Pharmacokinetic- and Pharmacodynamic-Guided Phase 1 Study of an Oral Fixed-Dose Combination of Decitabine and the Cytidine Deaminase Inhibitor Cedazuridine in Myelodysplastic Syndromes

Background: Decitabine (DAC), a DNA methyltransferase 1 inhibitor/hypomethylating agent, is not readily orally bioavailable due to rapid clearance by cytidine deaminase in the gut/liver. This first-in-human pharmacokinetic/pharmacodynamic-guided dose-escalation study evaluated whether simultaneous oral administration with the novel cytidine deaminase inhibitor cedazuridine increases DAC bioavailability for myelodysplastic syndromes (MDS) therapy. Methods: In this phase 1 study, patients with MDS received escalating oral doses of DAC and cedazuridine. The primary objectives were to assess the safety of ASTX727, a combination of the two drugs, and to determine the dose of each drug needed to achieve a mean area under the curve (AUC) for DAC similar to that for iv DAC. Findings: Forty-four patients (43 evaluable) with previously treated or newly diagnosed MDS or chronic myelomonocytic leukemia were treated in five cohorts: cohorts 1-4 included six evaluable patients each; cohort 5 included 19 patients in a 13-patient expansion. Twenty patients (46%) had received prior hypomethylating agent therapy. Dose-dependent increases in DAC AUC and peak plasma concentration occurred with each cohort dose escalation. There was no evident increase in toxicity compared with that reported for iv DAC. Decitabine 30 or 40 mg with cedazuridine 100 mg produced mean day 5 DAC AUCs of 146 and 221 ng*h/mL, respectively, compared with a mean iv DAC AUC of 153-166 ng*h/mL. Long interspersed nuclear element-1 demethylation increased with dose. Thirteen patients (30%) had a clinical response, including five (12%) with a complete response, two with a marrow complete response, and six with hematologic improvement. Six patients remain on therapy.   Interpretation: Oral ASTX727 emulated the pharmacokinetics of iv DAC, with a similar safety profile and dose-dependent demethylation. Clinical responses were similar to iv DAC treatment for 5 days. Funding: Astex Pharmaceuticals, Inc. and StandUp2Cancer.   Declaration of Interest: MRS has received research support from Astex, Boehringer Ingelheim, Celgen, Gilead, Incyte, Millennium, Sunesis, and TG Therapeutics; has consulted for Astex, Celgene, Gilead, Incyte, Karyopharm, Millennium, Sunesis, and TG Therapeutics; and has equity in Karyopharm. OO has received research support from Astex. AbbVie, Agios, AstraZeneca, Celgene, CTI/Baxalta, Gilead, Incyte, Janssen, NS-Pharma, Oncotherapy, Sanofi, and S*Bio; has participated in advisory board meetings for AbbVie, Celgene, CTI/Baxalta, Dava Oncology, Incyte, Jazz, and Pfizer; and has received drug supply support from Pfizer. PCA has received research support from Astex. DPS has received research support from Celgene, H3 Biosciences, and Janssen; and has received personal fees from Janssen, Onconova, Sensei, and Takeda. AED, SF, and WH have nothing to declare. LCM has received research support from Jazz; has consulted for Incyte; has participated in a speakers bureau for Celgene; has participated in advisory board meetings for Novartis and TG Therapeutics; and has equity in Pfizer. HK has received research support from Astex, AbbVie, Agios, Amgen, Ariad, BMS, Cyclacel, Immunogen, Jazz, and Pfizer; has received honoraria from AbbVie, Agios, Amgen, Immongen, Orsinex, Pfizer, and Takeda; and has participated in advisory board meetings for Actinium. JL, AO, and MA are employees of Astex. GG-M has research support and honoraria from Astex/Otsuka. Ethical Approval: All patients provided written informed consent. The protocol was approved by the institutional review board at each participating institution.