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189 PHASE 1 STUDY OF AN ANTI-GD3 MONOCLONAL ANTIBODY (KW-2871) IN PATIENTS WITH ADVANCED METASTATIC MELANOMA.
  1. J. Shah,
  2. A. Forero,
  3. R. Carlisle,
  4. P. Triozzi,
  5. A. LoBuglio,
  6. T. Kuwabara,
  7. A. Teitelbaum,
  8. M. Fujimori,
  9. M. Conry
  1. University of Alabama at Birmingham, Birmingham, AL; Kyowa Pharmaceuticals, Toyko, Japan

Abstract

Background Current 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).

Method Seventeen 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.

Results No 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.

Conclusion An 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.

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