Phase I Trial of the Anti–Lewis Y Drug Immunoconjugate BR96-Doxorubicin in Patients With Lewis Y–Expressing Epithelial Tumors
| Autor: | Joy B. Ostroff, James A. H. Murray, Hannah Brewer, Carol R. Daniel, Nicole Onetto, Albert F. LoBuglio, Diane Healey, Mansoor N. Saleh, Donna LeBherz, Steve Sugarman, Dennie Jones |
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| Rok vydání: | 2000 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty Phases of clinical research Antineoplastic Agents Enzyme-Linked Immunosorbent Assay Pharmacology Gastroenterology Lewis Blood Group Antigens Breast cancer Pharmacokinetics Internal medicine medicine Humans Antigens Tumor-Associated Carbohydrate Doxorubicin Neoplasms Glandular and Epithelial Aged Dose-Response Relationship Drug business.industry Immunotoxins Immunogenicity Antibodies Monoclonal Middle Aged medicine.disease Immunohistochemistry Immunoconjugate Treatment Outcome Oncology Area Under Curve Toxicity Female Premedication business medicine.drug |
| Zdroj: | Journal of Clinical Oncology. 18:2282-2292 |
| ISSN: | 1527-7755 0732-183X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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