Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.
Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.
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DOI：
10.1016/s1470-2045(20)30540-4
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发表时间：
2021-01
期刊：
影响因子：
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通讯作者：
Dinney CPN
中科院分区：
文献类型：
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作者：
Boorjian SA;Alemozaffar M;Konety BR;Shore ND;Gomella LG;Kamat AM;Bivalacqua TJ;Montgomery JS;Lerner SP;Busby JE;Poch M;Crispen PL;Steinberg GD;Schuckman AK;Downs TM;Svatek RS;Mashni J Jr;Lane BR;Guzzo TJ;Bratslavsky G;Karsh LI;Woods ME;Brown G;Canter D;Luchey A;Lotan Y;Krupski T;Inman BA;Williams MB;Cookson MS;Keegan KA;Andriole GL Jr;Sankin AI;Boyd A;O'Donnell MA;Sawutz D;Philipson R;Coll R;Narayan VM;Treasure FP;Yla-Herttuala S;Parker NR;Dinney CPN
卡介苗是治疗高危非肌肉浸润性膀胱癌最有效的治疗方法。Nadofaragene firadenovec(又称Rad-IFNA/Syn3)是一种复制缺陷的重组腺病毒，可将人干扰素α-2b基因导入膀胱上皮细胞，是一种治疗卡介苗无效的非肌肉浸润性膀胱癌的新方法。我们的目标是评估其在卡介苗无反应的非肌肉浸润性膀胱癌患者中的疗效。在这项在美国33个中心(医院和诊所)进行的第三阶段多中心开放标签重复剂量研究中，我们招募了年龄在18岁或以上的患者，他们患有卡介苗反应不敏感的非肌肉浸润性膀胱癌，东部合作肿瘤组状态为2或更低。如果患者有上尿路疾病、前列腺癌、淋巴血管侵犯、微乳头疾病或肾积水，则排除这些患者。符合条件的患者接受单次75mLNadofaragene firadenovec膀胱内注射(每毫升3×10？病毒颗粒)。在没有高级别复发的情况下，在3、6和9个月重复给药。主要终点是原位癌患者在任何时间的完全反应(有或没有高级别Ta或T1肿瘤)。零假设规定，在这个队列中，完全应答率不到27%。疗效分析按方案进行，只包括严格符合卡介苗无反应定义的患者。对所有接受至少一剂治疗的患者进行了安全性分析。这项研究正在进行中，计划进行为期4年的治疗和监测阶段。这项研究注册在ClinicalTrials.gov，NCT02773849。在2016年9月19日至2019年5月24日期间，198名患者接受了资格评估。41名患者被排除在外，157名患者入选并接受了至少一剂研究药物。6名患者不符合卡介苗无反应性非肌肉浸润性膀胱癌的定义，因此被排除在疗效分析之外；其余151名患者被纳入按方案进行的疗效分析。103例原位癌(伴或不伴高级别Ta或T1肿瘤)中，55例(53·4%)在首剂治疗后3个月内完全缓解，其中25例(45·5%)在12个月后维持有效。排尿紧迫症是3-4级研究中最常见的与药物相关的不良事件(157名患者中有2例[1%]，均为3级)，没有与治疗相关的死亡。在卡介苗反应无效的非肌肉浸润性膀胱癌患者中，奈多芬非拉地诺韦膀胱内注射是有效的，具有良好的益处：风险比。这代表了在治疗上具有挑战性的疾病状态下的一种新的治疗选择。FKD疗法Oy.
BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 10¹¹ viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849. Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3–4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. FKD Therapies Oy.