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Purpose/Objective: Previous radioimmunotherapy (RIT) clinical trials at this institution with ⁹⁰Y-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 ⁹⁰Y-DOTA and labeled with ⁹⁰Y in a comparable patient population. Experimental Design: Patients with metastatic CEA-producing cancers were entered in this trial. If antibody targeting to tumor was observed after the administration of ¹¹¹In-DTPA cT84.66, the patient then received the therapy infusion of ⁹⁰Y-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/m². Subsequent patients received systemic Ca-DTPA at 125 mg/m² every 12 hours for 3 days post-therapy to allow for a dose escalation to 16 mCi/m², where hematologic toxicity was observed with an associated maximum tolerated dose (MTD) of 13.4 mCi/m². Tumor doses ranged from 4.4 to 569 cGy/mCi, which translated to 97–12,500 cGy after a single infusion of ⁹⁰Y-DOTA-cT84.66. Human antichimeric antibody (HACA) response developed in 8 of 13 patients and prevented additional therapy in 4 patients. Conclusions: This study demonstrates the feasibility of using ⁹⁰Y-DOTA-cT84.66 for antibody-guided radiation therapy. Immunogenicity of the DOTA-conjugated cT84.66 antibody was not appreciably greater than that observed with ⁹⁰Y-DTPA-cT84.66 in previous trials. Dose-limiting hematopoietic toxicity with ⁹⁰Y-DOTA-cT84.66 decreased with Ca-DTPA infusions post-therapy and appears to be comparable to previously published results for ⁹⁰Y-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.