Schema of the adaptive parallel two-stage design. In the first stage of the design,
biomarker-negative (
NEG) subjects and
biomarker-positive (
POS) subjects are studied. If the number of responses to the drug in the biomarker-negative group in the first stage,
, meets or exceeds a cutoff of
, then
N un unselected subjects are accrued during the second stage. If
is less than
but the number of responses in the biomarker-positive group in the first stage,
, meets or exceeds a cutoff of
, then the design enrolls
additional biomarker-positive subjects during the second stage and no further biomarker-negative subjects are accrued. A total of
N + and
N − biomarker-positive and biomarker-negative subjects, respectively, will have been enrolled by the end of the second stage. A total of
(biomarker-positive group) and
(biomarker-negative group) responders will have been observed. To determine drug benefit, total responses
and
are compared against cutoffs
k + and
k − if unselected patients continued to be enrolled during the second stage or
is compared against the cutoff
if only biomarker-positive subjects were enrolled in the second stage. The trial stage- and group-specific samples sizes
,
,
N un,
and cutoffs
,
,
k −,
k +,
are determined so that they control the probability of correct conclusions in the biomarker-positive and unselected patient groups. Adapted from Jones CL and Holmgren E. An adaptive Simon two-stage design for phase 2 studies of targeted therapies. Contemp ClinTrials 2007:28;654–61, with permission from Elsevier.