TY - JOUR
T1 - A review of phase II trial designs for initial marker validation
AU - Mandrekar, Sumithra J.
AU - An, Ming Wen
AU - Sargent, Daniel J.
N1 - Funding Information:
Mandrekar and Sargent: National Cancer Institute Grant Nos CA-15083 (Mayo Clinic Cancer Center) and CA-25224 (North Central Cancer Treatment Group).
PY - 2013/11
Y1 - 2013/11
N2 - Phase II clinical trials aim to identify promising experimental regimens for further testing in phase III trials. In this review article, we focus on phase II designs for initial predictive biomarker validation to determine if a drug should be developed for an unselected patient population or for a biomarker-defined patient subset only. Several prospective designs for biomarker-directed therapy have been proposed, differing primarily in the study population, or randomization scheme, or both. The design choice is driven by scientific rationale, marker prevalence, strength of preliminary evidence, assay performance, and turn-around times for marker assessment. The enrichment design is most appropriate when compelling preliminary evidence suggests treatment benefit in only certain marker-defined subgroups, the all-comers design is useful when preliminary evidence regarding treatment effects in marker subgroups is unclear, and adaptive designs have the most potential in the setting of multiple treatment options and multiple marker-defined subgroups. We recently proposed a 2-stage phase II design that has the option for direct assignment (i.e., stop randomization and assign all patients to the experimental arm in stage 2) based on interim analysis (IA) results. This design not only recognizes the need for randomization but also acknowledges the possibility of promising but inconclusive results after pre-planned IA. Simulation studies demonstrated that the direct assignment-option design has minimal power loss, marginal increase in type I error rates, and reasonable robustness to population shift effects. Systematic evaluation and implementation of these design strategies in the phase II setting are essential for accelerating the clinical validation of biomarker guided-therapy.
AB - Phase II clinical trials aim to identify promising experimental regimens for further testing in phase III trials. In this review article, we focus on phase II designs for initial predictive biomarker validation to determine if a drug should be developed for an unselected patient population or for a biomarker-defined patient subset only. Several prospective designs for biomarker-directed therapy have been proposed, differing primarily in the study population, or randomization scheme, or both. The design choice is driven by scientific rationale, marker prevalence, strength of preliminary evidence, assay performance, and turn-around times for marker assessment. The enrichment design is most appropriate when compelling preliminary evidence suggests treatment benefit in only certain marker-defined subgroups, the all-comers design is useful when preliminary evidence regarding treatment effects in marker subgroups is unclear, and adaptive designs have the most potential in the setting of multiple treatment options and multiple marker-defined subgroups. We recently proposed a 2-stage phase II design that has the option for direct assignment (i.e., stop randomization and assign all patients to the experimental arm in stage 2) based on interim analysis (IA) results. This design not only recognizes the need for randomization but also acknowledges the possibility of promising but inconclusive results after pre-planned IA. Simulation studies demonstrated that the direct assignment-option design has minimal power loss, marginal increase in type I error rates, and reasonable robustness to population shift effects. Systematic evaluation and implementation of these design strategies in the phase II setting are essential for accelerating the clinical validation of biomarker guided-therapy.
KW - Adaptive design
KW - All-comers design
KW - Biomarker
KW - Direct assignment
KW - Enrichment design
KW - Interim analysis
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U2 - 10.1016/j.cct.2013.05.001
DO - 10.1016/j.cct.2013.05.001
M3 - Article
C2 - 23665336
AN - SCOPUS:84888132659
SN - 1551-7144
VL - 36
SP - 597
EP - 604
JO - Contemporary Clinical Trials
JF - Contemporary Clinical Trials
IS - 2
ER -