Tolcher A W, Sugarman S, Gelmon K A, Cohen R, Saleh M, Isaacs C, Young L, Healey D, Onetto N, Slichenmyer W
British Columbia Cancer Agency, Vancouver, Canada.
J Clin Oncol. 1999 Feb;17(2):478-84. doi: 10.1200/JCO.1999.17.2.478.
BMS-182248-1 (BR96-doxorubicin immunoconjugate) is a chimeric human/mouse monoclonal antibody linked to approximately eight doxorubicin molecules. The antibody is directed against the Lewis-Y antigen, which is expressed on 75% of all breast cancers but is limited in expression on normal tissues. Preclinical xenograft models demonstrated significant antitumor activity, including cures. A randomized phase II design was chosen to estimate the activity of the BR96-doxorubicin conjugate in metastatic breast cancer in a study population with confirmed sensitivity to single-agent doxorubicin.
Patients with measurable metastatic breast cancer and immunohistochemical evidence of Lewis-Y expression on their tumor received either BR96-doxorubicin conjugate 700 mg/m2 IV over 24 hours or doxorubicin 60 mg/m2 every 3 weeks. Patients were stratified on the basis of prior doxorubicin exposure, visceral disease, and institution. Cross-over to the opposite treatment arm was allowed with progressive or persistently stable disease.
Twenty-three patients who had received a median of one prior chemotherapy 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 doxorubicin. No patient experienced a clinically significant hypersensitivity reaction. The toxicities were significantly different between the two treatment groups, with the BR96-doxorubicin conjugate group having limited hematologic toxicity, whereas gastrointestinal toxicities, including marked serum amylase and lipase elevations, nausea, and vomiting with gastritis, were prominent.
The BR96-doxorubicin immunoconjugate has limited clinical antitumor activity in metastatic breast cancer. The gastrointestinal toxicities likely represent binding of the agent to normal tissues expressing the target antigen and may have compromised the delivery of the immunoconjugate to the tumor sites.
BMS - 182248 - 1（BR96 - 阿霉素免疫偶联物）是一种与人源/鼠源嵌合单克隆抗体相连的药物，该抗体连接有大约8个阿霉素分子。该抗体靶向Lewis - Y抗原，75%的乳腺癌均表达此抗原，但在正常组织中的表达有限。临床前异种移植模型显示出显著的抗肿瘤活性，包括治愈效果。在一项对单药阿霉素已证实敏感的研究人群中，采用随机II期设计来评估BR96 - 阿霉素偶联物对转移性乳腺癌的活性。
患有可测量的转移性乳腺癌且肿瘤有Lewis - Y表达免疫组化证据的患者，接受24小时静脉输注700mg/m²的BR96 - 阿霉素偶联物，或每3周接受60mg/m²阿霉素治疗。患者根据既往阿霉素暴露情况、内脏疾病及所在机构进行分层。病情进展或持续稳定的患者允许交叉至相反治疗组。
23例患者可评估，这些患者接受过的化疗方案中位数为1个。接受BR96 - 阿霉素偶联物治疗的14例患者中有1例部分缓解（7%），接受阿霉素治疗的9例可评估患者中有1例完全缓解和3例部分缓解（44%）。无患者发生具有临床意义的超敏反应。两个治疗组的毒性有显著差异，BR96 - 阿霉素偶联物组血液学毒性有限，而胃肠道毒性突出，包括血清淀粉酶和脂肪酶显著升高、恶心及伴有胃炎的呕吐。
BR96 - 阿霉素免疫偶联物在转移性乳腺癌中的临床抗肿瘤活性有限。胃肠道毒性可能代表该药物与表达靶抗原的正常组织结合，这可能影响了免疫偶联物向肿瘤部位的递送。
