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 endpoints: 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), % 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. ClinicalTrials.gov NCT02103478.

Decitabine- and 5-azacytidine resistance emerges from adaptive responses of the pyrimidine metabolism network

“…Stated another way, doseescalations of decitabine or 5-azacytidine are not a solution for resistance since this compromises therapeutic-index: AML cells indefinitely self-replicate/proliferate and therefore have the opportunity to be educated for resistance from repeated treatment exposures, but normal myelopoiesis proliferates and terminally differentiates in successive waves-each wave is treatment naïve and vulnerable to offtarget anti-metabolite effects of high doses. The clinical tools to translate these preclinical observations are available, since combination formulations of decitabine with the CDA inhibitors THU or cedazuridine (a THU analog) are in clinical trials [4,40,53]; these oral drugs can produce lower decitabine C max but longer half-life than with approved intravenous regimens of decitabine, to deplete DNMT1 without cytotoxicity and facilitate frequent-distributed ingestion, as well as counter auto-upregulation of CDA [4,40].…”

Myelodysplastic syndromes: 2021 update on diagnosis, risk stratification and management

“…Three azanuclesoides are approved for MDS: 5‐azacitidine (azacitidine) 81 5‐aza‐2′‐deoxycitidine (decitabine) 82 and, in 2020, ASTX727 (decitabine and cedazuridine) 83 . Azacitidine is approved for all subsets of MDS, whereas decitabine is approved for those with intermediate‐1 disease and above.…”

“…Decitabine was studied in an initial randomized trial comparing it to BSC 82 . In this study, the dose of decitabine was 15 mg/m 2 IV infused over 3 hours every 8 hours for 3 days (at a dose of 135 mg/m 2 per course) and repeated every 6 weeks.…”

Clinical Management of Anemia in Patients with Myelodysplastic Syndromes: An Update on Emerging Therapeutic Options

“…In a recent phase 2 study, 80 patients with intermediate-1/2- or high-risk MDS or chronic myelomonocytic leukemia (CMML) were randomized to receive ASTX727 or IV decitabine, with crossover occurring in cycle 2. 103 Clinical responses were observed in 48 patients (60%) including 17 (21%) with complete response. The study showed that the efficacy, side effect profile, and systemic decitabine exposure of ASTX727 are similar to that of IV decitabine, and it was approved by the FDA in July 2020 for IPSS intermediate-1, intermediate-2, and high-risk MDS.…”