Ofatumumab vs Physician's Choice in Subjects With Bulky Fludarabine-Refractory Chronic Lymphocytic Leukemia

An Open Label, Multicenter Study Investigating the Safety and Efficacy of Ofatumumab Therapy Versus Physicians' Choice in Patients With Bulky Fludarabine-Refractory Chronic Lymphocytic Leukaemia (CLL)

The purpose of this study was to confirm the clinical benefit observed in the pivotal registration study, Hx-CD20-406. The Committee for Medicinal Products for Human Use (CHMP) required that a randomized study be conducted in CLL patients with bulky fludarabine-refractory disease as a specific obligation for grant of conditional approval for ARZERRA™ in the European Union (EU). This study compared ofatumumab with the physicians' choice of therapy.

Patients with CLL that is refractory to fludarabine have few treatment options and a poor prognosis. There is a continued need for new therapies for these CLL patients, as demonstrated by the limited responses and substantial toxicities with existing therapies. This is supported by the lack of a consensus around standard of care treatment for CLL patients with bulky fludarabine-refractory disease. The objective of this study was to confirm the response rate and disease control in the refractory setting through a controlled trial comparing ofatumumab with the physicians' choice of therapy in fludarabine-refractory, bulky lymphadenopathy patients. After 24 weeks of treatment with ofatumumab, patients were further randomized to either extended ofatumumab treatment or observation. Patients on the physicians' choice arm had the option of receiving ofatumumab if they experience progressive disease.

Inclusion Criteria:

• Adults with documented diagnosis of active CLL requiring treatment
• Bulky lymphadenopathy, defined as at least 1 lymph node >5 cm
• Must be refractory to fludarabine treatment
• Age 18 yrs or older
• At least 2 prior therapies for CLL
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Signed written informed consent

Exclusion Criteria:

• Prior allogeneic stem cell transplant at any time, or autologous stem cell transplant within 6 months
• Treatment with any unapproved drug substance or experimental therapy within 4 weeks, or currently participating in another interventional clinical study
• CLL transformation, prolymphocytic leukemia, or central nervous system (CNS) involvement of CLL
• Active autoimmune hemolytic anemia (AIHA) requiring treatment except if associated with progressive disease requiring anti-CLL treatment
• Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment
• Human immunodeficiency virus (HIV) positive
• Significant concurrent, uncontrolled medical condition
• Other past or current malignancy (with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix or breast) unless the tumor was successfully treated with curative intent at least 2 years prior to trial entry
• Non-protocol corticosteroid usage except a maintenance dose corresponding to less than or equal to 10 mg prednisone
• Abnormal lab values: Creatinine > 2.0 times upper normal limit (unless normal creatinine clearance), or total bilirubin > 2.0 times upper normal limit (unless due to liver involvement of CLL or due to Gilbert's syndrome), or alanine transaminase (ALT) > 2.5 times upper normal limit (unless due to liver involvement of CLL)
• Known or suspected hypersensitivity to ofatumumab
• Lactating or pregnant women or female patients of child-bearing potential (or male patients with such partners) not willing to use adequate contraception