Application of a Sequential Multiple Assignment Randomized Trial (SMART) Design in Older Patients With Chronic Lymphocytic Leukemia

A. S. Ruppert; J. Yin; M. Davidian; A. A. Tsiatis; J. C. Byrd; J. A. Woyach; S. J. Mandrekar


Ann Oncol. 2019;30(4):542-550. 

In This Article

Abstract and Introduction


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.


Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia, with a median age of diagnosis of 72 years.[1] It is incurable outside of allogeneic stem cell transplant, which often is not an option for older patients.[2]

Ibrutinib is a Bruton's tyrosine kinase inhibitor approved by the US Food and Drug Administration as a first-line treatment of patients with CLL. In a randomized phase III study comparing ibrutinib to chlorambucil in older patients (RESONATE-2: NCT01722487), ibrutinib significantly extended progression-free survival (PFS) and overall survival (OS) (P < 0.01 for both end points).[3] Favorable long-term outcome of ibrutinib in previously untreated CLL patients was also observed in a pilot phase II study.[4]

Since response to therapy improves with longer duration of ibrutinib administration and the majority of patients achieve partial responses, ibrutinib currently follows a continuous dosing regimen until disease progression.[3,5] Ibrutinib combined with CD20 monoclonal antibodies such as rituximab and obinutuzumab is safe and is expected to be at least as effective as single-agent ibrutinib.[6,7] In a randomized phase III study comparing ibrutinib + rituximab versus ibrutinib alone versus bendamustine + rituximab in untreated older patients (Alliance for Clinical Trials in Oncology A041202: NCT01886872), both ibrutinib-based regimens significantly extended PFS (P < 0.01), but adding rituximab to ibrutinib did not significantly extend PFS compared with ibrutinib alone.[8] Whether or not results would be altered if adding a different CD20 antibody, such as obinutuzumab with ibrutinib, is undetermined.

Combining ibrutinib with additional targeted therapies will likely be required to achieve minimal residual negative disease with complete remission (MRD- CR) in a substantial number of patients to allow discontinuation of therapy.[8] Preclinical data suggest synergy between the B-cell lymphocyte 2 (Bcl-2) inhibitor venetoclax and ibrutinib.[9] Venetoclax as a single agent induces complete remission in 20% of patients with relapsed CLL,[10] and the combination of ibrutinib + venetoclax + obinutuzumab (IVO) is currently under investigation in the phase I/II setting in patients with relapsed/refractory CLL and in patients with treatment-naive CLL ( NCT02427451).

As part of Alliance A041702, a randomized phase III study in untreated older patients with CLL, clinical investigators had two treatment questions: (i) does limited front-line treatment with IVO and ibrutinib maintenance (IM) have superior PFS compared with limited front-line treatment with ibrutinib + obinutuzumab (IO) and IM and (ii) does the treatment strategy of IVO + IM for patients without MRD- CR and IVO + IM discontinuation for patients with MRD- CR have superior long-term PFS compared with IO + IM for all patients. To address both questions of interest in a single clinical trial design, a sequential multiple assignment randomized trial (SMART) design was considered.

A SMART design is a randomized clinical trial design for building adaptive interventions.[11] Adaptive interventions in which an individual's sequence of treatments depends on observed outcomes are also known as treatment policies, multi-stage treatment strategies, and dynamic treatment regimes. In a trial that uses a SMART design, each patient is randomly allocated to an initial treatment and subsequent treatments based on response, patient characteristics, or behaviors observed during the previous treatment. The intensity of the treatment can stay the same, increase, or decrease at each treatment decision time point depending on the goals of the individual study. Each treatment decision time point defines the beginning or ending of a treatment stage. The treatment options at each stage and the criteria on which randomizations are based determine a set of adaptive interventions said to be embedded in the SMART.

Trials with SMART designs are suitable for the discovery of which sequential treatments work better than stand-alone treatments and can be used to investigate the interplay between treatment strategies and disease development. The repeated randomizations in a SMART design ensures that patients assigned to each of the embedded treatment regimens are balanced in terms of both observed and unobserved patient characteristics. Data from a SMART design can be used to simultaneously address the effectiveness of treatments at each stage of the trial as well as the effectiveness of the overall embedded treatment regimens. Consistent with the aim of the SMART design, the data are analyzed across stages and not separately by stage when determining the optimal treatment strategy.

SMART design strategies have often been used in social and behavioral sciences studies.[12–15] Precursors to SMART design strategies could be seen in cancer clinical trials for the treatment of acute myeloid leukemia (AML),[16] small-cell lung carcinoma,[17] neuroblastoma,[18,19] and prostate cancer[20] but were not designed to analyze embedded treatment regimens. In each of these trials, patients were randomized to an initial therapy and, depending on response, re-randomized to a subsequent therapy. Results from the AML and small-cell lung carcinoma trials were reported separately for each stage, where all patients were included in the analysis of response before re-randomization, but only small subgroups of patients achieving remission were included in the analysis of patient outcomes post re-randomization. Results from the neuroblastoma trial were reported on subgroups of patients following a particular treatment sequence and showed survival differences between treatment sequences. The data have since been re-analyzed using all patients with statistical methods for comparing embedded treatment regimens and showed no survival differences among any of the embedded treatment regimens.[18,19,21] Results for the prostate cancer trial were initially reported using stage-specific analyses for 12 different treatment sequences (four first-stage treatments, and three second-stage treatments) and were reported across stages by defining overall treatment success as two consecutive favorable courses of therapy on patients with complete information. Data from this trial were re-analyzed, using all patients and with statistical methods for comparing embedded treatment regimens, with fairly consistent results.[20,22]

A recent SMART has been prospectively designed for patients with metastatic malignant melanoma.[23] In the first stage, patients will be randomized to one of two neurobehavioral therapies. If initial therapy is favorable, patients will continue on the same therapy. If initial therapy is unfavorable using a depression score, patients will either augment therapy or switch to the other drug. The analysis will compare embedded treatment regimens defined by the four different treatment paths an individual patient could take, with adherence rate to 12 weeks of therapy as the primary end point.

In general, there have been few cancer trials prospectively designed as a SMART in which the primary aim is to compare embedded treatment regimens.[21] There is a need to share information regarding the design, implementation, and analysis of cancer trials using SMART designs, particularly with time-to-event end points, which have not been well-represented in prospective SMART design analysis strategies. For this reason, we describe a SMART design approach considered for Alliance A041702, which compares PFS between embedded treatment regimens in the disease setting of CLL.