Purpose: This trial was designed to evaluate strategies to improve the efficacy of a radiolabeled monoclonal antibody (mCC49) against tumor-associated glycoprotein-72 (TAG-72) in patients with non-small cell lung cancer (NSCLC): The aims of this study were to determine: safety and maximum tolerated dose (MTD) of 90Y-mCC49 in combination with interferon α2β (IFN); whether calcium disodium versonate (EDTA) or diethylenetriamine penta-acetic acid (DTPA) could reduce myelosuppression; and safety and MTD of paclitaxel (Taxol®) in combination with 90Y-mCC49. Experimental Design: Patients with advanced (TAG-72 positive) non-small cell lung cancer were entered in three phases; the first was the dose escalation of a single agent 90Y-mCC49. In the second phase, the dose escalation of 90Y-mCC49 was attempted with concurrent EDTA or DTPA chelator therapy. In the third phase, radiosensitization with a continuous infusion of paclitaxel (96-hour) was administered with 90Y-mCC49. All patients received IFN for TAG-72 up-regulation. Results: Thirty-four patients were evaluable. Reversible Grade 4 neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs). The MTD of 90Y-mCC49/IFN was 14 mCi/m2. EDTA did not alter toxicity, while there was a modest reduction of myelosuppression with DTPA. The MTD of continuous infusion paclitaxel in combination with 14 mCi/m2 of 90Y-CC49 was 60 mg/m2. There were no objective tumor responses. Conclusions: 90Y-mCC49/IFN was well tolerated at a dose of 14 mCi/m2. The clinical effect of adjunctive chelating therapy with DTPA was modest. The MTD of coadministered continuous infusion (96-hour) paclitaxel was 60 mg/m 2. Because of the immunogenicity of the murine compound, future studies are planned using a humanized version of CC49. © Mary Ann Liebert, Inc.