Abstract B217: A Phase I study of CC-486 (oral azacitidine) to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of azacitidine administered alone and in combination with carboplatin or ABI-007 (NAB-paclitaxel) in subjects with solid tumors.
Authors: Laille Eric , Nguyen Aaron N. , Chen Gengxi , Rasco Drew , LoRusso Patricia , Von Hoff Daniel D. , Bendell Johanna , Munster Pamela , Edenfield William J. , Ramanathan Ramesh , Gonzalez Michael B. , Blackwood-Chirchir Anne , DiMartino Jorge 
Published: August 2014

Abstract
Background: CC-486 is an orally bioavailable formulation of azacitidine that has demonstrated clinical activity in subjects with Myelodysplastic Syndromes (MDS) and Acute Myleoid Leukemia (AML). In these patient populations, CC-486 in extended dosing regimens, 200 mg and 300 mg given daily on a 14 or 21 out of 28-day schedule, induces sustained global genomic hypomethylation.
Methods: This Phase I, multicenter, open-label study was conducted in subjects with solid tumors to evaluate: 1) the effect of carboplatin or ABI-007 on the PK of CC-486; 2) the effect of CC-486 on the PK of carboplatin or ABI-007; and 3) the PD (DNA methylation) effects of CC[[Unable to Display Character: &#8209;]]486 as a single agent and in combination with carboplatin or ABI-007. Safety and efficacy information of this trial are presented in a separate abstract submission.
Subjects received CC-486 on Days 1-14 with carboplatin AUC 4 on Day 8 of a 21-day cycle (Arm A), CC-486 on Days 1-14 with ABI-007 100 mg/m2 given weekly starting on Day 8 of a 21-day cycle (Arm B), or CC-486 on Days 1-21 of a 21-day cycle (Arm C).
Results: High inter-subject variability was observed in PK concentrations and parameters. In subjects from Arms A and B, following administration of CC-486 alone or in combination with carboplatin or ABI-007, CC-486 was rapidly absorbed and reached Tmax within approximately 1.0 hour post-dose (median); azacitidine PK parameters (AUC, Cmax, half-life elimination, apparent clearance, and volume of distribution) were comparable following administration of CC-486 alone or in combination. Similarly, carboplatin and ABI-007 PK parameters were similar following administration of carboplatin or ABI-007 alone or in combination with CC-486. In subjects from the 3 Arms, global genomic hypomethylation was observed in PBMCs, with maximum effect on Day 15. A PK/PD (AUC/hypomethylation change on Day 15) correlation was noted (r&gt;0.5; p&lt;0.01).
Conclusion: Carboplatin and ABI-007 had minimal to no effect on CC-486 PK parameters, and vice-versa. Following administration of CC-486, global genomic hypomethylation was correlated with plasma AUC.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B217.
Citation Format: Eric Laille*, Aaron N. Nguyen*, Gengxi Chen, Drew Rasco, Patricia LoRusso, Daniel D. Von Hoff, Johanna Bendell, Pamela Munster, William J. Edenfield, Ramesh Ramanathan, Michael B. Gonzalez, Anne Blackwood-Chirchir, Jorge DiMartino. A Phase I study of CC-486 (oral azacitidine) to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of azacitidine administered alone and in combination with carboplatin or ABI-007 (NAB-paclitaxel) in subjects with solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B217.