Significant Correlation between Survival Endpoints and Exposure to Ofatumumab (HuMax-CD20) in Chronic Lymphocytic Leukemia.

Background: The fully human monoclonal IgG₁ antibody HuMax-CD20 targets a novel epitope of the CD20 molecule on B-cells. HuMax-CD20 stops growth of engrafted B-cell tumors in SCID mice more efficiently than Rituximab and i.v. infusion of HuMax-CD20 in cynomolgus monkeys leads to profound, long lasting, dose-dependent B-cell depletion.

Aim: The objective of the present trial was to establish the safety, efficacy and the pharmacokinetics of HuMax-CD20 in patients with chronic lymphocytic leukemia.

Methods: Data are presented from an open label, dose-escalation, multicenter phase I/II clinical trial. 3 cohorts of 3 (A), 3 (B) and an extended cohort of 27 (C) patients with relapsed or refractory chronic lymphocytic leukemia (B-CLL) received 4 weekly i.v. infusions of HuMax-CD20 and were followed for 12 months. The first infusion was 100 mg, 300 mg and 500 mg in cohort A, B and C and the following 3 infusions were of 500, 1000 and 2000 mg, respectively. The endpoints were B-cell depletion, adverse events, objective response according to the NCI working group guidelines for CLL, time to progression, duration of response, time to next anti-CLL treatment, and pharmacokinetics. Data are presented from group C.

Results: Median age was 63 years (range, 27–82); median time since diagnosis was 6.1 years (range, 1–14). Maximum tolerated dose was not reached and none of the patients developed human anti human antibodies. 13 of 27 patients (48%) reported infections and infestations most frequently CTC grade 1 or 2 events of nasopharyngitis, gastroenteritis, sinusitis and upper respiratory tract infection without causal relation to ofatumumab. All patients had pronounced reduction of the leukemic CD19⁺CD5⁺ cell counts. Objective response rate was 46% (12 of 26 evaluable patients) with 1 nPR and 11 PR. Median time to progression (TTP) was 133 days (95 % CI 105–158) in the full analysis population and 161 days (95 % CI 140–220) in the subgroup of responders. The duration of response was 112 days (95 %CI 100–133). Time to next anti-CLL therapy was 366 days (95 % CI 258-N.A.). AUC (median 344697 μg/mL*h; range 62709–1362933) correlated significantly to both TTP and time to next anti-CLL therapy to which parameters the clearance (Cl) of ofatumumab (median 10 mL/h; range 3–42) correlated inversely.

Conclusion: This analysis of data from the first study of ofatumumab in CLL patients provides an indication of clinical benefit associated with high exposure and low clearance.