Rini B, Redman B, Garcia J A, Burris H A, Li S, Fandi A, Beck R, Jungnelius U, Infante J R
Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Glickman Urological Institute, Cleveland.
Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor.
Ann Oncol. 2014 Sep;25(9):1794-1799. doi: 10.1093/annonc/mdu212. Epub 2014 Jun 8.
This phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide plus sunitinib in metastatic renal cell carcinoma (RCC) patients.
Patients with histologically confirmed, metastatic RCC were treated with 10 mg/day lenalidomide plus 37.5 mg/day sunitinib, orally in 21-day cycles. Doses were escalated to determine the MTD in phase I, with additional patients planned at this dose in phase II. Primary end points were MTD and response rate.
Sixteen patients received a median of 2, 3, and 5 cycles in cohort 1 [lenalidomide 10 mg (days 1-21) and sunitinib 37.5 mg (days 1-21)], cohort 2 [lenalidomide 10 mg (days 1-21) and sunitinib 37.5 mg (days 1-14)], and cohort 3 [lenalidomide 15 mg (days 1-21) and sunitinib 37.5 mg (days 1-14)], respectively. Median treatment durations were 41, 63, and 97 days for lenalidomide; and 41, 57, and 97.5 days for sunitinib. The MTD was found to be continuous dosing of lenalidomide 10 mg/day plus sunitinib 37.5 mg/day for 14 of 21 days. Dose-limiting toxicities included neutropenia, leukopenia, thrombocytopenia, asthenia, atrial fibrillation, and increased transaminases. The most frequent grade 3-4 treatment-emergent adverse events were hematologic, including neutropenia and leukopenia. One patient achieved partial response, and seven had stable disease of which three were confirmed at subsequent tumor assessments. B cells and several T-cell subsets were modulated versus baseline.
The dose schedules of lenalidomide and sunitinib evaluated in this study were not well tolerated; cumulative toxicity precluded enrollment at the MTD.
本I/II期研究旨在确定来那度胺联合舒尼替尼治疗转移性肾细胞癌（RCC）患者的最大耐受剂量（MTD）、安全性和疗效。
经组织学确诊的转移性RCC患者接受10mg/天来那度胺联合37.5mg/天舒尼替尼治疗，口服给药，每21天为一个周期。在I期确定MTD时逐步增加剂量，并计划在II期用此剂量纳入更多患者。主要终点为MTD和缓解率。
队列1[来那度胺10mg（第1 - 21天）和舒尼替尼37.5mg（第1 - 21天）]、队列2[来那度胺10mg（第1 - 21天）和舒尼替尼37.5mg（第1 - 14天）]和队列3[来那度胺15mg（第1 - 21天）和舒尼替尼37.5mg（第1 - 14天）]中分别有16例患者接受了中位数为2、3和5个周期的治疗。来那度胺的中位治疗持续时间分别为41、63和97天；舒尼替尼的中位治疗持续时间分别为41、57和97.5天。MTD为来那度胺10mg/天连续给药加舒尼替尼37.5mg/天，共21天中的14天。剂量限制性毒性包括中性粒细胞减少、白细胞减少、血小板减少、乏力、心房颤动和转氨酶升高。最常见的3 - 4级治疗期间出现的不良事件为血液学事件，包括中性粒细胞减少和白细胞减少。1例患者获得部分缓解，7例病情稳定，其中3例在后续肿瘤评估中得到确认。与基线相比，B细胞和几个T细胞亚群受到调节。
本研究中评估的来那度胺和舒尼替尼的给药方案耐受性不佳；累积毒性导致无法在MTD剂量下继续入组患者。
