Karmanos Cancer Institute, Detroit, MI 48201, USA.
Cancer Chemother Pharmacol. 2011 Sep;68(3):703-12. doi: 10.1007/s00280-010-1536-1. Epub 2010 Dec 8.
To evaluate the maximum tolerated dose (MTD), safety, and antitumor activity of sunitinib combined with paclitaxel and carboplatin.
Successive cohorts of patients with advanced solid tumors received oral sunitinib (25, 37.5, or 50 mg) for 2 consecutive weeks of a 3-week cycle (Schedule 2/1) or as a continuous daily dose for 3-week cycles (CDD schedule) in combination with paclitaxel (175-200 mg/m(2)) plus carboplatin (AUC 6 mg min/ml) on day one of each of 4 cycles. Dose-limiting toxicities (DLTs) and adverse events (AEs) were evaluated to determine the MTD. Efficacy parameters were analyzed in patients with measurable disease.
Forty-three patients were enrolled (n = 25 Schedule 2/1; n = 18 CDD schedule). Across all doses, 6 DLTs were observed [grade 4 papilledema, grade 5 GI hemorrhage, grade 3 neutropenic infection, and grade 4 thrombocytopenia (n = 3)]. The MTD for Schedule 2/1 was sunitinib 25 mg plus paclitaxel 175 mg/m(2) and carboplatin AUC 6 mg min/ml. The MTD was not determined for the CDD schedule. Treatment-related AEs included neutropenia (77%), thrombocytopenia (56%), and fatigue (47%). Of 38 evaluable patients, 4 (11%) had partial responses and 12 (32%) had stable disease. PK data indicated an increase in maximum and total plasma exposures to sunitinib and its active metabolite when given with paclitaxel and carboplatin compared with sunitinib monotherapy.
Myelosuppression resulting in prolonged dose delays and frequent interruptions was observed, suggesting that this treatment combination is not feasible in the general cancer population.
评估舒尼替尼联合紫杉醇和卡铂的最大耐受剂量（MTD）、安全性和抗肿瘤活性。
连续入组晚期实体瘤患者，接受舒尼替尼（25、37.5 或 50mg）口服，每 2 周为一个周期，前 2 周为给药周期（方案 2/1），后 2 周停药；或每 3 周为一个周期，连续口服（CDD 方案），联合紫杉醇（175-200mg/m²）和卡铂（AUC 6mg/ml），每周期第 1 天用药 4 个周期。评价剂量限制性毒性（DLTs）和不良事件（AEs）以确定 MTD。分析可测量疾病患者的疗效参数。
共入组 43 例患者（方案 2/1 组 n=25；CDD 方案组 n=18）。所有剂量组均观察到 6 例 DLTs[4 级视乳头水肿，5 级胃肠道出血，3 级中性粒细胞感染和 4 级血小板减少症（n=3）]。方案 2/1 的 MTD 为舒尼替尼 25mg 联合紫杉醇 175mg/m²和卡铂 AUC 6mg/ml。CDD 方案未确定 MTD。治疗相关 AEs 包括中性粒细胞减少症（77%）、血小板减少症（56%）和乏力（47%）。38 例可评价患者中，4 例（11%）有部分缓解，12 例（32%）病情稳定。PK 数据表明，与舒尼替尼单药治疗相比，联合紫杉醇和卡铂治疗时舒尼替尼及其活性代谢物的最大和总血浆暴露量增加。
观察到骨髓抑制导致延长的剂量延迟和频繁中断，表明该治疗方案在一般癌症患者中不可行。
