Phase I Biodistribution Study Of Le(Y) Targeting Immunoconjugate In Advanced Epithelial Cancers

3025 Background: The Lewis Y (Ley) carbohydrate antigen is expressed in >70% of epithelial cancers including breast, gastrointestinal and lung cancers. This study explored the biodistribution and pharmacokinetics (PK) of the immunoconjugate CMD-193 (a humanized anti-Ley antibody conjugated with calicheamicin) in advanced Ley expressing cancers. Methods: The primary objectives were to determine biodistribution and PK of CMD-193. Secondary objectives included response rates, toxicity and immunogenicity. Cycle one was trace labeled with 111In for biodistribution assessment, and subsequent cycles were administered every 3 weeks, to a maximum of 6 cycles, depending on toxicity and response. Tumor targeting was assessed using gamma camera and single photon emission computerized tomography (SPECT) imaging, and PK analysis was based on gamma counting (111In-CMD-193) and ELISA (CMD-193 protein). There were 2 dose cohorts (1.0mg/m2 and 2.6mg/m2), and patients with Ley positive, measurable, advanced and treatment refractory malignancies, were eligible. Results: Nine patients (6 in dose cohort 1, 3 in cohort 2) were enrolled (and received 1–6 cycles of treatment) before the study was terminated. Biodistribution imaging demonstrated initial blood pooling, followed by markedly increased hepatic uptake by day 2 (persisting to day 8), and fast blood clearance. This pattern was seen for all patients and dose levels. There was no significant uptake in tumor visualized in any patient. The overall T 1/2 β of 111In-CMD- 193 was 102.88 ± 35.67 hours, with no statistically significant difference between the 2 dose levels. There was no evidence of free 111In chelate or 111In-CMD-193 complex formation in blood. One patient had a partial metabolic response on 18F-FDG PET after 4 cycles. No radiologic responses were observed. Myelosuppression and effects on liver function were the most significant toxicities, but no severe or unexpected toxicities were observed. Conclusions: CMD-193 demonstrates rapid blood clearance and increased hepatic uptake compared to prior studies of the original non-conjugated antibody. The results of this trial highlight the importance of biodistribution and pharmacodynamic assessment in early phase studies of new biologics to assist in clinical development. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Wyeth