Credit: Linda Bartlett
The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for ofatumumab (Arzerra), a monoclonal antibody targeting CD20.
The CHMP is recommending that ofatumumab receive conditional approval for use in combination with chlorambucil or bendamustine to treat patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and are not eligible for fludarabine-based therapy.
The European Commission (EC) will take the CHMP’s opinion into account when deciding whether to approve ofatumumab for this indication.
Ofatumumab already has conditional approval in the Europe Union to treat CLL patients who are refractory to fludarabine and alemtuzumab.
Ofatumumab received conditional approval because the drug’s benefits appear to outweigh the risks it poses. The drug will not receive full
approval until the companies developing ofatumumab, GlaxoSmithKline and Genmab, submit results of additional research to the EC.
The CHMP’s recommendation for expanded approval is based on results from 2 trials in patients with CLL who were ineligible for fludarabine-based treatment.
The first is a phase 2 study (OMB115991) in which researchers evaluated the efficacy of ofatumumab in combination with bendamustine. The second is the phase 3 COMPLEMENT 1 study (OMB110911), a randomized trial in which researchers compared ofatumumab and chlorambucil in combination to chlorambucil alone.
Phase 2 study
Results from this single-arm study were presented at the 2013 International Workshop on CLL. Researchers enrolled 97 patients with CLL, 44 of whom were previously untreated and 53 who had relapsed. The median ages were 62.5 and 68 years, respectively.
Treatment began with acetaminophen, an antihistamine, and a glucocorticoid. Patients then received ofatumumab at 300 mg on day 1 and 1000 mg on day 8 of cycle 1. For cycles 2 through 6, they received 1000 mg on day 1 every 28 days.
Patients received bendamustine on days 1 and 2, every 28 days for up to 6 cycles. The initial dose was 90 mg/m2 for the untreated patients and 70 mg/m2 for relapsed patients.
However, patients required a dose reduction due to toxicity. The previously untreated patients were reduced to 60 mg/m2, and the relapsed patients were reduced to 50 mg/m2.
The overall response rate was 95% in the previously untreated group and 74% in the relapsed group. Complete responses occurred in 43% and 11%, respectively.
CT results showed the overall response rate was 82% in the previously untreated group and 70% in the relapsed group. Complete responses occurred in 27% and 9%, respectively. The median time to response was 0.95 months for both groups.
Grade 3 or higher adverse events occurred in 25% of patients in the previously untreated group and 38% of those in the relapsed group.
This included infusion reactions (11% and 8%, respectively), neutropenia (16% and 29%, respectively), infections (11% and 15%, respectively), rash (2% of previously untreated patients), febrile neutropenia (4% of relapsed patients), and thrombocytopenia (4% of relapsed patients).
There were no deaths in the previously untreated group, but 4 patients died in the relapsed group. Two of these deaths may have been related to study treatment. One patient died of pneumonia and hemolytic anemia 15 days after the last dose of treatment, and 1 patient died of sepsis 4 days after the last dose of treatment.
Phase 3 study
Data from the COMPLEMENT 1 study were presented at ASH 2013. Researchers compared ofatumumab plus chlorambucil to chlorambucil alone in 447 previously untreated patients with CLL who were ineligible for fludarabine-based therapy.
Patients had a median age of 69 years (range, 35 to 92). Seventy-two percent had 2 or more comorbidities, and 48% had a creatinine clearance of less than 70 mL/min.
Patients in the ofatumumab arm received the drug at 300 mg in cycle 1 on day 1, 1000 mg in cycle 1 on day 8, and 1000 mg administered on day 1 of all subsequent 28-day cycles.
In both arms, patients received chlorambucil at a dose of 10 mg/m2 orally on days 1 to 7, every 28 days. Prior to each infusion of ofatumumab, patients received acetaminophen, an antihistamine, and a glucocorticoid.
The overall response rate was 82% in the ofatumumab-chlorambucil group and 69% in the chlorambucil-alone group (P=0.001). Complete response rates were 12% and 1%, respectively.
At a median follow-up of 29 months, the median overall survival was not reached for either treatment arm. However, ofatumumab-treated patients had longer progression-free survival than patients who received chlorambucil alone—22.4 months and 13.1 months, respectively (P<0.001).
Grade 3 or higher adverse events occurred in 50% of ofatumumab-treated patients and 43% of patients who received chlorambucil alone. The most common event was neutropenia, which occurred in 26% and 14% of patients, respectively.
Grade 3 or higher infections occurred in 15% of ofatumumab-treated patients and 14% of patients who received chlorambucil alone. The most common was pneumonia, which occurred in 4% and 3%, respectively.
In the entire cohort, grade 3 or higher infusion-related events occurred in 10% of patients, but there were no fatal infusion reactions. Two percent of subjects in both arms died during treatment.
