Departments of Melanoma Medical Oncology, Systems Biology, Biostatistics, Pathology, Experimental Therapeutics, and Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Clin Cancer Res. 2012 Feb 15;18(4):1120-8. doi: 10.1158/1078-0432.CCR-11-2436. Epub 2012 Jan 5.
This phase I clinical trial was conducted to determine the safety, efficacy, and molecular effects of sorafenib with temsirolimus in patients with advanced melanoma.
Patients with stage IV or unresectable or recurrent stage III melanoma and Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. Sorafenib was given orally once or twice daily and temsirolimus was given i.v. weekly, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per Response Evaluation Criteria in Solid Tumors criteria. Consenting patients with accessible tumors underwent optional tumor biopsies before treatment and after the second infusion of temsirolimus. Tumor biopsies were analyzed for activating mutations in BRAF and NRAS, and for expression of P-extracellular signal-regulated kinase (P-ERK) and P-S6 proteins.
A total of 25 patients were accrued to the study. The maximum tolerated doses were sorafenib 400 mg every morning and 200 mg every evening and temsirolimus 25 mg i.v. weekly. Dose-limiting toxicities included thrombocytopenia, hand-foot syndrome, serum transaminase elevation, and hypertriglyceridemia. There were no complete or partial responses with the combination; 10 patients achieved stabilization of disease as their best response. The median progression-free survival was 2.1 months. Matching pretreatment and day 15 tumor biopsies showed marked inhibition of P-S6 with treatment in 3 of 4 evaluable patients, but minimal inhibition of P-ERK.
Combination therapy with sorafenib and temsirolimus resulted in significant toxicity at higher dose levels, failed to achieve any clinical responses in genetically unselected patient population, and did not inhibit P-ERK.
本 I 期临床试验旨在确定索拉非尼联合替西罗莫司治疗晚期黑色素瘤患者的安全性、疗效和分子作用。
符合条件的患者为 IV 期或不可切除或复发性 III 期黑色素瘤，且东部合作肿瘤学组体能状态为 0 至 1。索拉非尼口服，每日 1 次或 2 次，替西罗莫司静脉注射，每周 1 次，均于第 1 天开始，每 4 周为 1 个周期。每 2 个周期按照实体瘤反应评价标准进行 1 次疗效评价。同意的患者在治疗前和第 2 次替西罗莫司输注后进行可选的肿瘤活检。对肿瘤活检进行 BRAF 和 NRAS 激活突变分析，以及 P-细胞外信号调节激酶（P-ERK）和 P-S6 蛋白表达分析。
共有 25 例患者入组该研究。最大耐受剂量为索拉非尼 400mg 每日清晨和 200mg 每日傍晚，替西罗莫司 25mg 每周静脉注射。剂量限制毒性包括血小板减少、手足综合征、血清转氨酶升高和高甘油三酯血症。联合治疗无完全或部分缓解，10 例患者疾病稳定为最佳缓解。中位无进展生存期为 2.1 个月。匹配的预处理和第 15 天肿瘤活检显示，3 例可评估患者中，治疗后 P-S6 显著抑制，但 P-ERK 抑制最小。
索拉非尼联合替西罗莫司治疗导致较高剂量水平下出现显著毒性，在未选择基因的患者群体中未获得任何临床缓解，且未抑制 P-ERK。
