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

A. S. Ruppert, Jun Yin, M. Davidian, A. A. Tsiatis, J. C. Byrd, J. A. Woyach, Sumithra J Mandrekar

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)542-550
Number of pages9
JournalAnnals of oncology : official journal of the European Society for Medical Oncology
Volume30
Issue number4
DOIs
StatePublished - Apr 1 2019
Externally publishedYes

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B-Cell Chronic Lymphocytic Leukemia
Maintenance
PCI 32765
Residual Neoplasm
Sample Size
Disease-Free Survival
Therapeutics
obinutuzumab

Keywords

  • adaptive interventions
  • CLL
  • design strategies
  • randomized clinical trials
  • SMART

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Application of a sequential multiple assignment randomized trial (SMART) design in older patients with chronic lymphocytic leukemia. / Ruppert, A. S.; Yin, Jun; Davidian, M.; Tsiatis, A. A.; Byrd, J. C.; Woyach, J. A.; Mandrekar, Sumithra J.

In: Annals of oncology : official journal of the European Society for Medical Oncology, Vol. 30, No. 4, 01.04.2019, p. 542-550.

Research output: Contribution to journalArticle

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