Sequential, Multiple Assignment, Randomized Trial Designs in Immuno-oncology Research

Abstract

Clinical trials investigating immune checkpoint inhibitors have led to the approval of anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4), anti-PD-1 (programmed death-1), and anti-PD-L1 (PD-ligand 1) drugs by the FDA for numerous tumor types. In the treatment of metastatic melanoma, combinations of checkpoint inhibitors are more effective than single-agent inhibitors, but combination immunotherapy is associated with increased frequency and severity of toxicity. There are questions about the use of combination immunotherapy or single-agent anti-PD-1 as initial therapy and the number of doses of either approach required to sustain a response. In this article, we describe a novel use of sequential, multiple assignment, randomized trial (SMART) design to evaluate immune checkpoint inhibitors to find treatment regimens that adapt within an individual based on intermediate response and lead to the longest overall survival. We provide a hypothetical example SMART design for BRAF wild-type metastatic melanoma as a framework for investigating immunotherapy treatment regimens. We compare implementing a SMART design to implementing multiple traditional randomized clinical trials. We illustrate the benefits of a SMART over traditional trial designs and acknowledge the complexity of a SMART. SMART designs may be an optimal way to find treatment strategies that yield durable response, longer survival, and lower toxicity. .

Quantitative Evidence Synthesis Methods for the Assessment of the Effectiveness of Treatment Sequences for Clinical and Economic Decision Making: A Review and Taxonomy of Simplifying Assumptions

“…loss of effectiveness, adverse events, non-adherence) might determine the average effectiveness for the next line of therapy, the reality is that this may also affect the choice of therapy for the next line. A tree structure is adopted in the SMART design, which is a multistage trial designed to develop and compare treatment pathways that are adapted over time based on individual’s response and/or adverse effects [ 28 ].…”

“…As the number of available treatments increases, the number of unique sequences will increase geometrically [ 4 , 25 ], making it impractical and prohibitively costly to evaluate all conceivable sequences in RCTs. The time-varying adaptive nature of many sequences also means that innovative and novel approaches, such as sequential multiple assignment randomised trials (SMARTs), are required for developing the dynamic treatment regimens [ 26 – 28 ]. RCTs of discrete treatments, used at single points in the treatment pathway, provide robust estimates of effectiveness for their specific context, but may not provide representative estimates for these treatments when used in different contexts, such as the later stages of sequences.…”

A technology-based intervention to improve safety, mental health and empowerment outcomes for immigrant women with intimate partner violence experiences: it’s weWomen plus sequential multiple assignment randomized trial (SMART) protocol

“…Compared to text, we hypothesize that the phone-based intervention will allow for more rapport building and personalized care through interaction with a trained interventionist using strengths-based motivational interviewing and solution focused approaches, so we expect an effect size in the small to moderate range (Cohen's d of .2-.4) when comparing the combination of text and phone to text only intervention arms. Interventions drawing from SMART design/SMART trials may be powered similar to a standard RCT, if stage-specific questions (e.g., comparison of first-stage interventions averaging over response and second-stage interventions) are of primary interest and embedded dynamic treatment regimen development is of secondary interest [44]. With power = 0.80, alpha = 0.05, and N = 253 per group, we will be able to detect significant differences in the change over time between the two groups when the effect size is 0.25 or greater.…”

Reinforcement Learning in Neurocritical and Neurosurgical Care: Principles and Possible Applications

“…SMART involves initial randomization of patients to possible treatment options, followed by rerandomizing the patients at each subsequent stage to other treatment options available at that stage. Examples of studies using SMART design (or its precursors) include the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for Alzheimer's disease [ 4 ], the Sequenced Treatment Alternatives to Relieve Depression (STARD) trial [ 5 ], a 2-stage trial designed to reduce mood and neurovegetative symptoms among patients with malignant melanoma [ 6 ], several trials that evaluated immune checkpoint inhibitors [ 7 ], and dynamic monitoring strategies based on CD4 cell counts [ 8 ]. In nonrandomized observational studies, Moodie et al extended this method to observational data in a breastfeeding research to investigate any breastfeeding habits' effect on verbal cognitive ability [ 9 ].…”