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FDA Approval for Ofatumumab

Brand name: Arzerra®

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.

Approved for previously treated chronic lymphocytic leukemia

On October 27, 2009, the Food and Drug Administration (FDA) approved ofatumumab (Arzerra®, made by GlaxoSmithKline) for patients with chronic lymphocytic leukemia (CLL), a slowly progressing cancer of the blood and bone marrow.

Ofatumumab is approved for patients with CLL whose cancer is no longer being controlled by other forms of chemotherapy.

CLL primarily affects people older than 50 years of age and arises from a group of white blood cells known as B-cells that are part of the body's immune system. Each year in the United States, about 16,000 people are diagnosed with CLL and about 4,400 people die from the disease.

Ofatumumab is a monoclonal antibody, a type of biotechnology product. Antibodies that occur in nature are produced by the immune system in response to invaders. Ofatumumab binds to a specific protein found on the surface of both normal and malignant B cells, making the cells more susceptible to immune system attack.

The product was approved under the FDA's accelerated approval process, which allows earlier approval of drugs that meet unmet medical needs. Products may receive accelerated approval based on a surrogate endpoint, such as a reduction in the size of the tumor or decrease in the number of cancerous white blood cells. These indirect measures for clinical outcomes are considered reasonably likely to predict that the drug will allow patients to live longer or with fewer side effects of a disease.

"The approval of Arzerra illustrates FDA's commitment to using the accelerated approval process to approve drugs for patients who have limited therapeutic options," said Richard Pazdur, M.D., director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research.

The accelerated approval process requires further study of the drug. (See below.)

Ofatumumab's effectiveness was evaluated in 59 patients with CLL whose disease no longer responded to the available therapies.

The product's safety was evaluated in 181 patients in two studies in patients with cancer. Common side effects included a decrease in normal white blood cells, pneumonia, fever, cough, diarrhea, lower red blood cell counts, fatigue, shortness of breath, rash, nausea, bronchitis, and upper respiratory tract infections.

The most serious side effect of Arzerra is an increased chance of infections, including progressive multifocal leukoencephalopathy (PML), a brain infection that is generally fatal. Patients at high risk for hepatitis B should be screened before being treated with ofatumumab. Patients with evidence of inactive hepatitis should be monitored for re-activation of the infection during and after completing treatment.

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Approved in combination with chlorambucil for previously untreated chronic lymphocytic leukemia

On April 17, 2014, the FDA approved ofatumumab (Arzerra® Injection, for intravenous infusion; made by 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 multicenter randomized open-label trial that compared 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 comorbidities. In the overall trial population, the median age was 69 years (35 to 92 years). Seventy-two percent of patients had two or more comorbidities, and 48 percent had a creatinine clearance of less than 70 mL/min. Patients received ofatumumab as an intravenous infusion according to the following schedule: 300 mg administered on day 1 of the first cycle, 1000 mg administered on day 8 of the first cycle, 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 premedication 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). Median PFS was 22.4 months (95 percent CI: 19.0, 25.2 months) for patients who received ofatumumab in combination with chlorambucil, compared with 13.1 months (95 percent CI: 10.6, 13.8 months) for patients who received single-agent chlorambucil [hazard ratio 0.57 (95 percent CI: 0.45, 0.72), stratified log-rank p-value <0.001].

The most common adverse reactions (at least 5 percent) with ofatumumab in combination with chlorambucil were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex viral infection, lower respiratory tract infection, joint pain, and upper abdominal pain. Overall, 67 percent 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.

 

This summary was provided by Richard Pazdur, M.D., director of the FDA's Office of Hematology and Oncology Products, or Patricia Keegan, M.D., director of the FDA's Division of Clinical Trials Design and Analysis.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

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  • Updated: April 23, 2014