A new approach to integrate toxicity grade and repeated treatment cycles in the analysis and reporting of phase I dose-finding trials
A new approach to integrate toxicity grade and repeated treatment cycles in the analysis and reporting of phase I dose-finding trials
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DOI：
10.1093/annonc/mdu523
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发表时间：
2015-02-01
影响因子：
50.5
通讯作者：
Paoletti, X.
中科院分区：
文献类型：
--
作者：
Doussau, A.;Thiebaut, R.;Paoletti, X.
背景资料：剂量限制性毒性评价期后的安全性评估提供了相关信息，以确定新治疗的推荐II期剂量（RP 2D）。我们回顾性分析了三个I期临床试验，以说明两个指标：每周期分级毒性的概率和治疗期间严重毒性的累积概率。患者和方法：数据收集自两个连续重新评估方法（CRM）试验（T1：治疗时间短的实体瘤中的阿维库明; T2：厄洛替尼+放射治疗脑干胶质瘤，治疗时间较长）和一个3 + 3设计（T3：脂质体阿霉素+环磷酰胺组合治疗卵巢癌）。采用混合比例优势模型估计各剂量水平下每个周期重度和中度或重度毒性的概率。严重毒性的累积概率也估计与时间事件CRM.Results：83例患者被纳入三项试验，94，96和72个治疗周期，分别在T1，T2和T3。中度毒性至少是重度毒性的两倍。在T3中检测到毒性概率随时间增加[P = 0.04;在RP 2D下，重度毒性的每个周期概率：27%（周期1）至59%（周期6）]。在RP 2D时，T2和T3治疗前6个周期中分别有37%和78%的患者发生了至少1次严重毒性反应。结论：可采用专门的方法对所有治疗周期的毒性反应进行分析。它们不会延迟累积，应纳入I期剂量探索试验的分析和报告中。
Background: Safety assessment beyond the dose-limiting toxicity evaluation period provides relevant information to define the recommended phase II dose (RP2D) of a new treatment. We retrospectively analyzed three phase I trials to illustrate two indicators: per-cycle probability of graded toxicity and cumulative probability of severe toxicity over the treatment period.Patients and methods: Data were collected from two continual reassessment method (CRM) trials (T1: aviscumine in solid tumors with short time on treatment; T2: erlotinib + radiotherapy in brainstem gliomas with longer time on treatment) and one 3 + 3 design (T3: liposomal doxorubicin + cyclophosphamide combination in ovarian carcinoma). The probability of severe and moderate or severe toxicity per cycle was estimated at each dose level with mixed proportional odds model. The cumulative probability of severe toxicity was also estimated with the time-to-event CRM.Results: Eighty-three patients were included in the three trials; 94, 96 and 72 treatment cycles were administered, in T1, T2 and T3, respectively. Moderate toxicities were at least twice as frequent as severe toxicities. An increased probability of toxicity over time was detected in T3 [P = 0.04; per-cycle probability of severe toxicity: 27% (cycle 1) to 59% (cycle 6) at the RP2D]. At the RP2D, 37% of patients experienced at least one severe toxicity over the first six cycles in T2, and 78% in T3.Conclusions: Dedicated methods can be used to analyze toxicities from all cycles of treatment. They do not delay accrual and should be integrated in the analysis and reporting of phase I dose-finding trials.