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Basic Science Investigations |
1 Memorial Sloan-Kettering Cancer Center, New York, New York
2 Ludwig Institute for Cancer Research, New York, New York
This trial was performed to determine the maximum tolerated whole-body radiation-absorbed dose of fractionated 131I-cG250. Methods: This was a phase 1 dose escalation trial. Dose escalation refers here to the escalation of average whole-body absorbed dose. Fifteen patients with measurable metastatic renal cancer were studied. For each treatment cycle, patients initially received a "scout" administration consisting of 5 mg of cG250 antibody labeled with 185 MBq (5 mCi) of 131I. Whole-body and serum activity was measured for 1 wk, and a simple pharmacokinetic model was fitted to the measured data. The pharmacokinetic model was used to calculate the required activities, administered in a fractionated pattern with 2–3 d between fractions, projected to deliver the prescribed whole-body absorbed dose. The initial cohort of 3 patients was prescribed an average whole-body absorbed dose of 0.50 Gy. In subsequent cohorts this was increased in 0.25-Gy increments. The first fraction in each cycle was 1,110 MBq (30 mCi) of 131I conjugated to 5 mg of antibody. Subsequent fractions consisted of variable activities depending on the patient-specific whole-body clearance rates and the times between fractions. Patients without evidence of disease progression were retreated after recovery from toxicity if there was no evidence of altered pharmacokinetics or serum human antichimeric antibody titers, for a total of no more than 3 treatments. Results: For the initial treatment course, the pharmacokinetics of the scout dose accurately predicted the pharmacokinetics of fractionated 131I-cG250 therapy. In 2 patients, altered clearance accurately predicted development of human antichimeric antibody. Targeting to known disease 
2 cm in diameter was noted in all patients. Dose-limiting toxicity was hematopoietic, and the maximum tolerated dose per cycle was 0.75 Gy. Conclusion: Measurements of whole-body and serum clearance of cG250 antibody can be used to accurately predict the clearance of subsequent administrations, thus enabling rational treatment planning. An additional practical benefit of real-time pharmacokinetic monitoring is that therapy can be altered dynamically to reduce toxic side effects. However, there was no evidence for fractionation-induced sparing of the hematopoietic system in this study.
Key Words: radioimmunotherapy • chimeric antibodies • renal cancer
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