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Abstract：
In clinical trials, laboratory values are assessed with high frequency. This can be stressful for patients, resource intensive, and difficult to implement, for example in office-based settings. In the prospective, multicentre phase 2 TITAN-RCC trial (NCT02917772), we investigated how many relevant changes in laboratory values would have been missed if laboratory values had been assessed less frequently. Patients with metastatic renal cell carcinoma (n = 207) received a response-based approach with nivolumab and nivolumab+ipilimumab boosts for non-response. We simulated that laboratory values were obtained before every second dose instead of every dose of the study drug(s). We assessed elevated leukocyte counts, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, amylase, lipase, and thyroid-stimulating hormone. Dose delay and discontinuation criteria were defined according to the study protocol. With the reduced frequency of laboratory analyses, dose delay criteria were rarely missed: in a maximum of <0.1% (3/4382) of assessments (1% [2/207] of patients) during nivolumab monotherapy and in a maximum of 0.2% (1/465) of assessments (1% [1/132] of patients) during nivolumab+ipilimumab boosts. An exception was lipase-related dose delay which would have been missed in 0.6% (25/4204) of assessments (7% [15/207] of patients) during nivolumab monotherapy and in 0.8% (4/480) of assessments (3% [4/134] of patients) during nivolumab+ipilimumab boosts, but would have required the presence of symptoms. Discontinuation criteria would have only been missed for amylase (<0.1% [1/3965] of assessments [0.5% (1/207) of patients] during nivolumab monotherapy, none during nivolumab+ipilimumab boosts) and lipase (0.1% [5/4204] of assessments [2% (4/207) of patients] during nivolumab monotherapy; 0.2% [1/480] of assessments [0.7% (1/134) of patients] during nivolumab+ipilimumab boosts). However, only symptomatic patients would have had to discontinue treatment due to amylase or lipase laboratory values. In conclusion, a reduced frequency of laboratory testing appears to be acceptable in asymptomatic patients with metastatic renal cell carcinoma treated with nivolumab or nivolumab+ipilimumab.
摘要：
在临床试验中,以高频率评估实验室值。这对患者来说可能会有压力，资源密集型，并且难以实施，例如在基于办公室的设置中。在未来，多中心2期TITAN-RCC试验（NCT02917772），我们调查了如果不那么频繁地评估实验室值,会遗漏多少相关的实验室值变化.转移性肾细胞癌患者（n=207）接受了基于反应的方法，使用nivolumab和nivolumab+ipilimumab增强治疗无反应。我们模拟了在每个第二剂量之前而不是每个剂量的研究药物之前获得的实验室值。我们评估了白细胞计数升高，丙氨酸氨基转移酶，天冬氨酸转氨酶,胆红素,肌酐,淀粉酶，脂肪酶,和促甲状腺激素.根据研究方案定义剂量延迟和停药标准。随着实验室分析频率的降低，很少错过剂量延迟标准:在纳武单抗单药治疗期间,最高<0.1%(3/4382)的评估(1%[2/207]的患者),在纳武单抗+伊匹单抗强化治疗期间,最高为0.2%(1/465)的评估(1%[1/132]的患者).一个例外是脂肪酶相关的剂量延迟，在nivolumab单药治疗期间，在0.6%(25/4204)的评估(7%[15/207]的患者)和0.8%(4/480)的评估(3%[4/134]的患者)在nivolumab+ipilimumab增强期间，但需要出现症状。在nivolumab单药治疗期间，只有淀粉酶（<0.1％[1/3965]的评估[0.5％（1/207）的患者]才会错过停药标准，在nivolumab+ipilimumab期间没有)和脂肪酶(0.1%[5/4204]的评估[2%(4/207)的患者]在nivolumab单药治疗期间;0.2%[1/480]的评估[0.7%(1/134)的患者]在nivolumab+ipilimumab期间).然而,只有有症状的患者会因为淀粉酶或脂肪酶实验室值而不得不停止治疗.总之,在接受nivolumab或nivolumab+ipilimumab治疗的无症状转移性肾细胞癌患者中,减少实验室检查频率似乎是可以接受的.
