FDA Considering Expanded Indication for Ofatumumab in CLL

The FDA has recieved a supplemental new drug application for a combination of ofatumumab (Arzerra), fludarabine, and cyclophosphamide, for patients with relapsed chronic lymphocytic leukemia (CLL).

This application is based on an improvement in progression-free survival (PFS) in the phase III COMPLEMENT-2 study, where the median PFS was 28.9 months with the addition of ofatumumab compared with 18.8 months with chemotherapy alone (HR, 0.67; 95% CI, 0.51-0.88;P= .0032). The overall response rate (ORR) with the triplet was 84% versus 68% in the control arm (P= .0003), with complete response rates of 27% versus 7%.

The FDA will review the application submitted by Novartis within 60 days, at which time the agency will assign a decision deadline under the Prescription Drug User Fee Act. Under a standard review, the agency will make a ruling on the medication within 10 months.

"The data from the COMPLEMENT-2 study demonstrated the potential of ofatumumab in combination with FC to help patients with relapsed CLL," said Jan van de Winkel, PhD, chief executive officer of Genmab, the company developing ofatumumab in collaboration with Novartis. "We are pleased that Novartis has moved forward with a regulatory application for ofatumumab in this indication in the United States."

In the phase III COMPLEMENT-2 study, 365 patients with relapsed CLL were randomized to receive ofatumumab plus fludarabine and cyclophosphamide (n = 183) or fludarabine cyclophosphamide alone (n = 182). Ofatumumab was administered at 300 mg on day 1 of the first cycle followed by 1000 mg on day 8. For subsequent cycles, the drug was administered at 1000 mg on day 1. The maximum number of cycles was six in each arm.

The median age of patients in the trial was 61 years, with 7% over the age of 75. A third of patients had high Rai stage CLL (34%) and 69% were IGHV unmutated. Seventy-five percent of patients had a chromosomal aberration. The primary endpoint of the study was PFS. Secondary outcome measures focused on overall survival (OS), response, and safety.

Duration of response was 29.6 versus 24.9 months in the ofatumumab versus control arms, respectively (HR, 0.77; 95% CI, 0.56-1.05;P= .0878). Time to progression was also improved with the triplet, at 42.1 months versus 26.8 months (HR, 0.63; 95% CI, 0.45-0.87;P= .0036).

The time to next cancer therapy was 48.1 months with ofatumumab versus 40.1 months in the control arm (HR, 0.73; 95% CI, 0.51-1.05;P= .073). Additionally, there was a numerical improvement in median OS with ofatumumab at 56.4 months versus 45.8 months with chemotherapy alone; however, the result was not statistically significant (HR, 0.78; 95% CI, 0.56-1.09;P= .1410).

The adverse event (AE) profile for ofatumumab was similar to what has been reported in other trials with the drug. Adverse events reported in ≥5% of patient in the ofatumumab arm included neutropenia, thrombocytopenia, anemia, nausea, leukopenia, vomiting, pyrexia, rash, fatigue, and pneumonia.

The rate of grade ≥3 AEs with the ofatumumab combination was 74%, compared with 69% in the control arm. Fifty-three percent of patients who received ofatumumab had grade ≥3 neutropenia versus 39% of patients who received chemotherapy alone.

In the ofatumumab cohort, 4% of patients had grade 3/4 infusion-related reactions (IRRs) compared with <1% in the control group. There were no fatalities associated with IRRs.

The FDA initially approved ofatumumab in 2009 for previously treated patients with CLL that is no longer responding to chemotherapy. In April 2014, the FDA approved ofatumumab plus chlorambucil for previously untreated patients with CLL who were considered inappropriate for treatment with fludarabine.


  1. Robak T, Grosicki S, Warzocha K, et al. Ofatumumab in Combination With Fludarabine and Cyclophosphamide (FC) Versus FC in Patients With Relapsed Chronic Lymphocytic Leukemia (CLL): Results of the Phase III Study COMPLEMENT 2. Presented at: 20th Congress of the European Hematology Association (EHA); June 11-14, 2015; Vienna, Austria. Abstract #5782.