Abstract：
BACKGROUND: Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors.
METHODS: Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1.
RESULTS: Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), and decreased white blood cell count (n = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response.
CONCLUSIONS: The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.
METHODS: Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1.
RESULTS: Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), and decreased white blood cell count (n = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response.
CONCLUSIONS: The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.
摘要：
背景：紫杉醇耐药性限制了具有初始临床获益的患者的反应持久性。已提出脾酪氨酸激酶（SYK）的过表达作为可能的抗性机制。这项I期试验评估了SYK抑制剂TAK-659联合紫杉醇在晚期紫杉烷难治性实体瘤患者中的安全性和初步活性。
方法：患有晚期实体瘤且先前以紫杉烷为基础的治疗进展的患者在第1、8和15天接受紫杉醇静脉输注，并每天口服TAK-659，为期28天。剂量递增阶段包括以不同剂量水平治疗的六个队列;剂量扩展阶段包括以最高剂量水平治疗的卵巢癌患者。使用美国国家癌症研究所不良事件通用术语标准5.0版对毒性进行分级。使用实体瘤版本1.1中的反应评估标准评估功效。
结果：我们的研究包括49例患者。未达到最大耐受剂量，但在较高剂量水平下观察到较高的不良事件发生率.没有治疗相关的死亡。任何级别的最常见的治疗相关不良事件是天冬氨酸转氨酶升高（n=31;63%），丙氨酸转氨酶增加（n=26；53%），中性粒细胞计数减少（n=26；53%），白细胞计数减少（n=26；53％）。大多数不良事件为1级或2级。在44名患有可评估疾病的患者中，12人(27%)疾病稳定为最佳总体反应，包括三名长期稳定的患者，和4名患者（9％）获得部分缓解。
结论：紫杉醇和TAK-659的组合在晚期实体瘤患者中显示出初步活性，可能克服了对紫杉烷治疗的耐药性，并具有可耐受的安全性。
方法：患有晚期实体瘤且先前以紫杉烷为基础的治疗进展的患者在第1、8和15天接受紫杉醇静脉输注，并每天口服TAK-659，为期28天。剂量递增阶段包括以不同剂量水平治疗的六个队列;剂量扩展阶段包括以最高剂量水平治疗的卵巢癌患者。使用美国国家癌症研究所不良事件通用术语标准5.0版对毒性进行分级。使用实体瘤版本1.1中的反应评估标准评估功效。
结果：我们的研究包括49例患者。未达到最大耐受剂量，但在较高剂量水平下观察到较高的不良事件发生率.没有治疗相关的死亡。任何级别的最常见的治疗相关不良事件是天冬氨酸转氨酶升高（n=31;63%），丙氨酸转氨酶增加（n=26；53%），中性粒细胞计数减少（n=26；53%），白细胞计数减少（n=26；53％）。大多数不良事件为1级或2级。在44名患有可评估疾病的患者中，12人(27%)疾病稳定为最佳总体反应，包括三名长期稳定的患者，和4名患者（9％）获得部分缓解。
结论：紫杉醇和TAK-659的组合在晚期实体瘤患者中显示出初步活性，可能克服了对紫杉烷治疗的耐药性，并具有可耐受的安全性。
