Journal of Clinical Oncology, Vol 18, Issue 11
(June), 2000: 2282-2292
© 2000 American Society for Clinical Oncology
Phase I Trial of the Anti–Lewis Y Drug Immunoconjugate BR96-Doxorubicin in Patients With Lewis Y–Expressing Epithelial Tumors
By Mansoor N. Saleh,
Steve Sugarman,
James Murray,
Joy B. Ostroff,
Diane Healey,
Dennie Jones,
Carol R. Daniel,
Donna LeBherz,
Hannah Brewer,
Nicole Onetto,
Albert F. LoBuglio
From the Department of Medicine, Division of Hematology/Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL; the Department of Medical Oncology, M.D. Anderson Cancer Center, Houston, TX; and Bristol-Myers Squibb, Wallingford, CT.
Address reprint requests to Mansoor N. Saleh, MD, Department of Medicine, Division of Hematology/Oncology, Comprehensive Cancer Center, 1824 Sixth Ave South, Wallace Tumor Institute 223, University of Alabama at Birmingham, Birmingham, AL 35294-3300; email mansoor.saleh{at}ccc.uab.edu
PURPOSE: We conducted a phase I clinical trial of BR96-Doxorubicin (BR96-Dox), a chimeric anti–Lewis Y (LeY) monoclonal antibody conjugated to doxorubicin, in patients whose tumors expressed the LeY antigen. The study aimed 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 was initially administered alone as a 2-hour infusion every 3 weeks. The occurrence 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 underwent GI endoscopy. All patients underwent restaging after two cycles.
RESULTS: A total of 66 patients predominantly with metastatic colon and breast cancer were enrolled onto the study. The most common side effects were GI toxicity, fever, and elevation of pancreatic lipase. At higher doses, BR96-Dox was associated with nausea, vomiting, and endoscopically documented exudative gastritis of the upper GI tract, which was dose-limiting at a maximum dose of 875 mg/m2 (doxorubicin equivalent, 25 mg/m2) administered every 3 weeks. Toxicity was reversible and generally of short duration. Premedication with the antiemetic Kytril (granisetron hydrochloride; SmithKline Beecham, Philadelphia, PA), the antacid omeprazole, and dexamethasone was most effective in ameliorating GI toxicity. A dose of 700 mg/m2 BR96-Dox (doxorubicin equivalent, 19 mg/m2) every 3 weeks was determined to be the optimal phase II dose when administered with antiemetic and antigastritis prophylaxis. BR96-Dox deposition on tumor tissue was documented immunohistochemically and by confocal microscopy. At the 550-mg/m2 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 patients. Objective clinical responses were seen in two patients.
CONCLUSION: BR96-Dox provides a unique strategy to deliver doxorubicin to LeY-expressing tumor and was well tolerated at doses of 700 mg/m2 every 3 weeks. BR96-Dox was not associated with the typical side-effect profile of native doxorubicin and can potentially deliver high doses of doxorubicin to antigen-expressing tumors. A phase II study in doxorubicin-sensitive tumors is warranted.
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