Phase I Study of Intravenous 177lu-labeled CC49 Murine Monoclonal Antibody in Patients with Advanced Adenocarcinoma

Timothy Mulligan, Jorge A. Carrasquillo, Yoomie Chung, Diane E. Milenic, Jeffrey Schlom, Irwin Feuerstein, Chong Paik, Patricia Perentesis, James Reynolds, Gregory Curt, William Goeckeler, William Fordyce, Roberta Cheng, David Riseberg, Kenneth Cowan, Joyce O’Shaughnessy

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83 Scopus citations

Abstract

CC49, a murine monoclonal antibody that recognizes the tumor-associated glycoprotein 72, was conjugated to the chemical chelate l,4,7,10-tetraaza-l-(l-carboxy-3-(4-amino- phenyl) propyl)-tris-4,7,10- ((carboxy)methyl)cyclododecane that had been labeled with a $$ emitter, l77Lu. Preclinical studies had shown that 177Lu-labeled CC49 caused regression of human colon adenocarcinoma xenografts in nude mice. Patients with advanced adenocarcinoma who had failed standard treatment and whose tumors expressed the tumor- associated glycoprotein 72 antigen were eligible for treatment to determine the maximum tolerated dose of 177Lu- labeled CC49. The starting dose of l77Lu was 10 mCi/m2 given i.v. with the dose of CC49 held constant at 20 mg. Pharmacokinetic sampling and immunoscintigraphy were performed over the ensuing 3 weeks. The dose of radioactive 177Lu was escalated by 15 mCi/m2 for each successive dose level. Unexpected bone marrow toxicity developed in patients treated at the second dose level with 25 mCi/m2, 177Lu; two patients developed grade 4 thrombocytopenia, while the third patient developed grade 3 thrombocytopenia. Pharmacokinetic studies showed that the plasma half-life of the immunoconjugate was 67 h; whole-body retention, however, was prolonged with a biological half-life of 258 h. Serial gamma camera imaging localized known tumor in all patients, and also demonstrated prolonged, 177Lu retention in the reticuloendothelial system (RES). Bone marrow dosimetry estimates ranged from 4 to 5 REMS/mCi l77Lu based on imaging and biopsy data. Analysis of bone marrow biopsies demonstrated that most of the177 Lu was localized in the cellular compartment and not in the bone. No antitumor responses were observed. Intravenous administration of 15 mCi/m2 l77Lu-labeled CC49 to previously treated advanced cancer patients was associated with acceptable hematological toxicity and was the maximum tolerated dose. However, prolonged retention of 177Lu in the RES, including the bone marrow, was observed and limited the dose ofl77Lu that could be given. Additional studies are indicated to reduce RES uptake and retention of this immunoconjugate.

Original languageEnglish (US)
Pages (from-to)1447-1454
Number of pages8
JournalClinical Cancer Research
Volume1
Issue number12
StatePublished - Aug 1 1995

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Mulligan, T., Carrasquillo, J. A., Chung, Y., Milenic, D. E., Schlom, J., Feuerstein, I., Paik, C., Perentesis, P., Reynolds, J., Curt, G., Goeckeler, W., Fordyce, W., Cheng, R., Riseberg, D., Cowan, K., & O’Shaughnessy, J. (1995). Phase I Study of Intravenous 177lu-labeled CC49 Murine Monoclonal Antibody in Patients with Advanced Adenocarcinoma. Clinical Cancer Research, 1(12), 1447-1454.