Phase I Study of Yttrium-90 Radiolabeled M5A Anti-Carcinoembryonic Antigen Humanized Antibody in Patients with Advanced Carcinoembryonic Antigen Producing Malignancies.

Background: M5A is a humanized monoclonal antibody (mAb) directed against carcinoembryonic antigen (CEA) The purpose of this first in human phase I dose-escalation trial was to characterize the toxicities and determine the maximum tolerated dose (MTD) of yttrium-90 (90Y)-DOTA-M5A as a single agent and in combination with gemcitabine (gem). Methods: Patients with advanced metastatic CEA-producing malignancies who had progressed on standard therapies were first administered indium-111 (111In)-DOTA-M5A. If tumor targeting was observed, the patient then received the therapy dose of 90Y-DOTA-M5A. Serial scans, blood sampling, and 24 h urine collections were then performed to estimate radiation doses to organs and total body. Assays for human antihuman antibody (HAHA) responses were performed out to 6 months. Results: Of the 18 patients who received 111In-DOTA-M5A, 16 received 90Y-DOTA-M5A therapy; 1 patient at 14 mCi/m2 with gem (150 mg/m2 days 1and 3), 3 patients at 12 mCi/m2 with gem, 6 patients at 12 mCi/m2 without gem, and 6 at 10 mCi/m2 without gem. Prolonged cytopenias resulted in discontinuation of dose escalation with gemcitabine. A single agent MTD of 10 mCi/m2 was established based on dose-limiting hematopoietic toxicities. HAHA immune response was identified in 2 of 16 patients (12.5%). Stable disease at 3 months was seen in 10 patients and 2 patients demonstrated an 88% and 64% decrease in CEA back to normal levels. In 2 patients 111In-DOTA-M5A imaging revealed previously unknown brain metastases. Conclusion: This study demonstrates the potential utility of the 90Y-DOTA-M5A anti-CEA mAb as a therapeutic antibody. There is decreased immunogenicity compared with murine and chimeric mAbs, allowing for the potential of multiple administrations. Combined modality therapy approaches incorporating this agent should continue to be evaluated.