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BackgroundCurrent therapeutic options for metastatic melanoma are limited. KW-2871 is an IgG1 kappa chimeric monoclonal antibody targeting ganglioside antigen GD3, expressed on neuroectodermal tumors including melanoma, glioma, and neuroblastoma. GD3 expression is known to be up-regulated with malignant transformation of melanoma and tumor progression. KW-2871 has mediated antibody-dependent cellular cytotoxicity (ADCC).MethodSeventeen patients with stage IV melanoma not amenable to surgical intervention with ECOG performance status of 0, 1, or 2 were enrolled in the study to evaluate the safety, tolerance, and pharmokinetics of KW-2871. All patients received a test dose of 10 mg/m2 IV. Patients were stratified into 4 cohorts receiving 4 doses at 2-week intervals of 20, 40, 80, and 120 mg/m2. No premedications were administered prior to infusion of KW-2871.ResultsNo dose-limiting toxicities (DLT: grade $ 2 allergic reaction and/or grade $ 3 toxicity) were observed in the 20 and 40 mg/m2 cohorts. The first two patients in the 80 mg/m2 had DLTs (grade 3 urticaria, grade 3 seizures, grade 3 edema of the larynx, and grade 3 chest tightness). No patients were enrolled in the 120 mg/m2 cohort. A fifth cohort with 6 patients was then opened at a dose of 60 mg/m2 and this dose level exceeded the MTD (grade 3 urticaria, grade 3 laryngeal edema, and grade 3 chest tightness). KW-2871 had no myelosuppression. The plasma KW-2871 disappearance curves fit a two-compartment model best. The mean T1/2 beta at 40 mg/m2 dose level was 13 6 6 days (range 8-21 days). The mean AUC at 40 mg/m2 was 3,965 μg*hr/mL. Two patients in the 40 mg/m2 cohort had stable disease for 8 and 3 months. Antibody development against KW-2871 was not detected in the study.ConclusionAn MTD of 40 mg/m2 without premedication was established in this initial dose escalation study. A second phase 1 dose escalation study with the use of premedication including diphenhydramine, corticosteroids, and H2 blockers is active currently and will help identify a higher MTD to maximize potential efficacy.