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

Herbertson, Rebecca A., Tebbutt, Niall C., Lee, Fook-Thean, MacFarlane, David J., Chappell, Bridget, Micallef, Noel, Lee, Sze-Ting, Saunder, Timothy, Hopkins, Wendie, Smyth, Fiona E., Wyld, David K., Bellen, John, Sonnichsen, Daryl S., Brechbiel, Martin W., Murone, Carmel and Scott, Andrew M. (2009) Phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers. Clinical Cancer Research, 15 21: 6709-6715. doi:10.1158/1078-0432.CCR-09-0536


Author Herbertson, Rebecca A.
Tebbutt, Niall C.
Lee, Fook-Thean
MacFarlane, David J.
Chappell, Bridget
Micallef, Noel
Lee, Sze-Ting
Saunder, Timothy
Hopkins, Wendie
Smyth, Fiona E.
Wyld, David K.
Bellen, John
Sonnichsen, Daryl S.
Brechbiel, Martin W.
Murone, Carmel
Scott, Andrew M.
Title Phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers
Journal name Clinical Cancer Research   Check publisher's open access policy
ISSN 1078-0432
1557-3265
Publication date 2009-11-01
Sub-type Article (original research)
DOI 10.1158/1078-0432.CCR-09-0536
Volume 15
Issue 21
Start page 6709
End page 6715
Total pages 7
Place of publication Philadelphia, PA, United States
Publisher American Association for Cancer Research
Language eng
Formatted abstract
Purpose:
This phase I study explored the biodistribution and pharmacokinetics of the immunoconjugate CMD-193 [a humanized anti–Lewis Y (Ley) antibody conjugated with calicheamicin in patients with advanced cancers expressing the Ley antigen. 

Experimental Design:
The primary objectiveswere to determine biodistribution and pharmacokinetics of CMD-193. Secondary objectives included response rates and change in tumor metabolism. Patients with progressive, measurable, and Ley positive malignancies were eligible for enrollment in one of two dose cohorts, 1.0 and 2.6 g/m2. The first cycle was trace labeled with 111In for biodistribution assessment using γ camera imaging. Subsequent cycleswere administered every 3weeks up to a maximumof 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 T½β of 111In-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  in 18F-fluorodeoxyglucose-positron emission tomography (18F-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. 
Keyword Acute Myeloid Leukemia
Blood Group Antigens
Gemtuzumab Ozogamicin
Ovarian Cancer
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: ERA 2012 Admin Only
School of Medicine Publications
 
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