Initial Safety and Efficacy Results of a Second-Generation Humanized Anti-CD20 Antibody, IMMU-106 (hA20), in Non-Hodgkin's Lymphoma.

Abstract

Background. Infusion reactions, prolonged infusion times and immunogenicity of the chimeric anti-CD20 antibody, rituximab, may in part be related to its murine component. The humanized anti-CD20 antibody, IMMU-106 (hA20), may offer potential advantages because only the CDRs are of murine origin and the remaining >90% human framework regions are identical to humanized anti-CD22 IgG1 antibody epratuzumab, whose safety and short infusion times have been reported.Methods. An open-label, multicenter, phase I/II, dose escalation study conducted in patients with recurrent B cell lymphoma to establish the safety, tolerance, pharmacokinetics, and immunogenicity of hA20 administered once weekly for 4 doses.Results. Twenty patients (11 M/9 F, 40–81 y.o) with grade 1–2 follicular (n=16) or other CD20+ B-cell lymphomas (mantle cell, small lymphocytic, marginal zone x 2) were enrolled in the dose escalation portion of this study, receiving 120 mg/m2 (n=7), 200 mg/m2 (n=6), 375 mg/m2 (n=4) or 750 mg/m2 (n=3) weekly x 4. These patients had previously received 1-7 prior therapies (median, 2.5), including treatments with one (n=12) or 2–4 (n=6) rituximab-containing regimens (without progression within 6 months). Five patients (25%) had grade 1–2 infusion reactions predominantly with first hA20 infusion. Median infusion times for 375 mg/m2 of hA20 were 3.3 hours for first infusion, 2.0 hours for subsequent infusions, and were generally shorter at lower doses. Standard laboratory values obtained at each infusion were generally observed to be within normal limits, and human anti-human antibody (HAHA) serum evaluations are negative to date. Peripheral blood B-cell depletion occurred after first infusion and persisted for samples obtained up to 12 weeks following fourth infusion with analysis ongoing. Pharmacokinetic results after first and fourth infusions demonstrate a mean antibody serum half-life of 5.3 ± 5.3 and 12.0 ± 8.7 days, respectively. To date, of 15 pts with at least one post-treatment assessments now completed, there are at least 8 objective responses (53%) by Cheson criteria, including 6 patients (40%) with complete responses [CR, CRu] at a median follow-up of 12 weeks. Complete responses have been observed at all dose levels, including 3/7 patients receiving 120 mg/m2/wk.Conclusion. This study demonstrates the safety, tolerability, and preliminary efficacy of this humanized anti-CD20 antibody administered weekly for 4 doses, mostly to patients with follicular lymphomas who relapsed after rituximab-containing regimens. The demonstration of CRs, tolerability, and relatively short infusion times is encouraging. This study is continuing and expanding to assess the durability of responses and the optimal dose for subsequent studies.