Title

A phase I trial of radioimmunotherapy with 1311-A5B7 anti-CEA antibody in combination with combretastatin-A4-phophate in advanced gastronintestinal carinomas

RIS ID

93984

Publication Details

Meyer, T., Gaya, A. M., Dancey, G., Stratford, M., Othman, S., Sharma, S. K., Wellsted, D., Taylor, N. Jane., Stirling, J. James., Poupard, L., Folkes, L. K., Chan, P., Pedley, R. Barbara., 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 1311-A5B7 anti-CEA antibody in combination with combretastatin-A4-phophate in advanced gastronintestinal carinomas. Clinical Cancer Research, 15 (13), 4484-4492.

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 microg/L, QTc < or =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/m(2) of (131)I-A5B7 on day 1 and 45 mg/m(2) CA4P given 48 and 72 hours post-(131)I-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/m(2), and CA4P escalated to 54 mg/m(2). 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 (K(trans)/IAUGC(60)) 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.

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Link to publisher version (DOI)

http://dx.doi.org/10.1158/1078-0432.CCR-09-0035