Phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers

Abstract

Purpose: This phase I study explored the biodistribution and pharmacokinetics of the immunoconjugate CMD-193 [a humanized anti-Lewis Y (Le(y)) antibody conjugated with calicheamicin in patients with advanced cancers expressing the Le(y) antigen.

Experimental design: The primary objectives were to determine biodistribution and pharmacokinetics of CMD-193. Secondary objectives included response rates and change in tumor metabolism. Patients with progressive, measurable, and Le(y) positive malignancies were eligible for enrollment in one of two dose cohorts, 1.0 and 2.6 mg/m(2). The first cycle was trace labeled with (111)In for biodistribution assessment using gamma camera imaging. Subsequent cycles were administered every 3 weeks up to a maximum of six cycles, depending on toxicity and response. Pharmacokinetic analysis was based on radioassay and ELISA.

Results: Nine patients were enrolled in the study. Biodistribution images showed initial blood pool activity, followed by markedly increased hepatic uptake by day 2, and fast blood clearance in all patients. There was low uptake in tumor in all patients. The overall T(1/2)beta of (111)In-CMD-193 was 102.88 +/- 35.67 hours, with no statistically significant difference between the two dose levels. One patient had a partial metabolic response on (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG PET) after four cycles, but no radiological responses were observed. Myelosuppression and effects on liver function were the most significant adverse effects.

Conclusions: CMD-193 shows rapid blood clearance and increased hepatic uptake compared with prior studies of the parental antibody hu3S193. These results highlight the importance of biodistribution and pharmacodynamic assessment in early phase studies of new biologics to assist in clinical development.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

D.S. Sonnichsen, employment, Wyeth Research. Funding for this study was provided by Wyeth Research.

Figures

Fig. 1.

Representative biodistribution pattern of 111In-CMD-193. Anterior whole body γ camera images in patient 106 (1.0 mg/m2 dose cohort) following infusion are shown for day 1 (A), day 3 (B), and day 8 (C). Following infusion of 111In-CMD-193, there was initial blood pooling, followed by markedly increased hepatic uptake by day 2 that persisted to day 8. No tumor uptake was apparent in the whole body γ camera images (arrow) or SPECT (D). E, corresponding CT scan shows the large hepatic metastasis, also evident in F, coregistered SPECT/CT scan.

Fig. 2.

PMR to CMD-193: assessment by 18F-FDG-PET. According to RECIST criteria, patient 103 had stable disease following four cycles of CMD-193 at a dose of 1.0 mg/m2, with a large liver lesion (arrow) remaining similar in size on CT. The patient did however show a PMR in this lesion, with a 41.7% reduction in SUVmax observed on 18F-FDG-PET. Prestudy and post–CMD-193 cycle 4 imaging is shown: A and D, CT image; B and E, 18F-FDG-PET; C and F, fused PET/CT images.

Fig. 3.

111In-CMD-193 biodistribution pattern compared with the biodistribution of the parental anti-Ley antibody 111In-hu3S193 observed in the prior phase I study13. Patient 103 had participated in both clinical studies, allowing direct comparison of biodistribution, clearance, and hepatic uptake between CMD-193 and hu3S193 in the same patient. A, 1 d; B, 7 d postinfusion of 111In-CMD-193 (arrow, tumor in liver); C, day 0; D, 2 d; and E, 7 d postinfusion of 111In-hu3S193. Note that in the original hu3S193 trial, a small tumor in the liver was visualized on SPECT imaging.