A Phase I Trial of Radioimmunotherapy with 131I-A5B7 Anti-CEA Antibody in Combination with Combretastatin-A4-Phosphate in Advanced Gastrointestinal Carcinomas

Abstract

Purpose: In preclinical models, radioimmunotherapy with 131 I-A5B7 anti^carcinoembryonic antigen (CEA) antibody ( 131 I-A5B7) combined with the vascular disruptive agent combretastatin-A4-phosphate (CA4P) produced cures unlike either agent alone. We conducted a phase I trial determining the dose-limiting toxicity (DLT), maximum tolerated dose, efficacy, and mechanism of this combination in patients with gastrointestinal adenocarcinomas. Experimental Design: Patients had CEA of 10 to 1,000 Ag/L, QTc V450 ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry.Tumor was suitable for blood flow analysis by dynamic contrast enhanced-magnetic resonance imaging (MRI).

Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer

“…Similarly, another study also demonstrated increased efficacy with combination therapy in preclinical models of head and neck cancer (29). However, the activities of radioimmunotherapy used in this study were in excess of what is normally administered to patients (6,7,30). To our knowledge, our study is the first to demonstrate that activities as low as 1 MBq of radioimmunotherapy can be therapeutically effective, particularly when combined with radiosensitizing agents, such as cetuximab, which would greatly facilitate the use of repeated radioimmunotherapy administration in patients.…”

“…Extrapolating 1 MBq to the human equivalent activity corresponds to approximately 154 MBq/m 2 (31), which is significantly lower than clinically used activities. Data from an early phase I trial of single-agent 131 I-murine A5B7 in patients with advanced CRC defined bone marrow suppression as the doselimiting toxicity at 2,400 MBq/m 2 , which was further reduced to 1,600 MBq/m 2 in another trial, as a cohort of patients experienced grade 4 neutropenia (6,7,30). Our findings with the humanized version of A5B7 strongly suggest that combining cetuximab with lower activity of radioimmunotherapy could translate into significantly better clinical outcomes with minimal toxicity.…”

“…Radioimmunotherapy can selectively target tumor cell-or tumor microenvironment-associated antigens with radiolabeled antibodies, delivering the greatest dose of ionizing radiation (IR) to tumor sites, while minimizing toxicity to normal tissues (3)(4)(5). We, and others, have previously shown that radioimmunotherapy against carcinoembryonic antigen (CEA) produced response in patients with advanced CRC; however, although some patients experienced partial remission or disease stabilization, most had disease progression (6)(7)(8)(9). Radioimmunotherapy has been successfully used for the treatment of lymphoma, but its use in solid tumors remains to be optimized.…”

One‐Pot Synthesis of an 125I‐Labeled Trifunctional Reagent for Multiscale Imaging with Optical and Nuclear Techniques

“…CEA is expressed by most gastrointestinal tumors, and A5B7 and its fragments are in regular preclinical and clinical use. [12][13][14] 125 I]-3/A5B7 was subsequently evaluated in mice bearing human colorectal xenografts. [13] The isotype-matched dual-labeled antibody […”

Imaging in targeted delivery of therapy to cancer

“…However the commonly used measurements of vascular parameters such as K trans are complex in that they relate to both blood flow and permeability. Furthermore such measurements are subject to considerable intrapatient variability requiring a minimum of two baseline images for robust interpretation [144]. Nevertheless, there is now data demonstrating that these measurements correlate not just with tumor vascular changes but also with clinically relevant endpoints.…”