| dc.identifier.citation | Meyer , T , Gaya , A M , Dancey , G , Stratford , M R L , Othman , S , Sharma , S , Wellsted , D , Taylor , N J , Stirling , J J , Poupard , L , Folkes , L K , Chan , P S , Pedley , R B , Chester , K A , Owen , K , Violet , J A , Malaroda , A , Green , A J , Buscombe , J , Padhani , A R , Rustin , G J & Begent , R H 2009 , ' A Phase I Trial of Radioimmunotherapy with 131I-A5B7 Anti-CEA Antibody in Combination with Combretastatin-A4-Phosphate in Advanced Gastrointestinal Carcinomas ' , Clinical Cancer Research , vol. 15 , no. 13 , pp. 4484-4492 . https://doi.org/10.1158/1078-0432.CCR-09-0035 | |
| dc.description.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 of 10 to 1,000 µg/L, QTc 450 ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry. Tumor was suitable for blood flow analysis by dynamic contrast enhanced-magnetic resonance imaging (MRI). The starting dose was 1,800 MBq/m2 of 131I-A5B7 on day 1 and 45 mg/m2 CA4P given 48 and 72 hours post-131I-A5B7, then weekly for up to seven weeks. 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 had DLTs (neutropenia). Of ten assessable patients, three had stable disease and seven had progressive disease. Single-photon emission computed tomography confirmed tumor antibody uptake in all 10 patients. DCE-MRI confirmed falls in kinetic parameters (Ktrans/IAUGC60) in 9 of 12 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 seem necessary for efficacy. | en |
