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Background: An open-label, multicenter, dose-escalation study in patients with recurrent NHL was initially undertaken to establish the safety, tolerance, PK, and immunogenicity (HAHA) of humanized anti-CD20 antibody, IMMU-106 (hA20), administered once-weekly for 4 weeks at different doses. Additional patients have now been entered to confirm the efficacy of 120 and 375 mg/m2 dosing, and to determine the feasibility of using even lower hA20 doses. Methods: A total of 55 patients (23 male, 32 female; 51 Caucasian; 40–84 years old) received hA20 at 120 (N=21), 200 (N=6), 375 (N=25) or 750 mg/m2 (N=3). They had follicular (FL, N=37) or other (N=18) B-cell lymphomas, were predominantly stage III/IV (N=44) at study entry, and had received 1–7 prior treatments (median, 2), including 1 (N=34) or more (N=14) rituximab regimens (without progression within 6 months). Results: Fifty-two patients completed all 4 infusions, 2 are currently being treated, and one patient with hives and chills after prior rituximab discontinued treatment after similar NCI CTC v.3 grade 1–2 reactions at 1st hA20 infusion. hA20 was generally well tolerated with a median infusion time at the lowest dose of 120 mg/m2 of 2.2 h for 1st infusion and 1.2 h for subsequent infusions. Twenty-one patients had drug-related adverse events; these were all transient, mild-to-moderate (Grade 1–2) events, most occurring only at first infusion. No consistent pattern of abnormal laboratory changes occurred, and there was no evidence of immunogenicity in 29 patients now evaluated for HAHA. Mean antibody serum levels increased with dose and with repeated infusions, and limited post-treatment data indicate the serum clearance at 375 mg/m2 dosing is similar to rituximab. Even at 120 mg/m2, peripheral blood B-cell depletion occurred after the first infusion and persists after 4th infusion, with analysis continuing > 6 mo. Thirty-nine patients with at least 12 wks follow-up had one or more responses evaluated by Cheson criteria (Table), with all CR/CRu occurring in follicular lymphoma except for one patient with marginal zone lymphoma; 6 pts progressed by week 4. Of 18 pts with OR’s, 9 have continuing responses (median follow-up, 9 mos post-treatment), including 4 with long-lived responses (12–18 mos). Conclusions: hA20 is well tolerated, with no evidence of significant toxicity or pattern of adverse events other than minor infusion reactions, even at short infusion times. All dose levels studied so far, including the lowest dose of 120 mg/m2, resulted in B-cell depletion and objective responses (including CR/CRu), with no clear-cut evidence of dose response in efficacy. As such, further dose de-escalation is ongoing. Treatment Response hA20 Dose OR CR/CRu All patients (n = 39) 46% (18/39) 21% (8/39) 120 mg/m2 (n = 11) 36% (4/11) 27% (3/11) 200 mg/m2 (n = 6) 67% (4/6) 33% (2/6) 375 mg/m2 (n =19) 42% (8/19) 11% (2/19) 750 mg/m2 (n = 3) 67% (2/3) 33% (1/3)

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.