cedazuridine decitabine Inqovi

Oral Cedazuridine/Decitabine For MDS And CMML: A Phase 2 Pharmacokinetic/Pharmacodynamic Randomized Crossover Study

Oral Cedazuridine/Decitabine For MDS And CMML: A Phase 2 Pharmacokinetic/Pharmacodynamic Randomized Crossover Study

In the August 6, 2020 publication of the Journal Blood, investigators reported on the utilization of oral cedazuridine / decitabine in myelodysplastic syndrome and chronic myelomonocytic leukemia.  

The study was a phase 2 trial, whose purpose was to compare systemic decitabine exposure, demethylation activity and safety during the first 2 cycles with cedazuridine at 100 mg plus decitabine 35 mg versus standard decitabine at 20 mg/m² intravenously.  Adults who had IPSS intermediate 1 and IPSS intermediate 2 or high risk myelodysplastic syndrome or chronic myelomonocytic leukemia, were randomized in a one-to-one fashion to oral doublet therapy or intravenous decitabine in cycle 1, followed by crossover to the other treatment of cycle 2.  All patients received oral doublet therapy in subsequent cycles.  The doublet therapy was given initially as separate capsules and a dose confirmation stage and then as a single fixed dose combination tablet.  There were 4 primary endpoints.  These included median decitabine systemic exposure (geometric least squares mean of oral or IV 5-day area under the curve from time 0 the last measurable concentration, percentage long interspersed nuclear element 1 DNA methylation for oral cedazuridine/decitabine versus intravenous decitabine, and clinical response.  

80 patients were randomized and offered treatment.  Oral and intravenous ratios of geometric least scores need 5-day areas under the curve last (80% confidence interval) were 93.5% and 97.6% for the dose confirmation and fixed dose combination stages, respectively.  Differences in the medium percent line 1 demethylation between oral and intravenous therapy were less </= 1%.  Clinical responses were observed in n=48 patients, 60%.  This included 21% of patients, n=17 patients with a complete response.  Grade 3 or higher adverse events were seen in up to 46% of patients.  Neutropenia was seen at 46%, thrombocytopenia 38% and febrile neutropenia 29%.  The authors concluded “oral Cedazuridine/decitabine (100mg/35 mg) produced similar systemic decitabine exposure, DNA methylation, and safety versus decitabine 20 mg/m² intravenous in the first 2 cycles, with similar efficacy.”