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Phase I clinical trial using escalating single-dose infusion of chimeric
anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell
lymphoma
DG Maloney, TM Liles, DK Czerwinski, C Waldichuk, J Rosenberg, A Grillo-Lopez and R Levy
Department of Medicine, Stanford University Medical Center, CA.
The B-cell antigen CD20 is expressed on normal B cells and by nearly all
B-cell lymphomas. This nonmodulating antigen provides an excellent target
for antibody-directed therapies. A chimeric anti-CD20 antibody (IDEC-C2B8),
consisting of human IgG1-kappa constant regions and variable regions from
the murine monoclonal anti-CD20 antibody IDEC- 2B8, has been produced for
clinical trials. It lyses CD20+ cells in vitro via complement and
antibody-dependent cell-mediated lysis. Preclinical studies have shown that
the chimeric antibody selectively depletes B cells in blood and lymph nodes
in macaque monkeys. In this phase I clinical trial, 15 patients (3 per dose
level) with relapsed low-grade B-cell lymphoma were treated with a single
dose (10, 50, 100, 250, or 500 mg/m2) of antibody administered
intravenously. Treatment- related symptoms correlated with the number of
circulating CD20 cells and grade II events consisted of fever (5 patients);
nausea (2), rigor (2), orthostatic hypotension (2), bronchospasm (1), and
thrombocytopenia (1). No significant toxicities were observed during the 3
months of follow-up. Serum C3, IgG, and IgM levels, neutrophils, and T
cells were largely unchanged. At the three higher dose levels,
pharmacokinetics of the free antibody showed a serum half-life of 4.4 days
(range, 1.6 to 10.5). Levels greater than 10 micrograms/mL persisted in 6
of 9 patients for more than 14 days. No quantifiable immune responses to
the infused antibody have been detected. CD20+ B cells were rapidly and
specifically depleted in the peripheral blood at 24 to 72 hours and
remained depleted for at least 2 to 3 months in most patients. Two-week
postinfusion tumor biopsies showed the chimeric antibody bound to tumor
cells and a decrease in the percentage of B cells. Tumor regressions
occurred in 6 of 15 patients (2 partial and 4 minor responses). The results
of this single-dose trial have been used to design a multiple-dose phase
I/II study.
Volume 84,
Issue 8,
pp. 2457-2466,
10/15/1994
Copyright © 1994 by The American Society of Hematology
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