Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study

Abstract

This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage and then as a single fixed-dose combination (FDC) tablet. Primary end points: mean decitabine systemic exposure (geometric least-squares mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), percentage long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1-106.5) and 97.6% (80.5-118.3) for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35 mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar efficacy. This study is registered at www.clinicaltrials.gov as #NCT02103478.

Conflict of interest statement

Conflict-of-interest disclosure: G.G.-M. has received research funding and honoraria from Astex/Otsuka. E.A.G. has consulted for Astex, AbbVie, Boston Scientific, Celgene, New Link Genetics, Novartis, Otsuka, Palmer, and Persimmune; has received research funding from Astex, Celgene, Genentech, and Otsuka; and has served as Principal Investigator on clinical trials for Appelis and Onconova. D.P.S. has received research funding from Celgene, H3 Biosciences, and Janssen; and has received personal fees from Janssen, Onconova, Sensei, and Takeda. G.J.R. has consulted or served on advisory boards or data and safety monitoring committees for Astex, AbbVie, Actinium, Agios, Amphivena, Argenx, Astellas, Bayer, Celgene, Celltrion, Daiichi Sankyo, Eisai, Janssen, Jazz, MEI, Novartis, Orsenix, Otsuka, Pfizer, Roche/Genentech, Sandoz, Takeda, and Trovagene; and has received research support from Cellectis. R.W. has received honoraria and research funding from Alexion, Celgene, and Novartis. O.O. has received research funding from Astex. AbbVie, Agios, AstraZeneca, Celgene, CTI/Baxalta, Gilead, Incyte, Janssen, NS-Pharma, Oncotherapy, Sanofi, and S*Bio; has served on advisory boards for AbbVie, Celgene, CTI/Baxalta, Dava Oncology, Incyte, Jazz, and Pfizer; and has received drug supply support from Pfizer. K.Y. has received research funding from Astex, MedImmune, Millennium, MSD, and Roche/Genentech; has received honoraria from Novartis and Pfizer; and has served on boards of directors or advisory committees for Astellas, Celgene, Novartis, Pfizer, and Takeda. L.B. has consulted for BMS, Novartis, Paladin, and Pfizer; and has received royalties for patents from ExCellThera. C.O. has served on boards of directors or advisory committees for Astex, BMS, Pfizer, and Shionogi; and has received research funding from Astex and Genentech. L.C.M. has received research funding from Jazz; has consulted for Incyte; has served on a speakers bureau for Celgene; has served on advisory boards for Novartis and TG Therapeutics; and has equity in Pfizer. J.B. has consulted for and received honoraria from Celgene, Jazz, Novartis, and Pfizer; has received honoraria from Otsuka; and has received research funding from Celgene, Pfizer, and Roche. H.K. has received research funding from Astex, AbbVie, Agios, Amgen, Ariad, BMS, Cyclacel, Immunogen, Jazz, and Pfizer; has received honoraria from AbbVie, Agios, Amgen, Immunogen, Orsinex, Pfizer, and Takeda; and has served on advisory boards for Actinium. A.O. and M.A. are employees of Astex. M.R.S. has received research funding from Astex, Incyte, Millennium, and TG Therapeutics; has consulted for Astex, Celgene, BMS, Incyte, Karyopharm, Millennium, Ryvu, Sierra Oncology, and TG Therapeutics; and has equity in Karyopharm and a licensed patent from Boehringer Ingelheim. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Patient disposition. Six patients did not receive study treatment, including 2 who became ineligible because of elevated liver enzymes, 1 with progressive disease, 1 who died, 1 misdiagnosed, and 1 who withdrew consent after randomization and before start of treatment.

Figure 2.

Mean decitabine plasma concentrations-time profiles following single and multiple oral doses of cedazuridine/decitabine, and following single IV infusion of decitabine during dose confirmation and fixed-dose combination stages. (A-B) Linear and (C-D) semilogarithmic plots are shown. LLOQ, lower limit of quantitation.

Figure 3.

Time to first response and time to best response by cycle (N = 80). HI, hematologic improvement; mCR, marrow complete response.

Figure 4.

Kaplan-Meier survival by sequence and overall.