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 131I-A5B7 anti - carcinoembryonic antigen (CEA) antibody (131I-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 of10 to1,000 Ag/L, QTc V450ms, no cardiac arrhythmia/ ischaemia, and adequate hematology/biochemistry.Tumorwas suitable for blood flowanalysis by dynamic contrast enhanced-magnetic resonance imaging (MRI). The starting dose was 1,800MBq/m2 of131I-A5B7 on day1and 45mg/m2CA4Pgiven 48 and 72 hourspost-131I-A5B7, thenweekly for up to sevenweeks. Results: Twelve patients were treated, with mean age of 63 years (range, 32-77). Two of six patients at the first dose level had DLTs (grade 4 neutropenia). The dose was reduced to 1,600 MBq/m2, and CA4P escalated to 54 mg/m2. Again, two of six patients hadDLTs (neu tropenia). Of ten assessable patients, three had stable disease and seven had progressive disease. Singlephoton emission computed tomography confirmed tumor antibody uptake in all10 patients. DCEMRI confirmed falls in kinetic parameters (Ktrans/IAUGC60) in 9 of12 patients. The change of both pharmacokinetic parameters reached a level expected to produce efficacy in one patient who had a minor response on computed tomography and a reduced serum tumor marker level. Conclusions: This is believed to be the first trial reporting the combination of radioimmunotherapy and vascular disruptive agent; each component was shown to function, and myelosuppression was dose-limiting. Optimal dose and timing of CA4P, and moderate improvements in the performance of radioimmunotherapy seemnecessary for efficacy. © 2009 American Association for Cancer Research.