HuMax CD20 Fully Human Monoclonal Antibody in Chronic Lymphocytic Leuchemia. Early Results from an Ongoing Phase I/II Clinical Trial.

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. 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 will be followed for 12 months. The first infusion administered was 100 mg, 300 mg and 500 mg in cohort A, B and C. The following 3 infusions were of 500, 1000 and 2000 mg, respectively. Patients were premedicated with oral acetaminophen and i.v antihistamine and received i.v. glucocorticoids before first and second infusions. The endpoints are 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. Biopsies and CT images are evaluated centrally. Median age was 61 years; median time since diagnosis was 6.3 years. Maximum tolerated dose was not reached. Adverse events were predominantly observed on days of infusion and as expected most frequently symptoms of cytokine release e.g. rash, increased sweating, fatigue, rigors, pyrexia, and headache. 5 serious adverse events assessed as related to HuMax-CD20 treatment have been reported: hepatic cytolysis, herpes zoster, neutropenia (2 patients) and one death from pneumonia at week 4. In cohorts A and B, markedly reduced CD19⁺CD5⁺ cell counts were observed in 3 of 6 patients one week after final treatment and the depletion was sustained in one of these patients. In cohort C a pronounced CD19⁺CD5⁺ reduction was demonstrated by all patients; in fact the lymphocyte counts were ≤4.0 x 10⁹/L in 21 patients. At week 11, ≥50% reduction in the product of diameters of lymph nodes was observed in 12 of 20 evaluable patients with enlarged lymph nodes. A response rate of 52% (11 of 21 evaluable patients in cohort C) was observed at week 11: 4 clinical CR (bone marrow and CT pending), 7 PR, 3 SD and 7 PD. In conclusion, this preliminary analysis of data from the first 33 CLL patients treated with HuMax-CD20 demonstrated significant depletion of CD19⁺CD5⁺ cells, a favorable safety profile and an indication of clinical efficacy. An updated report for all patients at week 19 will be presented.