Pharmacokinetics and Pharmacodynamics with Extended Dosing of CC-486 in Patients with Hematologic Malignancies

Abstract

CC-486 (oral azacitidine) is an epigenetic modifier in development for patients with myelodysplastic syndromes and acute myeloid leukemia. In part 1 of this two-part study, a 7-day CC-486 dosing schedule showed clinical activity, was generally well tolerated, and reduced DNA methylation. Extending dosing of CC-486 beyond 7 days would increase duration of azacitidine exposure. We hypothesized that extended dosing would therefore provide more sustained epigenetic activity. Reported here are the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of CC-486 extended dosing schedules in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) or acute myeloid leukemia (AML) from part 2 of this study. PK and/or PD data were available for 59 patients who were sequentially assigned to 1 of 4 extended CC-486 dosing schedules: 300mg once-daily or 200mg twice-daily for 14 or 21 days per 28-day cycle. Both 300mg once-daily schedules and the 200mg twice-daily 21-day schedule significantly (all P < .05) reduced global DNA methylation in whole blood at all measured time points (days 15, 22, and 28 of the treatment cycle), with sustained hypomethylation at cycle end compared with baseline. CC-486 exposures and reduced DNA methylation were significantly correlated. Patients who had a hematologic response had significantly greater methylation reductions than non-responding patients. These data demonstrate that extended dosing of CC-486 sustains epigenetic effects through the treatment cycle.

Trial registration: ClinicalTrials.gov NCT00528983.

Conflict of interest statement

Competing Interests: EL, TS, JH, KK, BS, and KM are employed by Celgene Corporation and own Celgene stock. GG-M has received research support from Celgene Corp, and is a consultant and speaker for Celgene. SDG receives research support from and consults for the Celgene Corporation. CRC serves on the Scientific Advisory Board for the Connect MDS/AML Disease Registry study, which is sponsored by Celgene. This study was funded by Celgene Corporation. Sheila Truten and Brian Kaiser of MC2 provided editorial support, funded by Celgene. There are no patents or marketed products to declare. This paper describes data for a product in clinical development, CC-486. This does not alter the authors' adherence to all PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Study flow-chart.

Fig 2. Patient populations.

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.

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).

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.

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.