Phase I study of intravenous Lu-labeled CC49 murine monoclonal antibody in patients with advanced adenocarcinoma.
CC49, a murine monoclonal antibody that recognizes the tumor-associated glycoprotein 72, was conjugated to the chemical chelate 1,4,7,10-tetraaza-1-(1-carboxy-3-(4-aminophenyl) propyl)-tris-4,7,10- ((carboxy)methyl)cyclododecane that had been labeled with a beta emitter, Lu. Preclinical studies had shown that Lu-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 Lu-labeled CC49. The starting dose of Lu 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 Lu 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 Lu; 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 Lu retention in the reticuloendothelial system (RES). Bone marrow dosimetry estimates ranged from 4 to 5 REMS/mCi Lu based on imaging and biopsy data. Analysis of bone marrow biopsies demonstrated that most of the Lu was localized in the cellular compartment and not in the bone. No antitumor responses were observed. Intravenous administration of 15 mCi/m2 Lu-labeled CC49 to previously treated advanced cancer patients was associated with acceptable hematological toxicity and was the maximum tolerated dose. However, prolonged retention of Lu in the RES, including the bone marrow, was observed and limited the dose of Lu that could be given. Additional studies are indicated to reduce RES uptake and retention of this immunoconjugate.
Mulligan
T
T
Medicine Branch, Laboratory of Tumor Immunology & Biology, Division of Cancer Biology & Diagnosis, National Cancer Institute, Clinical Center, NIH, Bethesda, Maryland 20982, USA.
Carrasquillo
J A
JA
Chung
Y
Y
Milenic
D E
DE
Schlom
J
J
Feuerstein
I
I
Paik
C
C
Perentesis
P
P
Reynolds
J
J
Curt
G
G
D000230:Adenocarcinoma / Q000473:pathology / Q000532:radiotherapy*; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D000912:Antibodies, Neoplasm / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000473:pathology / Q000532:radiotherapy; D003110:Colonic Neoplasms / Q000473:pathology / Q000532:radiotherapy; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000532:radiotherapy; D008187:Lutetium / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000379:methods; D011868:Radioisotopes / Q000008:administration & dosage* / Q000009:adverse effects; D011879:Radiotherapy Dosage
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; C091202:B72.3 antibody; D011868:Radioisotopes; D008187:Lutetium