Application of a sequential multiple assignment randomized trial (SMART) design in older patients with chronic lymphocytic leukemia.

TitleApplication of a sequential multiple assignment randomized trial (SMART) design in older patients with chronic lymphocytic leukemia.
Publication TypeJournal Article
Year of Publication2019
AuthorsRuppert, A S., J Yin, M Davidian, A A. Tsiatis, J C. Byrd, J A. Woyach, and S J. Mandrekar
JournalAnn Oncol
Volume30
Issue4
Pagination542-550
Date Published2019 04 01
ISSN1569-8041
KeywordsAge Factors, Aged, Antineoplastic Combined Chemotherapy Protocols, Data Analysis, Disease Progression, Feasibility Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Progression-Free Survival, Randomized Controlled Trials as Topic, Research Design, Sample Size
Abstract

BACKGROUND: 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.DESIGN: 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.RESULTS: 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.CONCLUSION: 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.

DOI10.1093/annonc/mdz053
Alternate JournalAnn Oncol
Original PublicationApplication of a sequential multiple assignment randomized trial (SMART) design in older patients with chronic lymphocytic leukemia.
PubMed ID30799502
PubMed Central IDPMC6735877
Grant ListUG1 CA233331 / CA / NCI NIH HHS / United States
U10 CA180821 / CA / NCI NIH HHS / United States
U10 CA180882 / CA / NCI NIH HHS / United States
P01 CA142538 / CA / NCI NIH HHS / United States
R35 CA197734 / CA / NCI NIH HHS / United States