Hidalgo Manuel, Buckner Jan C, Erlichman Charles, Pollack Marilyn S, Boni Joseph P, Dukart Gary, Marshall Bonnie, Speicher Lisa, Moore Laurence, Rowinsky Eric K
Institute for Drug Development, Cancer Therapy and Research Center, Brook Army Medical Center, San Antonio, TX, USA.
Clin Cancer Res. 2006 Oct 1;12(19):5755-63. doi: 10.1158/1078-0432.CCR-06-0118.
Patients with advanced cancer received temsirolimus (Torisel, CCI-779), a novel inhibitor of mammalian target of rapamycin, i.v. once daily for 5 days every 2 weeks to determine the maximum tolerated dose, toxicity profile, pharmacokinetics, and preliminary antitumor efficacy.
Doses were escalated in successive cohorts of patients using a conventional phase I clinical trial design. Samples of whole blood and plasma were collected to determine the pharmacokinetics of temsirolimus and sirolimus, its principal metabolite.
Sixty-three patients were treated with temsirolimus (0.75-24 mg/m(2)/d). The most common drug-related toxicities were asthenia, mucositis, nausea, and cutaneous toxicity. The maximum tolerated dose was 15 mg/m(2)/d for patients with extensive prior treatment because, in the 19 mg/m(2)/d cohort, two patients had dose-limiting toxicities (one with grade 3 vomiting, diarrhea, and asthenia and one with elevated transaminases) and three patients required dose reductions. For minimally pretreated patients, in the 24 mg/m(2)/d cohort, one patient developed a dose-limiting toxicity of grade 3 stomatitis and two patients required dose reductions, establishing 19 mg/m(2)/d as the maximum acceptable dose. Immunologic studies did not show any consistent trend toward immunosuppression. Temsirolimus exposure increased with dose in a less than proportional manner. Terminal half-life was 13 to 25 hours. Sirolimus-to-temsirolimus exposure ratios were 0.6 to 1.8. A patient with non-small cell lung cancer achieved a confirmed partial response, which lasted for 12.7 months. Three patients had unconfirmed partial responses; two patients had stable disease for >/=24 weeks.
Temsirolimus was generally well tolerated on this intermittent schedule. Encouraging preliminary antitumor activity was observed.
晚期癌症患者接受替西罗莫司（Torisel，CCI - 779）治疗，其为一种新型的雷帕霉素哺乳动物靶点抑制剂，静脉注射，每2周每日1次，共5天，以确定最大耐受剂量、毒性特征、药代动力学及初步抗肿瘤疗效。
采用传统的I期临床试验设计，在连续的患者队列中逐步增加剂量。采集全血和血浆样本以确定替西罗莫司及其主要代谢产物西罗莫司的药代动力学。
63例患者接受了替西罗莫司治疗（0.75 - 24mg/m²/d）。最常见的与药物相关的毒性反应为乏力、黏膜炎、恶心和皮肤毒性。对于既往接受广泛治疗的患者，最大耐受剂量为15mg/m²/d，因为在19mg/m²/d队列中，有2例患者出现剂量限制性毒性反应（1例出现3级呕吐、腹泻和乏力，1例转氨酶升高），3例患者需要降低剂量。对于预处理较少的患者，在24mg/m²/d队列中，1例患者出现3级口腔炎的剂量限制性毒性反应，2例患者需要降低剂量，确定19mg/m²/d为最大可接受剂量。免疫学研究未显示出任何一致的免疫抑制趋势。替西罗莫司的暴露量随剂量增加，但增加比例小于剂量增加比例。终末半衰期为13至25小时。西罗莫司与替西罗莫司的暴露量比值为0.6至1.8。1例非小细胞肺癌患者获得了确认的部分缓解，持续了12.7个月。3例患者有未经确认的部分缓解；2例患者疾病稳定≥24周。
替西罗莫司在这种间歇给药方案下总体耐受性良好。观察到了令人鼓舞的初步抗肿瘤活性。
