Purpose: Although eligibility criteria are essential in trial design, overly restrictive criteria contribute to low accrual and limited generalizability. To enhance trial inclusivity, there has been growing interest in broadening eligibility criteria, especially for patients with advanced or treatment-refractory disease. Yet, the impact on patient safety remains uncertain. In the Drug Rediscovery Protocol (DRUP), protocol exceptions are frequently requested and occasionally granted. Here we describe the impact of these waivers on treatment safety and efficacy. Patients and methods: DRUP is a multicenter, non-randomized clinical basket trial treating therapy-refractory cancer patients with molecularly targeted- and immunotherapies outside their registered indications (NCT02925234). Here, all granted waivers were revised, analyzed in terms of safety and efficacy outcome, and compared with outcomes of included patients that did not receive a waiver. Results: Between September 1st 2016 and September 1st 2021, protocol waivers were granted for 82 patients (8%) out of 1019 included patients in DRUP. Most waivers (45%) were granted for general- or drug-related eligibility criteria, other categories were out-of-window testing, treatment and testing exceptions. Serious adverse event rate was similar between patients that received a waiver (pW) and patients that did not (pNW): 39% vs. 41%, respectively (P=0.81). The clinical benefit (either objective response or stable disease ≥ 16 weeks) rate of pW was 40% versus 33% in pNW (P=0.43). Conclusion: Safety and clinical benefit were preserved in patients for whom a waiver was granted. These data support a more personalized approach in assessing eligibility criteria, especially in trials with widely used and approved drugs accruing patients without other treatment options.

中文翻译：

---

最大化治疗机会：评估协议豁免对药物重新发现协议中的安全性和结果的影响


目的：虽然资格标准在试验设计中至关重要，但过度限制的标准会导致应计率低和普遍性有限。为了提高试验的包容性，人们越来越有兴趣扩大资格标准，特别是对于患有晚期或难治性疾病的患者。然而，对患者安全的影响仍不确定。在药物重新发现协议 (DRUP) 中，经常要求协议例外，偶尔也会批准。在这里，我们描述这些豁免对治疗安全性和疗效的影响。患者和方法：DRUP 是一项多中心、非随机临床篮子试验，采用注册适应症之外的分子靶向和免疫疗法治疗难治性癌症患者 (NCT02925234)。在此，对所有授予的豁免进行了修订，从安全性和有效性结果方面进行了分析，并与未获得豁免的患者的结果进行了比较。结果：2016 年 9 月 1 日至 2021 年 9 月 1 日期间，DRUP 纳入的 1019 名患者中，有 82 名患者 (8%) 获得了方案豁免。大多数豁免（45%）是根据一般或药物相关的资格标准授予的，其他类别是窗外检测、治疗和检测例外。获得豁免的患者 (pW) 和未获得豁免的患者 (pNW) 的严重不良事件发生率相似：分别为 39% 和 41%（P=0.81）。 pW 的临床获益率（客观缓解或疾病稳定≥ 16 周）率为 40%，而 pNW 为 33%（P=0.43）。结论：获得豁免的患者保留了安全性和临床益处。 这些数据支持在评估资格标准时采用更加个性化的方法，特别是在使用广泛使用和批准的药物进行的试验中，患者没有其他治疗选择。