2017 ASH: A Phase 2 Dose-Confirmation Study of Oral ASTX727, a Combination of Oral Decitabine with a Cytidine Deaminase Inhibitor (CDAi) Cedazuridine (E7727), in Subjects with Myelodysplastic Syndromes (MDS)

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Summary

An oral hypomethylating agent which could be administered at a dose which would emulate parenteral pharmacokinetics would be more convenient and potentially enhance adherence to treatment. Heretofore, rapid clearance by cytidine deaminase (CDA) during first pass has prevented good oral bioavailability for decitabine (DAC). Cedazuridine (E7727), a novel CDAi, is orally bioavailable with a large safety margin and reproducible effectiveness in preclinical models. A phase I dose finding study found that a fixed oral combination of 35 mg of decitabine and 100 mg of E7727 (ASTX727 with 35 mg decitabine/100 mg cedazuridine (ASTX727 35/100 mg) should produce similar PK to decitabine administered intravenously at 20 mg/m2 as a 1-hour infusion.3 We tested this hypothesis in a phase 2 cross-over study, and report the preliminary results here.

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A Phase 2 Dose-Confirmation Study of Oral ASTX727, a Combination of Oral Decitabine with a Cytidine Deaminase Inhibitor (CDAi) Cedazuridine (E7727), in Subjects with Myelodysplastic Syndromes (MDS)

2017 ACOP8: Evaluation of Potential Doses and Regimens of an Oral Fixed Dose Combination of Cytidine Deaminase Inhibitor E7727 with Decitabine (ASTX727) to Minimize Decitabine-Mediated Neutropenia in Low-Risk MDS Subjects Using Systems Pharmacology Modeling

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Evaluation  of Potential Doses and Regimens of an Oral Fixed Dose Combination of Cytidine Deaminase Inhibitor E7727 with Decitabine (ASTX727) to Minimize Decitabine-Mediated Neutropenia in Low-Risk MDS Subjects Using Systems Pharmacology Modeling

Objectives: To simulate the effect of decitabine on neutrophils for optimization of dose and regimen(s) of an Oral Fixed-Dose Combination (ASTX727 Low Dose) of Cytidine Deaminase Inhibitor E7727 with Decitabine for treatment of subjects with Low-Risk myelodisplastic syndromes.

Methods: A quantitative systems pharmacology (QSP) model was previously developed describing myeloblasts cell cycle; leukemic blasts, neutrophils and platelets in physiological compartments (bone marrow and blood); PK of decitabine after IV infusion, after dosing with SQ guadecitabine (SGI-110) (dinucleotide of decitabine linked to deoxyguanosine) and oral ASTX727; LINE-1 demethylation; effect of decitabine on leukemic cells, neutrophils and platelets. Model parameters were identified against in vitro and clinical data. The effect of decitabine on neutrophils was calibrated against clinical data on neutrophil counts during treatment of AML patients with guadecitabine. The model was validated against clinical data on blast dynamics in blood and bone marrow of AML patients during treatment with guadecitabine.

Results: The model was succesfully calibrated and validated against various types of data. It succesfully reproduces clinical data on neutrophil count changes during treatment with guadecitabine. Simulations with different doses and regimens of low-dose ASTX727 administration were performed and the model predicts that neutrophil levels depend on dose and frequency of ASTX727.

2017 EHA: DOSE-CONFIRMATION STUDY OF ORAL ASTX727, A COMBINATION OF ORAL DECITABINE WITH A CYTIDINE DEAMINASE INHIBITOR (CDAI) E7727, IN SUBJECTS WITH MYELODYSPLASTIC SYNDROMES (MDS): PRELIMINARY RESULTS

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Summary
An oral hypomethylatingagent which could be administered in a dose which would emulate parenteral pharmacokinetics would be more convenient and potentially enhance adherence to treatment. Heretofore, rapid clearance by cytidine deaminase (CDA) during first pass has prevented oral administration.1E7727, a novel CDAi, is orally bioavailable with a large safety margin and reproducible effectiveness in preclinical models.2A phase I dose finding study found that a fixed oral combination of 35 mg of decitabine and 100 mg of E7727 (ASTX727) should produce similar pharmacokinetics (PK) to decitabineadministered intravenously at 20 mg/m2 as a 1-hour infusion (DAC IV).3We tested this hypothesis in a randomized cross-over study of DAC IV vs ASTX727 and report the preliminary results here.

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ASTX727_Poster_EHA_abst-E1192_Garcia-Manero_final.pdf

2017 ASCPT: Development of a Semi-Mechanistic PK/PD Model of an Oral Fixed Dose Combination (FDC) of Cytidine Deaminase Inhibitor E7727 with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes.

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Summary

ASTX727 is an oral Fixed Dose Combination of a novel and potent oral CDA inhibitor, E7727 with decitabine for the treatment of patients with MDS. Decitabine is an approved IV treatment of MDS that is rapidly degraded by cytidine deaminase resulting in poor and variable oral bioavailability. Low doses of oral decitabine co-administered with E7727 were shown to produce exposures similar to IV decitabine with acceptable inter-patient variability.

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2017 ASCPT: Development of a Semi-Mechanistic PK/PD Model of an Oral Fixed Dose Combination (FDC) of Cytidine Deaminase Inhibitor E7727 with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes