SGN-40, a humanized anti-CD40 monoclonal antibody, is being evaluated in a phase I dose escalation study for patients with relapsed and/or refractory multiple myeloma. This single-arm trial is designed to evaluate safety, pharmacokinetics, immunogenicity, antitumor activity, and the maximum tolerated dose. SGN-40 has demonstrated potent in vitro and in vivo efficacy against cell lines expressing CD40, a member of the tumor necrosis factor receptor family. CD40 is widely expressed on tumors of B-cell origin, including myeloma, non-Hodgkin’s lymphoma, Hodgkin’s disease, and chronic lymphocytic lymphoma. The original protocol called for cohorts of patients to be treated with four weekly infusions of 0.5, 1.0, 2.0, 4.0, 8.0, or 16.0 mg/kg. Sixteen patients were treated at doses ranging from 0.5 – 4.0 mg/kg/wk for four weeks. Enrollment of new patients was temporarily halted after two of three patients developed severe headaches and aseptic meningitis following the first dose at 4 mg/kg. Grade 1 headaches were seen after the first dose in three of six patients receiving 2 mg/kg, but no patients at lower doses reported headaches. We have determined that this drug-related event is a first-dose effect, and was not seen clinically after second or subsequent infusions of SGN-40. SGN-40 appears to trigger cytokine release, and TNF-alpha levels in the plasma are elevated following the first infusion only. Initial pharmacokinetic data in humans demonstrate that the half-life of SGN-40 depends on the dose given: mean values after the first and third infusions were 0.9 and 1.3 days, respectively, at 0.5 mg/kg; 1.7 and 2.6 days at 1.0 mg/kg; and 2.9 and 4.2 days at 2.0 mg/kg. This is consistent with results in non-human primates, in which the half-life was relatively short at low doses. These data suggest that there is a rapid elimination pathway and/or redistribution volume that has not been saturated at the doses used to date. Although human anti-human antibodies (HAHA) have not yet been measured, the preliminary analysis suggests that if antibodies were formed, they did not significantly affect pharmacokinetics. Even at the low doses tested thus far, there is preliminary evidence for antitumor activity; four of sixteen patients had declining serum and/or urine M-protein during treatment. Of note, these four individuals also demonstrated the most profound B-cell depletion during therapy, an expected consequence of SGN-40 activity. This protocol has been amended to include a drug-loading period that should eliminate first-dose cytokine release syndrome. Dose escalation is ongoing under the revised protocol, and no headaches have been seen in the first cohort at a peak dose of 3 mg/kg. In conclusion, SGN-40 demonstrated an apparent first-dose cytokine release reaction that required a modification in the dosing strategy. Pharmacokinetic data suggest that higher doses are required to saturate the elimination pathway, and preliminary antitumor activity is encouraging.