Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes

G Garcia-Manero, S D Gore, S Kambhampati, B Scott, A Tefferi, C R Cogle, W J Edenfield, J Hetzer, K Kumar, E Laille, T Shi, K J MacBeth, B Skikne, G Garcia-Manero, S D Gore, S Kambhampati, B Scott, A Tefferi, C R Cogle, W J Edenfield, J Hetzer, K Kumar, E Laille, T Shi, K J MacBeth, B Skikne

Abstract

CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half-life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300 mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31-87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2-24) for the 14-day dosing schedule and 6 (1-24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC-486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS.

Conflict of interest statement

GG-M has received research support from Celgene Corporation, and is a consultant for Celgene; SDG receives research support from and consults for the Celgene; SK declares no relevant conflicts of interest; B Scott has received research support from Celgene, and is a consultant and speaker for Celgene; AT declares no relevant conflicts of interest; CRC serves on the Scientific Advisory Board for the Connect MDS/AML Disease Registry study, which is sponsored by Celgene; WJE declares no relevant conflicts of interest; JH, KK, EL, TS, KJM and B Skikne are employees of, and own stock in, Celgene Corporation, Summit, NJ, USA.

Figures

Figure 1
Figure 1
Duration of CC-486 treatment and response. Gray bars indicate no response and green bars indicate a response.
Figure 2
Figure 2
(a) Mean (+s.d.) plasma concentration-vs-time profiles following SC azacitidine administration on days 1 and 7, and CC-486 300 mg once daily on days 1 and 14; and (b) Cumulative azacitidine exposure per cycle with extended CC-486 dosing regimens relative to azacitidine exposure with subcutaneous (SC) azacitidine 75 mg/m2 administered for 7 days. CC-486 480 mg/day was identified as the maximally tolerated dose (MTD).
Figure 3
Figure 3
(a) Kernel density plots of averaged genome-wide DNA methylation profiles across patients throughout the first treatment cycle. Shifts to the left from baseline (black line) represent overall reduction in methylation level. The x axis shows the percent of methylation on a locus and the y axis shows the density of loci at the different methylation levels; and (b) changes in global DNA methylation scores (GDMS) from baseline to day 28 (cycle end) in treatment cycle 1 vs clinical response. *Each dashed line represents one patient whereas the solid lines are the mean profiles of GDMS changes. The error bars represent one standard error away from the means. NR=no response; R=response. Response categories include overall response (complete remission (CR), any hematologic improvement (HI), RBC transfusion independence (TI) and platelet TI) and marrow CR (mCR). (*at any cycle of CC-486).

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