Phase I Study of 90Y-CC49 Monoclonal Antibody Therapy in Patients with Advanced Non-Small Cell Lung Cancer: Effect of Chelating Agents and Paclitaxel Co-Administration

Abstract

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 (90)Y-mCC49 in combination with interferon alpha2beta (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 (90)Y-mCC49. 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 (90)Y-mCC49. In the second phase, the dose escalation of (90)Y-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 (90)Y-mCC49. All patients received IFN for TAG-72 up-regulation. Thirty-four patients were evaluable. Reversible Grade 4 neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs). The MTD of (90)Y-mCC49/IFN was 14 mCi/m(2). 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/m(2) of (90)Y-CC49 was 60 mg/m(2). There were no objective tumor responses. (90)Y-mCC49/IFN was well tolerated at a dose of 14 mCi/m(2). 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.