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Clinical Trials |
Department of Internal Medicine [M. T.], University of California San Francisco, San Francisco, California 94115; Department of Radiation Oncology [P. L., J. B-K.], Pathology and Microbiology [S. A., J. W., D. C.], Preventive and Societal Medicine [J. A.], and Radiology [K. H.], University of Nebraska Medical Center, Omaha, Nebraska 68198; and Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, Maryland 20892 [J. S.]
A Phase I trial of increasing administered activities of
90yttrium (90Y)-labeled monoclonal antibody
(MAb) CC49 was conducted to determine whether extrahematopoietic
toxicity occurred with this radioimmunoconjugate. Twelve patients with
various gastrointestinal tract cancers were administered a tracer dose
of 111In-labeled MAb CC49 for biodistribution and
pharmacokinetic studies. Patients then underwent a single treatment
with increasing administered activities of 90Y-labeled MAb
CC49 (0.3, 0.4, and 0.5 mCi/kg). Biodistribution studies, using
111In-labeled MAb CC49 as a surrogate, were determined
using planar and single photon emission computed tomography imaging.
Pharmacokinetic studies were performed by measuring radioactivity in
blood samples taken at intervals after radioimmunoconjugate infusions.
Tissue biopsies of tumor metastases and related normal tissues (liver
and bone marrow) were obtained for radioactivity measurements.
Radiation dosimetry estimates were calculated using these data.
Toxicity was evaluated using the National Cancer Institute Common
Toxicity Criteria. No dose limiting extrahematopoietic toxicity was
identified in the range of administered activities used in this study.
Radioimmunolocalization based on planar and single photon emission
computed tomography images 111In-labeled MAb CC49 showed
heterogeneous (nonspecific) liver and splenic uptake. Liver metastases
were usually photopenic, and extrahepatic metastases showed faint to
moderate uptake. The 
and ß half-lives of
111In-labeled MAb CC49 and 90Y-labeled MAb CC49
in the blood were similar. Absorbed radiation dose estimates in
metastatic tumor sites ranged from 180 to 3000 cGy. The percentage of
injected dose/kg of tumor ranged from 1.12 to 18.14; however,
tumor:normal liver ratios were consistently <1. No objective responses
were observed. Doses of up to 0.5 mCi/kg could be administered with
reversible grade IV myelotoxicity. Absorbed radiation dose in tumor was
suboptimal, even at the highest administered activity level. Deposition
of 90Y in liver was high, and estimates of absorbed dose in
liver equaled or exceeded that which could be achieved in metastatic
tumor sites. Strategies to enhance access of radioimmunoconjugates in
tumor and diminish deposition in the liver need to be developed for
effective treatment using MAb CC49 with chelated radiometals.
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