Fig 1.
Study flow-chart.
Fig 2.
Patient populations.
Table 1.
Baseline demographics of patients with available PK and/or PD samples.
Fig 3.
Azacitidine plasma concentrations over time following CC-486 administration (200 mg and 300 mg doses) on the first day (day 1) and last day (day 14/21) of cycle 1.
(A) linear and (B) semi-log scales.
Table 2.
CC-486 PK parameters on day 1 and the last dosing day (day 14 or 21) of cycle 1.
Table 3.
Changes in global DNA methylation score (GDMS) with CC-486 in extended dosing schedules.
Fig 4.
Mean GDMS changes in cycle 1 following CC-486 administration in extended dosing schedules.
* (*Too few samples were available to evaluate GDMS changes over time with the CC = 486 200 mg twice daily x 14-day dosing regimen).
Table 4.
Numbers of significantly regulated genomic loci, by CC-486 dosing schedule.*
Fig 5.
Venn diagrams showing overlaps of significantly regulated genomic loci, by CC-486 dosing schedule.
Red numbers represent upregulated loci; green numbers represent down-regulated loci.
Table 5.
Top 20 biological pathways affected by CC-486 treatment (ranked in order of significance, assessed by Fisher’s exact test.
Additional significant pathways are shown in S4 Table.
Fig 6.
Correlation between azacitidine exposures and methylation changes.
(A) Azacitidine AUC at Cycle 1, Day 1 (ng*hr/mL) vs methylation change at Cycle 1, Day 15; (B) Extrapolated cumulative azacitidine AUC for Cycle 1 vs methylation change at Cycle 1, Day 22, and (C) vs methylation change at Cycle 1, Day 28 (cycle end).
Fig 7.
Changes in GDMS during cycle 1 by clinical response (any CC-486 treatment cycle).
Fig 8.
Changes in GDMS at cycle 2 end and cycle 3 end by clinical response (any CC-486 treatment cycle).
NR = no response; R = response. Response categories include complete remission (CR), any hematologic improvement (HI), HI-erythroid, HI-platelet, HI-neutrophil, RBC transfusion.