title: High-dose therapy with 90Yttrium-labeled monoclonal antibody CC49: a phase I trial.
abstract: 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 alpha and beta 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.
authors.affiliation: Department of Internal Medicine, University of California San Francisco, 94115, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tempero
authors.forename: P
authors.initials: P
authors.lastname: Leichner
authors.forename: J
authors.initials: J
authors.lastname: Baranowska-Kortylewicz
authors.forename: K
authors.initials: K
authors.lastname: Harrison
authors.forename: S
authors.initials: S
authors.lastname: Augustine
authors.forename: J
authors.initials: J
authors.lastname: Schlom
authors.forename: J
authors.initials: J
authors.lastname: Anderson
authors.forename: J
authors.initials: J
authors.lastname: Wisecarver
authors.forename: D
authors.initials: D
authors.lastname: Colcher
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000532:radiotherapy; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000096:biosynthesis; D001706:Biopsy; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000532:radiotherapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D000922:Immunotoxins / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007205:Indium Radioisotopes; D008297:Male; D008875:Middle Aged; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D015021:Yttrium Radioisotopes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D007074:Immunoglobulin G; D000922:Immunotoxins; D007205:Indium Radioisotopes; D015021:Yttrium Radioisotopes