Randomized phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer

Purpose: BMS-182248-1 (BR96-doxorubicin immunoconjugate) is a chimeric huma n/mouse monoclonal antibody linked to approximately eight doxorubicin molec ules. The antibody is directed against the Lewis-Y antigen, which is expres sed on 75% of all breast cancers but is limited in expression on normal tis sues, Preclinical xenograft models demonstrated significant antitumor activ ity, including cures. A randomized phase II design was chosen to estimate t he activity of the BR96-doxorubicin conjugate in metastatic breast cancer i n a study population with confirmed sensitivity to single-agent doxorubicin . Patients and Methods: Patients with measurable metastatic breast cancer and immunohistochemical evidence of Lewis-Y expression on their tumor received either BR96-doxorubicin conjugate 700 mg/m(2) IV over 24 hours or doxorubi cin 60 mg/m(2) every 3 weeks. Patients were stratified on the basis of prio r doxorubicin exposure, visceral disease, and institution. Cross-over to th e opposite treatment arm was allowed with progressive or persistently stabl e disease. Results: Twenty-three patients who had received a median of one prior chemo therapy regimen were assessable. There was one partial response (7%) in 14 patients receiving the BR96-doxorubicin conjugate and one complete response and three partial responses (44%) in nine assessable patients receiving do xorubicin, No patient experienced a clinically significant hypersensitivity reaction, The toxicities were significantly different between the two trea tment groups, with the BR96-doxorubicin conjugate group having limited hema tologic toxicity, whereas gastrointestinal toxicities, including marked ser um amylase and lipase elevations, nausea, and vomiting with gastritis, were prominent. Conclusion: The BR96-doxorubicin immunoconjugate has limited clinical antit umor activity in metastatic breast cancer. The gastrointestinal toxicities likely represent binding of the agent to normal tissues expressing the targ et antigen and may have compromised the delivery of the immunoconjugate to the tumor sires. (C) 1999 by American Society of Clinical Oncology.