BACKGROUND Patients with locally advanced bladder cancer (cT3/4 cN0/N+ cM0) have a poor prognosis despite radical surgical therapy and perioperative chemotherapy. Preliminary data suggest that the combination of radiation and immunotherapy does not lead to excess toxicity and may have synergistic (abscopal) anti-tumor effects. We hypothesize that the combined preoperative application of the PD-1 checkpoint-inhibitor Nivolumab with concomitant radiation therapy of the bladder and pelvic region followed by radical cystectomy with standardized lymphadenectomy is safe and feasible and might improve outcome for patients with locally advanced bladder cancer. METHODS Study design: "RACE IT" (AUO AB 65/18) is an investigator initiated, prospective, multicenter, open, single arm phase II trial sponsored by Technical University Munich. Study drug and funding are provided by the company Bristol-Myers Squibb. Study treatment: Patients will receive Nivolumab 240 mg i.v. every 2 weeks for 4 cycles preoperatively with concomitant radiation therapy of bladder and pelvic region (max. 50.4 Gy). Radical cystectomy with standardized bilateral pelvic lymphadenectomy will be performed between week 11-15. Primary endpoint: Rate of patients with completed treatment consisting of radio-immunotherapy and radical cystectomy at the end of week 15. Secondary endpoints: Acute and late toxicity, therapy response and survival (1 year follow up). Main inclusion criteria: Patients with histologically confirmed, locally advanced bladder cancer (cT3/4, cN0/N+), who are ineligible for neoadjuvant, cisplatin-based chemotherapy or who refuse neoadjuvant chemotherapy. Main exclusion criteria: Patients with metastatic disease (lymph node metastasis outside pelvis or distant metastasis) or previous chemo-, immune- or radiation therapy. Planned sample size: 33 patients, interim analysis after 11 patients. DISCUSSION This trial aims to evaluate the safety and feasibility of the combined approach of preoperative PD-1 checkpoint-inhibitor therapy with concomitant radiation of bladder and pelvic region followed by radical cystectomy. The secondary objectives of therapy response and survival are thought to provide preliminary data for further clinical evaluation after successful completion of this trial. Recruitment has started in February 2019. TRIAL REGISTRATION Protocol Code RACE IT: AB 65/18; EudraCT: 2018-001823-38; Clinicaltrials.gov: NCT03529890; Date of registration: 27 June 2018.

中文翻译：

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根治性膀胱切除术前的放射疗法与免疫疗法联合治疗局部晚期膀胱癌-一项前瞻性，单臂，多中心II期临床试验的研究方案（RACE IT）。

背景技术尽管进行了彻底的手术治疗和围手术期化疗，但局部晚期膀胱癌（cT3 / 4 cN0 / N + cM0）患者的预后较差。初步数据表明，放射线和免疫疗法的结合不会导致过度的毒性，并且可能具有协同（绝对）抗肿瘤作用。我们假设，PD-1检查点抑制剂Nivolumab的术前联合膀胱和盆腔区域放疗，然后行根治性膀胱切除术与标准的淋巴结切除术相结合是安全可行的，并且可能会改善局部晚期膀胱癌患者的预后。方法研究设计：“ RACE IT”（AUO AB 65/18）是由慕尼黑工业大学赞助的一项由研究人员发起的，前瞻性，多中心，开放，单臂II期临床试验。研究药物和资金由Bristol-Myers Squibb公司提供。研究治疗：术前，患者每2周静脉注射Nivolumab 240 mg，共4个周期，并伴有膀胱和骨盆区域的放射治疗（最大50.4 Gy）。在第11至15周之间将进行根治性膀胱切除术以及标准化的双侧盆腔淋巴结切除术。主要终点：在第15周末完成了包括放射免疫治疗和根治性膀胱切除术在内的完整治疗的患者比率。次要终点：急性和晚期毒性，治疗反应和生存期（随访1年）。主要纳入标准：经组织学确认的局部晚期膀胱癌（cT3 / 4，cN0 / N +），不符合新辅助化疗，顺铂化疗或拒绝新辅助化疗的患者。主要排除标准：患有转移性疾病（骨盆外淋巴结转移或远处转移）或先前进行过化学，免疫或放射治疗的患者。计划的样本量：33例，11例后进行中期分析。讨论本试验旨在评估术前PD-1检查点抑制剂治疗与膀胱和骨盆区域同时放疗再行根治性膀胱切除术相结合的安全性和可行性。治疗反应和生存的次要目标被认为是成功完成该试验后提供的初步数据，可用于进一步的临床评估。招聘工作已于2019年2月开始。试用注册协议代码RACE IT：AB 65/18；EudraCT：2018-001823-38; Clinicaltrials.gov：NCT03529890；注册日期：2018年6月27日。