Margolin Kim, Longmate Jeffrey, Baratta Tracey, Synold Tim, Christensen Scott, Weber Jeffrey, Gajewski Thomas, Quirt Ian, Doroshow James H
Division of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California 91010, USA.
Cancer. 2005 Sep 1;104(5):1045-8. doi: 10.1002/cncr.21265.
CCI-779 is an analog of the immunosuppressive agent, rapamycin, that has demonstrated activity against melanoma in preclinical models and shown clinical benefit in patients with breast and renal carcinoma. CCI-779 is not immunosuppressive when administered on an intermittent schedule, and its toxicity is modest, consisting of nausea, diarrhea, hypertriglyceridemia, thrombocytopenia, asthenia, and follicular dermatitis.
The current trial was designed to detect a median time to disease progression of >18 weeks in patients with metastatic melanoma treated with a 250-mg weekly dose of CCI-779 administered intravenously after diphenhydramine premedication. Patients with measurable disease, no more than one previous chemotherapy regimen for metastatic disease, and normal organ function were eligible, and patients with central nervous system involvement, P450-inducing or P450-suppressing drugs, or hypertriglyceridemia were excluded.
Thirty-three patients (21 males) were treated, 21 of whom had been treated previously with chemotherapy and/or biologic agents for advanced-stage disease. One patient had a partial response lasting 2 months. The median time to disease progression and overall survival were 10 weeks and 5 months, respectively. Toxicity was mild and predominantly mucocutaneous (stomatitis, diarrhea, and rash). Hyperlipidemia was cumulative and was managed with lipid-lowering agents.
CCI-779 was not sufficiently active in melanoma to warrant further testing as a single agent.
CCI-779是免疫抑制剂雷帕霉素的类似物，在临床前模型中已显示出对黑色素瘤的活性，并在乳腺癌和肾癌患者中显示出临床益处。当间歇性给药时，CCI-779没有免疫抑制作用，其毒性较小，包括恶心、腹泻、高甘油三酯血症、血小板减少、乏力和滤泡性皮炎。
本试验旨在检测接受250mg CCI-779每周静脉注射一次（在使用苯海拉明进行预处理后）治疗的转移性黑色素瘤患者的疾病进展中位时间是否大于18周。符合条件的患者需有可测量的疾病、转移性疾病既往化疗方案不超过一种且器官功能正常，排除有中枢神经系统受累、P450诱导或P450抑制药物或高甘油三酯血症的患者。
33例患者（21例男性）接受了治疗，其中21例曾接受过晚期疾病的化疗和/或生物制剂治疗。1例患者出现持续2个月的部分缓解。疾病进展中位时间和总生存期分别为10周和5个月。毒性较轻，主要为皮肤黏膜毒性（口腔炎、腹泻和皮疹）。高脂血症具有累积性，通过降脂药物进行处理。
CCI-779在黑色素瘤中的活性不足，不足以作为单一药物进行进一步试验。
