A Pretherapy Biodistribution and Dosimetry Study of Indium-111-Radiolabeled Trastuzumab in Patients with Human Epidermal Growth Factor Receptor 2-Overexpressing Breast Cancer

Purpose: The purposes of this study were to evaluate the organ biodistribution, pharmacokinetics, immunogenicity, and tumor uptake of (111)Indium (In-111)-MxDTPA-trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancers and to determine whether Y-90-MxDTPA-trastuzumab should be evaluated in subsequent clinical therapy trials. Experimental Design: Patients with HER2-overexpressing breast cancers who were to undergo planned trastuzumab therapy first received unlabeled trastuzumab (4-8 mg/kg IV), followed 4 hours later by 5 mCi In-111-MxDTPA-trastuzumab (10 mg antibody). Serial blood samples, 24-hour urine collections, and nuclear scans were performed at defined time points for 7 days. Results: Eight (8) patients received In-111-MxDTPA-trastuzumab, which was well tolerated with no adverse side-effects. Three (3) of 7 patients with known lesions demonstrated positive imaging on nuclear scans. No anti-antibody responses were observed for 2 months postinfusion. Organ doses (cGy/mCi) assuming radiolabeling with Y-90 were 19.9 for heart wall, 17.6 for liver, 4.6 for red marrow, and 2.8 for the whole body. Tumor doses ranged from 24 to 172 cGy/mCi. Conclusions: In summary, results from this study indicate that Y-90-MxDTPA-trastuzumab is an appropriate agent to evaluate in therapy trials. No evidence of an immune response to In-111-MxDTPA-trastuzumab was detected, predicting for the ability to administer multiple cycles. With the exception of cardiac uptake, pharmacokinetics and organ biodistribution were comparable to other Y-90-labeled monoclonal antibodies previously evaluated in the clinic. Cardiac uptake was comparable to hepatic uptake and therefore predicted to not be prohibitively high as to result in dose-limiting cardiotoxicity.