Division of Hematology, The Ohio State University, Columbus; Alliance Statistics and Data Center, The Ohio State University, Columbus.
Alliance Statistics and Data Center, Mayo Clinic, Rochester.
Ann Oncol. 2019 Apr 1;30(4):542-550. doi: 10.1093/annonc/mdz053.
Ibrutinib therapy is safe and effective in patients with chronic lymphocytic leukemia (CLL). Currently, ibrutinib is administered continuously until disease progression. Combination regimens with ibrutinib are being developed to deepen response which could allow for ibrutinib maintenance (IM) discontinuation. Among untreated older patients with CLL, clinical investigators had the following questions: (i) does ibrutinib + venetoclax + obinutuzumab (IVO) with IM have superior progression-free survival (PFS) compared with ibrutinib + obinutuzumab (IO) with IM, and (ii) does the treatment strategy of IVO + IM for patients without minimal residual disease complete response (MRD- CR) or IVO + IM discontinuation for patients with MRD- CR have superior PFS compared with IO + IM.
Conventional designs randomize patients to IO with IM or IVO with IM to address the first objective, or randomize patients to each treatment strategy to address the second objective. A sequential multiple assignment randomized trial (SMART) design and analysis is proposed to address both objectives.
A SMART design strategy is appropriate when comparing adaptive interventions, which are defined by an individual's sequence of treatment decisions and guided by intermediate outcomes, such as response to therapy. A review of common applications of SMART design strategies is provided. Specific to the SMART design previously considered for Alliance study A041702, the general structure of the SMART is presented, an approach to sample size and power calculations when comparing adaptive interventions embedded in the SMART with a time-to-event end point is fully described, and analyses plans are outlined.
SMART design strategies can be used in cancer clinical trials with adaptive interventions to identify optimal treatment strategies. Further, standard software exists to provide sample size, power calculations, and data analysis for a SMART design.
伊布替尼疗法在慢性淋巴细胞白血病（CLL）患者中安全且有效。目前，伊布替尼持续给药直至疾病进展。正在开发伊布替尼联合方案以加深缓解，从而可以停止伊布替尼维持（IM）。在未经治疗的老年 CLL 患者中，临床研究者有以下问题：（i）伊布替尼+维奈托克+奥妥珠单抗（IVO）联合 IM 与伊布替尼+奥妥珠单抗（IO）联合 IM 相比，是否具有更高的无进展生存期（PFS），以及（ii）对于无微小残留病灶完全缓解（MRD-CR）的患者，IVO+IM 治疗策略或对于有 MRD-CR 的患者停止 Ivo+IM，与 IO+IM 相比，是否具有更高的 PFS。
常规设计将患者随机分配至 IO+IM 或 IVO+IM 以解决第一个目标，或随机分配患者至每种治疗策略以解决第二个目标。提出了序贯多重分配随机试验（SMART）设计和分析方法来解决这两个目标。
当比较自适应干预措施时，SMART 设计策略是合适的，自适应干预措施是由个体的治疗决策序列定义的，并由中间结果（如治疗反应）指导。提供了对 SMART 设计常见应用的综述。具体针对先前考虑用于 Alliance 研究 A041702 的 SMART 设计，介绍了 SMART 的一般结构，充分描述了当比较 SMART 中嵌入的自适应干预措施与时间事件终点时，比较自适应干预措施的样本量和功效计算方法，并概述了分析计划。
SMART 设计策略可用于具有自适应干预措施的癌症临床试验，以确定最佳治疗策略。此外，标准软件可用于提供 SMART 设计的样本量、功效计算和数据分析。
