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Statistical controversies in clinical research: building the bridge to phase
II-efficacy estimation in dose-expansion cohorts
#MMPMID28200082
Boonstra PS
; Braun TM
; Taylor JMG
; Kidwell KM
; Bellile EL
; Daignault S
; Zhao L
; Griffith KA
; Lawrence TS
; Kalemkerian GP
; Schipper MJ
Ann Oncol
2017[Jul]; 28
(7
): 1427-1435
PMID28200082
show ga
BACKGROUND: Regulatory agencies and others have expressed concern about the
uncritical use of dose expansion cohorts (DECs) in phase I oncology trials.
Nonetheless, by several metrics-prevalence, size, and number-their popularity is
increasing. Although early efficacy estimation in defined populations is a common
primary endpoint of DECs, the types of designs best equipped to identify efficacy
signals have not been established. METHODS: We conducted a simulation study of
six phase I design templates with multiple DECs: three dose-assignment/adjustment
mechanisms multiplied by two analytic approaches for estimating efficacy after
the trial is complete. We also investigated the effect of sample size and interim
futility analysis on trial performance. Identifying populations in which the
treatment is efficacious (true positives) and weeding out inefficacious
treatment/populations (true negatives) are competing goals in these trials. Thus,
we estimated true and false positive rates for each design. RESULTS: Adaptively
updating the MTD during the DEC improved true positive rates by 8-43% compared
with fixing the dose during the DEC phase while maintaining false positive rates.
Inclusion of an interim futility analysis decreased the number of patients
treated under inefficacious DECs without hurting performance. CONCLUSION: A
substantial gain in efficiency is obtainable using a design template that
statistically models toxicity and efficacy against dose level during expansion.
Design choices for dose expansion should be motivated by and based upon expected
performance. Similar to the common practice in single-arm phase II trials, cohort
sample sizes should be justified with respect to their primary aim and include
interim analyses to allow for early stopping.
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