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

Research output: Contribution to journalArticle

83 Citations (Scopus)

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

Fingerprint

Adenocarcinoma
Monoclonal Antibodies
Mononuclear Phagocyte System
Bone Marrow
Immunoconjugates
Maximum Tolerated Dose
Half-Life
Pharmacokinetics
Biopsy
Neoplasms
Heterografts
Nude Mice
Radionuclide Imaging
Intravenous Administration
Colon
Antigens
Bone and Bones
Therapeutics
tumor-associated antigen 72

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Mulligan, T., Carrasquillo, J. A., Chung, Y., Milenic, D. E., Schlom, J., Feuerstein, I., ... 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.

Phase I Study of Intravenous 177lu-labeled CC49 Murine Monoclonal Antibody in Patients with Advanced Adenocarcinoma. / Mulligan, Timothy; Carrasquillo, Jorge A.; Chung, Yoomie; Milenic, Diane E.; Schlom, Jeffrey; Feuerstein, Irwin; Paik, Chong; Perentesis, Patricia; Reynolds, James; Curt, Gregory; Goeckeler, William; Fordyce, William; Cheng, Roberta; Riseberg, David; Cowan, Kenneth; O’Shaughnessy, Joyce.

In: Clinical Cancer Research, Vol. 1, No. 12, 01.08.1995, p. 1447-1454.

Research output: Contribution to journalArticle

Mulligan, T, Carrasquillo, JA, Chung, Y, Milenic, DE, 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, vol. 1, no. 12, pp. 1447-1454.
Mulligan T, Carrasquillo JA, Chung Y, Milenic DE, Schlom J, Feuerstein I et al. Phase I Study of Intravenous 177lu-labeled CC49 Murine Monoclonal Antibody in Patients with Advanced Adenocarcinoma. Clinical Cancer Research. 1995 Aug 1;1(12):1447-1454.
Mulligan, Timothy ; Carrasquillo, Jorge A. ; Chung, Yoomie ; Milenic, Diane E. ; Schlom, Jeffrey ; Feuerstein, Irwin ; Paik, Chong ; Perentesis, Patricia ; Reynolds, James ; Curt, Gregory ; Goeckeler, William ; Fordyce, William ; Cheng, Roberta ; Riseberg, David ; Cowan, Kenneth ; O’Shaughnessy, Joyce. / Phase I Study of Intravenous 177lu-labeled CC49 Murine Monoclonal Antibody in Patients with Advanced Adenocarcinoma. In: Clinical Cancer Research. 1995 ; Vol. 1, No. 12. pp. 1447-1454.
@article{992188d12051420181bb9a411a62d446,
title = "Phase I Study of Intravenous 177lu-labeled CC49 Murine Monoclonal Antibody in Patients with Advanced Adenocarcinoma",
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.",
author = "Timothy Mulligan and Carrasquillo, {Jorge A.} and Yoomie Chung and Milenic, {Diane E.} and Jeffrey Schlom and Irwin Feuerstein and Chong Paik and Patricia Perentesis and James Reynolds and Gregory Curt and William Goeckeler and William Fordyce and Roberta Cheng and David Riseberg and Kenneth Cowan and Joyce O’Shaughnessy",
year = "1995",
month = "8",
day = "1",
language = "English (US)",
volume = "1",
pages = "1447--1454",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "12",

}

TY - JOUR

T1 - Phase I Study of Intravenous 177lu-labeled CC49 Murine Monoclonal Antibody in Patients with Advanced Adenocarcinoma

AU - Mulligan, Timothy

AU - Carrasquillo, Jorge A.

AU - Chung, Yoomie

AU - Milenic, Diane E.

AU - Schlom, Jeffrey

AU - Feuerstein, Irwin

AU - Paik, Chong

AU - Perentesis, Patricia

AU - Reynolds, James

AU - Curt, Gregory

AU - Goeckeler, William

AU - Fordyce, William

AU - Cheng, Roberta

AU - Riseberg, David

AU - Cowan, Kenneth

AU - O’Shaughnessy, Joyce

PY - 1995/8/1

Y1 - 1995/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0029564367&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029564367&partnerID=8YFLogxK

M3 - Article

C2 - 9815943

AN - SCOPUS:0029564367

VL - 1

SP - 1447

EP - 1454

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 12

ER -