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

Laille E, Shi T, Garcia-Manero G, Cogle CR, Gore SD, Hetzer J, Kumar K, Skikne B, MacBeth KJ - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Celgene Corporation, Summit, New Jersey, United States of America.

ABSTRACT

Unlabelled: 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.

No MeSH data available.


Related in: MedlinePlus

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.
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pone.0135520.g005: 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.

Mentions: The numbers of individual loci with methylation changes at each time point for each dosing regimen are shown in Table 4. The overlap of hypomethylated loci across regimens/times is shown in Fig 5. The greatest demethylation effect was observed on day 22 across treatment groups (Tables 3 and 4), with the exception of the 200 mg twice-daily 14-day schedule, in which no significantly hypomethylated loci were observed, potentially due to small sample size (n = 3). The number of loci with significantly reduced methylation at cycle end was greatest for the 200 mg twice-daily 21-day schedule, followed by the 300 mg once-daily 21-day and 14-day schedules, consistent with what was observed for GDMS changes. The extent and significance of local DNA methylation changes were also evaluated at select genes (S2 Table and S2 Fig). Methylation of CDKN2B and CDH1, genes previously reported for tracking the PD activity of hypomethylating agents, [33, 34] showed wide variation and predominantly low baseline methylation levels (averaged baseline methylation levels of all 10 CDKN2B loci and 6 of 8 CDH1 loci across patients were below 0.5), making them poor surrogates for the global hypomethylating effect of azacitidine. CDH1 locus cg24765079 was an exception, with significant methylation changes observed at all time-points post-treatment with both once-daily dosing schedules and with the 200 mg twice-daily 21-day schedule. Methylation changes in immune checkpoint genes (PD1/PDCD1, PDL1/CD274, PDL2/PDCD1LG2, and CTLA4) were also detected. The kinetics of methylation change in the top 5 CpG loci with the greatest hypomethylation following 21-dosing of CC-486 300 mg once daily (listed in S3 Table) are shown in S3 Fig; methylation changes in these 5 loci reflected global changes, as measured by GDMS (Fig 4).


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

Laille E, Shi T, Garcia-Manero G, Cogle CR, Gore SD, Hetzer J, Kumar K, Skikne B, MacBeth KJ - PLoS ONE (2015)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4546409&req=5

pone.0135520.g005: 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.
Mentions: The numbers of individual loci with methylation changes at each time point for each dosing regimen are shown in Table 4. The overlap of hypomethylated loci across regimens/times is shown in Fig 5. The greatest demethylation effect was observed on day 22 across treatment groups (Tables 3 and 4), with the exception of the 200 mg twice-daily 14-day schedule, in which no significantly hypomethylated loci were observed, potentially due to small sample size (n = 3). The number of loci with significantly reduced methylation at cycle end was greatest for the 200 mg twice-daily 21-day schedule, followed by the 300 mg once-daily 21-day and 14-day schedules, consistent with what was observed for GDMS changes. The extent and significance of local DNA methylation changes were also evaluated at select genes (S2 Table and S2 Fig). Methylation of CDKN2B and CDH1, genes previously reported for tracking the PD activity of hypomethylating agents, [33, 34] showed wide variation and predominantly low baseline methylation levels (averaged baseline methylation levels of all 10 CDKN2B loci and 6 of 8 CDH1 loci across patients were below 0.5), making them poor surrogates for the global hypomethylating effect of azacitidine. CDH1 locus cg24765079 was an exception, with significant methylation changes observed at all time-points post-treatment with both once-daily dosing schedules and with the 200 mg twice-daily 21-day schedule. Methylation changes in immune checkpoint genes (PD1/PDCD1, PDL1/CD274, PDL2/PDCD1LG2, and CTLA4) were also detected. The kinetics of methylation change in the top 5 CpG loci with the greatest hypomethylation following 21-dosing of CC-486 300 mg once daily (listed in S3 Table) are shown in S3 Fig; methylation changes in these 5 loci reflected global changes, as measured by GDMS (Fig 4).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Celgene Corporation, Summit, New Jersey, United States of America.

ABSTRACT

Unlabelled: 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.

No MeSH data available.


Related in: MedlinePlus