Background: There is increasing use of Phase I statistical designs to find a dose that causes rapidly emerging and particularly concerning severe or life-threatening toxicities (dose-limiting toxicities, DLTs) in a specified percent of patients most commonly 25%. While a convenient statistical framework, the foundation for selecting any specified target DLT rate, and its relevance to the recommended Phase II dose is generally lacking. Method: We surveyed 78 medical oncologists, most (69%) with experience as a principal investigator on a Phase I study, to ascertain their opinions related to this approach to Phase I studies and the targets often chosen. Results:Eighty-seven percent of respondents preferred severe toxicities in only 5%-10% of patients, consistent with 58% of respondents noting that 10% or fewer patients experience severe toxicities in the first cycle with standard outpatient treatments. The survey also documented in an example that the majority (62%) of physicians modify their patient selection during the conduct of the study based on observed toxicity and 78% note that higher toxicity is acceptable in patients where a cure is more likely. Conclusion: DLT-target rate designs search for a single target that is rarely well-supported in a patient population that is not stable. The most common target used is inconsistent with the toxicity of most clinically used drugs and investigator preference and can lead to the pursuit of unacceptable doses. Use of Phase I trial designs with a target DLT rate should be limited to settings with a well-justified target and should specify how the target relates to the recommended Phase II dose.

背景：越来越多地使用 I 期统计设计来寻找导致快速出现的剂量，特别是在特定百分比的患者中引起严重或危及生命的毒性（剂量限制性毒性，DLT），最常见的是 25%。虽然是一个方便的统计框架，但通常缺乏选择任何指定目标 DLT 率的基础，以及它与推荐的 II 期剂量的相关性。方法：我们调查了 78 名医学肿瘤学家，其中大多数 (69%) 有作为 I 期研究的主要研究者的经验，以确定他们对 I 期研究的这种方法和经常选择的目标的看法。结果：87% 的受访者希望只有 5%-10% 的患者出现严重毒性，这与 58% 的受访者一致指出，10% 或更少的患者在标准门诊治疗的第一个周期中出现严重毒性。该调查还在一个例子中记录到，大多数 (62%) 的医生在研究期间根据观察到的毒性修改了他们的患者选择，78% 的医生指出，在更有可能治愈的患者中，更高的毒性是可以接受的。结论：DLT 目标率设计搜索在不稳定的患者群体中很少得到很好支持的单个目标。使用的最常见目标与大多数临床使用药物的毒性和研究者偏好不一致，可能导致追求不可接受的剂量。使用具有目标 DLT 率的 I 期试验设计应仅限于具有充分理由的目标的设置，并应指定目标与推荐的 II 期剂量的关系。