Single Arm Phase I/II Study of Everolimus and Intravesical Gemcitabine in Patients with Primary or Secondary Carcinoma In Situ of the Bladder who failed Bacillus Calmette Guerin (NCT01259063).
Single Arm Phase I/II Study of Everolimus and Intravesical Gemcitabine in Patients with Primary or Secondary Carcinoma In Situ of the Bladder who failed Bacillus Calmette Guerin (NCT01259063).
复制标题
DOI：
10.3233/blc-170095
复制
发表时间：
2017-04-27
期刊：
影响因子：
--
通讯作者：
Bajorin DF
中科院分区：
文献类型：
--
作者：
Dalbagni G;Benfante N;Sjoberg DD;Bochner BH;Machele Donat S;Herr HW;Mc Coy AS;Fahrner AJ;Retinger C;Rosenberg JE;Bajorin DF
背景：卡介苗耐药的尿路上皮癌的标准治疗方法是根治性膀胱切除术。确定活性物质显然是有必要的。目的：确定口服依维莫司与标准吉西他滨联合应用的安全剂量，并评价其疗效。方法：选择对卡介苗膀胱内耐药、不愿行膀胱切除术的原位癌患者。在试验的第一阶段，患者接受了三种剂量水平的口服依维莫司。患者还接受了固定剂量的膀胱内吉西他滨治疗。患者接受维持性依维莫司治疗12个月，通过膀胱镜和细胞学检查证实完全缓解。II期患者接受维拉莫司的持续治疗，每日10 毫克，联合吉西他滨膀胱内注射，然后维持维持性治疗12个月。第二阶段的招募目标是33名患者。结果：14例患者进入试验I期。23名患者参加了试验的第二阶段，19名患者可以评估主要和次要终点。四名患者在治疗开始前撤回了同意。在19例可评价疗效的患者中，3例(16%，95%可信区间[CI]3%-40%)在1 年无病。12个月时发生RFS的概率为20%(95%可信区间为5%~42%)。19名患者中有10名出现了3级或更大的毒性事件。其中七人撤回同意或被停学。结论：许多患者退出，登记被叫停。在耐受性阈值较低的患者群体中，连续口服依维莫司加膀胱内注射吉西他滨的耐受性不佳。
Background: Standard treatment for BCG-refractory urothelial cancer is radical cystectomy. Identification of active agents is clearly warranted. Objective: To determine a safe dose of oral everolimus in combination with standard intravesical gemcitabine and to evaluate the efficacy of this combination. Methods: Patients with carcinoma in situ refractory to intravesical bacillus Calmette-Guérin and refusing cystectomy were eligible. Patients in the phase I part of the trial received one of three dose levels of oral everolimus. Patients also received a fixed dose of intravesical gemcitabine. Maintenance everolimus was given for 12 months in patients achieving a complete response confirmed by cystoscopy and cytology. Patients in phase II received continuous everolimus administered at 10 mg daily with intravesical gemcitabine followed by everolimus maintenance for 12 months of total therapy. The enrollment goal for the phase II was 33 patients. Results: 14 patients were enrolled in phase I of the trial. 23 patients were enrolled in phase II of the trial and 19 were evaluable for primary and secondary endpoints. Four patients withdrew consent prior to treatment initiation. Of the 19 patients evaluable for response, 3 (16%, 95% confidence interval [CI] 3% – 40%) were disease free at 1 yr. The probability of RFS was 20% (95% CI 5% – 42%) at 12 months. Ten patients out of 19 had grade 3 or greater toxicity events. Seven withdrew consent or were taken off study. Conclusions: Many patients withdrew, and enrollment was halted. Continuous oral everolimus plus intravesical gemcitabine was not well tolerated in this patient population where the threshold for tolerability is low.