A phase I trial of (90)Y-DOTA-anti-CEA chimeric T84.66 (cT84.66) radioimmunotherapy in patients with metastatic CEA-producing malignancies.
OBJECTIVE
Previous radioimmunotherapy (RIT) clinical trials at this institution with (90)Y-labeled cT84.66 anti-CEA (carcinoembryonic antigen) evaluated the antibody conjugated to diethylenetriaminepentaacetic acid (DTPA). The aim of this phase I therapy trial was to evaluate cT84.66 conjugated to the macrocyclic chelate (90)Y-DOTA and labeled with (90)Y in a comparable patient population.


METHODS
Patients with metastatic CEA-producing cancers were entered in this trial. If antibody targeting to tumor was observed after the administration of (111)In-DTPA cT84.66, the patient then received the therapy infusion of (90)Y-DOTA-cT84.66 1 week later. Serial nuclear scans, blood and urine collections, and computed tomography (CT) scans were performed to assess antibody biodistribution, pharmacokinetics, toxicities, and antitumor effects.


RESULTS
Thirteen (13) patients were treated in this study. Dose-limiting hematologic toxicity was experienced at initial starting activity levels of 12 and 8 mCi/m(2). Subsequent patients received systemic Ca-DTPA at 125 mg/m(2) every 12 hours for 3 days post-therapy to allow for a dose escalation to 16 mCi/m(2), where hematologic toxicity was observed with an associated maximum tolerated dose (MTD) of 13.4 mCi/m(2). Tumor doses ranged from 4.4 to 569 cGy/mCi, which translated to 97-12,500 cGy after a single infusion of (90)Y-DOTA-cT84.66. Human anti-chimeric antibody (HACA) response developed in 8 of 13 patients and prevented additional therapy in 4 patients.


CONCLUSIONS
This study demonstrates the feasibility of using (90)Y-DOTA-cT84.66 for antibody-guided radiation therapy. Immunogenicity of the DOTA-conjugated cT84.66 antibody was not appreciably greater than that observed with (90)Y-DTPA-cT84.66 in previous trials. Dose-limiting hematopoietic toxicity with (90)Y-DOTA-cT84.66 decreased with Ca-DTPA infusions post-therapy and appears to be comparable to previously published results for (90)Y-DTPA-cT84.66. The highest antibody uptake and tumor doses were to small nodal lesions, which supports the predictions from preclinical and clinical data that RIT may be best applied in the minimal tumor burden setting.
Wong
Jeffrey Y C
JY
City of Hope National Medical Center and Beckman Research Institute, Duarte, CA 91010, USA. JWong@coh.org
Chu
David Z
DZ
Williams
Lawrence E
LE
Liu
An
A
Zhan
Jiping
J
Yamauchi
Dave M
DM
Wilczynski
Sharon
S
Wu
Anna M
AM
Yazaki
Paul J
PJ
Shively
John E
JE
Leong
Lucille
L
Raubitschek
Andrew A
AA
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000096:biosynthesis / Q000276:immunology*; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D000922:Immunotoxins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D015021:Yttrium Radioisotopes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D006573:Heterocyclic Compounds, 1-Ring; D007074:Immunoglobulin G; D000922:Immunotoxins; D015021:Yttrium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid