), stratified log-rank p-value <0.001].
The most common adverse reactions (greater than or equal to 5%) with ofatumumab in combination with chlorambucil (greater than or equal to 2% more than in the control arm) were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia and upper abdominal pain. Overall, 67% of patients who received ofatumumab experienced one or more symptoms of infusion reaction. Ten percent of patients experienced a grade 3 or greater infusion reaction.
The results of this randomized trial were adequate to fulfill the postmarketing requirement for GlaxoSmithKline to verify the clinical benefit of ofatumumab and, therefore, the approval of ofatumumab was converted from accelerated approval to regular approval.
The recommended dose and schedule for the approved regimen for ofatumumab in previously untreated CLL is:
- 300 mg on Day 1 followed 1 week later by 1,000 mg on Day 8 (Cycle 1) followed by
- 1,000 mg on Day 1 of subsequent 28 day cycles for a minimum of 3 cycles until best response or a maximum of 12 cycles.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm
, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).