Phase I trial of the anti-Lewis Y drug immunoconjugate BR96-Doxorubicin inpatients with Lewis Y-expressing epithelial tumors

Purpose: We conducted a phase I clinical trial of BR96-Doxorubicin (BR96-Do x), a chimeric anti-Lewis Y (Le(Y)) monoclonal antibody conjugated to doxor ubicin, in patients whose tumors expressed the Le(Y) antigen. The study aim ed to determine the toxicity, maximum-tolerated dose, pharmacokinetics, and immunogenicity of BR96-Dox, Patients and Methods: This was a phase I dose escalation study. BR96-Dox wa s initially administered alone as a 2-hour infusion every 3 weeks. The occu rrence of gastrointestinal (GI) toxicity necessitated the administration of BR96-Dox as a continuous infusion over 24 hours and use of antiemetics and antigastritis premedication. Patients experiencing severe GI toxicity unde rwent GI endoscopy. All patients underwent restaging after two cycles. Results: A total of 66 patients predominantly with metastatic colon and bre ast cancer were enrolled onto the study. The most common side effects were GI toxicity, fever, and elevation of pancreatic lipase. At higher doses, BR 96-Dox was associated with nausea, vomiting, and endoscopically documented exudative gastritis of the upper GI tract, which was dose-limiting at a max imum dose of 875 mg/m(2) (doxorubicin equivalent, 25 mg/m(2)) administered every 3 weeks. Toxicity was reversible and generally of short duration. Pre medication with the antiemetic Kytril (granisetron hydrochloride; SmithKlin e Beecham, Philadelphia, PA), the antacid omeprazole, and dexamethasone was most effective in ameliorating GI toxicity. A dose of 700 mg/m(2) BR96-Dox (doxorubicin equivalent, 19 mg/m(2)) every 3 weeks wets determined to be t he optimal phase II dose when administered with antiemetic and antigastriti s prophylaxis. BR96-Dox deposition on tumor tissue was documented immunohis tochemically and by confocal microscopy. Al the 550-mg/m(2) dose, the half- life (mean +/- SD) of BR96 and doxorubicin was 300 +/- 95 hours and 43 +/- 4 hours, respectively. BR96-Dox elicited a weak immune response in 37% of p atients. Objective clinical responses were seen in two patients. Conclusion: BR96-Dox provides a unique strategy to deliver doxorubicin to L e(Y)-expressing tumor and was well tolerated at doses of 700 mg/m(2) every 3 weeks. BR96-Dox was not associated with the typical side-effect profile o f native doxorubicin and can potentially deliver high doses of doxorubicin to antigen-expressing tumors. A phase II study in doxorubicin-sensitive tum ors is warranted. J Clin Oncol 18:2282-2292. (C) 2000 by American Society o f Clinical Oncology.