Lessons learned: First trial to report safety and activity of the microtubule inhibitor vinflunine plus the tyrosine kinase inhibitor sorafenib in post-platinum metastatic urothelial cancer (mUC) patients.A recommended phase II dose was identified for the treatment combination of vinflunine plus sorafenib, with main adverse events including fatigue, febrile neutropenia, neutropenia, hypertension, and hyponatremia.An overall response rate of 41% to second-line vinflunine plus sorafenib treatment in patients with platinum-resistant mUC was confirmed.
Background: Platinum-progressive metastatic urothelial carcinoma (mUC) is a clinical challenge. The tyrosine kinase inhibitor sorafenib has demonstrated varied activity in mUC. This trial was designed to examine safety and activity of vinflunine plus sorafenib in mUC.
Methods: In addition to standard dose of vinflunine (320 or 280 mg/m2), patients received sorafenib (400, 600, or 800 mg/day), in a 3 + 3 dose-escalation phase I design.
Results: Twenty-two patients (median age 62.5 years) were included. Five patients received vinflunine 320 mg/m2 and 17 received 280 mg/m2. The maximum tolerated dose (MTD) of sorafenib with vinflunine 280 mg/m2 was 600 mg, and with vinflunine 320 mg/m2 it was not determined, owing to toxicity. Adverse events (AEs) grades 3 + 4 consisted of neutropenia (6 patients), febrile neutropenia (5), and hyponatremia (5). The overall response rate (ORR) in the efficacy-evaluable patients was 41% (7 of 17), all partial responses evaluated by RECIST version 1.1. Median overall survival (OS) was 7.0 months (1.8-41.7).
Conclusion: The defined recommended phase II dose (RPTD) was vinflunine 280 mg/m2 plus sorafenib 400 mg. Sorafenib was too toxic in combination with vinflunine 320 mg/m2. The ORR of 41% to this second-line combination treatment of mUC is noteworthy and supports further trials.
经验获取
• 第一个报告微管抑制剂长春氟宁加用酪氨酸激酶抑制剂索拉非尼治疗经铂类药物治疗后转移性尿路上皮癌 (mUC) 患者的安全性和活性的试验。
• 确定了长春氟宁和索拉非尼联合用药的推荐 II 期剂量，主要不良反应包括疲劳、发热性嗜中性白血球减少症、嗜中性白血球减少症、高血压和低钠血症。
• 确认了二线长春氟宁加用索拉非尼治疗铂类耐药 mUC 患者的总缓解率为 41%。
摘要
背景。铂类进展性转移性尿路上皮癌 (mUC) 是一项临床挑战。酪氨酸激酶抑制剂索拉非尼已在 mUC 中显示出不同的活性。本试验旨在检查长春氟宁加用索拉非尼治疗 mUC 的安全性和活性。
方法。按照 3 + 3 剂量递增 I 期试验设计，除了标准剂量的长春氟宁(320 或 280 mg/m2)之外， 患者还要服用索拉非尼(400、600 或 800 mg/天)。
结果。22 名患者(中位年龄为 62.5 岁)入组。5 名患者的长春氟宁用药剂量为 320 mg/m2， 17 名患者的用药剂量为 280 mg/m2。在加用长春氟宁280 mg/m2时，索拉非尼的最大耐受剂量 (MTD) 为 600 mg；在加用长春氟宁320 mg/m2时，由于毒性的缘故而无法确定索拉非尼的MTD。3 + 4 级不良反应 (AE) 包括中性粒细胞减少症(6 名患者)、发热性中性粒细胞减少症(5 名患者)以及低钠血症(5 名患者)。在有效性可评估的患者中，总缓解率(ORR)为 41%(17 名患者中的 7 名患者)，所有的部分缓解均以 1.1 版实体瘤疗效评价标准 (RECIST) 进行评估。中位总生存期 (OS) 为 7.0 个月 (1.8–41.7)。
结论。确定的推荐 II 期剂量 (RPTD) 为长春氟宁 280 mg/m2 加用索拉非尼 400 mg。索拉非尼与长春氟宁 320 mg/m2 联合用药的毒性太大。本次 mUC 二线联合治疗的 ORR 为41%，值得注意且支持进一步试验。
Trial registration: ClinicalTrials.gov NCT01844947.
© AlphaMed Press; the data published online to support this summary are the property of the authors.