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 EORTC: Phase 1 study of the IAP inhibitor ASTX660 in adults with advanced cancers and lymphomas

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Summary
Due to their roles in the evasion of apoptosis, Inhibitor of Apoptosis Proteins (IAPs) are considered attractive targets for anti-cancer therapy. ASTX660 is a potent, next generation, non-peptidomimetic, dual antagonist of both XIAP and cIAP1, discovered using fragment-based drug design (1-3). We report here the results of the first-in-human phase 1 dose escalation and dose expansion study of ASTX660 administered orally to adults with advanced solid tumors and lymphoma.

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Phase 1 study of the IAP inhibitor ASTX660 in adults with advanced cancers and lymphomas

2017 ESH-AML: LINE-1 and P15 Demethylation May Predict Response to Guadecitabine

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Summary
Guadecitabine (formerly known as SGI-110) is a next-generation hypomethylating agent (HMA) composed of a dinucleotide of decitabine and deoxyguanosine (Figure 1). Guadecitabine is a dinucleotide resistant to degradation by cytidine deaminase (CDA) resulting in longer in vivo exposure to its active metabolite, decitabine, after a small volume ( ~ 1 mL) subcutaneous (SC) administration. A prospective phase 2 trial in 103 patients with relapsed or refractory AML (r/r AML) investigated 60 mg/m2 and 90mg/m2 doses in a 5-day regimen, and 60 mg/m2 in a 10-day regimen given every 28 days. In that trial, LINE-1 was used to measure general DNA demethylation and P15 gene promotor methylation was used to measure a specific tumor suppressor gene demethylation during Cycle 1 as potential markers of biological activity that may predict clinical response (See Trial Design in Figure 2).

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2017 ESH-AML: LINE-1 and P15 Demethylation May Predict Response to Guadecitabine

2017 ACCP: Population Pharmacokinetics Analysis for Guadecitabine (SGI-110) and Decitabine after Subcutaneous Dosing with SGI-110 in Patients with Relapsed/Refractory AML and MDS

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Summary
Guadecitabine is next-generation HMA formulated as a dinucleotide of decitabine and deoxyguanosine delivered as a low volume and pharmaceutically stable subcutaneous (SC) injection. In vivo conversion to active metabolite decitabine results in longer effective half-life and more extended decitabine exposure window than decitabine IV infusion. The differentiated PK profile may lead to improved biological and clinical activity and safety over currently available HMAs (Issa et al. Lancet Oncology 2015).
SGI-110-01 (NCT01261312) was a phase 1-2, dose escalation, multicenter study of subcutaneous regimens of SGI-110 in subjects with intermediate or high-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Several dosing regimens were tested. In regimen 1 and its phase 2 expansion, guadecitabine was administered daily for 5 days of a 28-day cycle. In regimens 2a and 2b, it was administered weekly or twice-weekly, respectively, for 3 weeks of a 28-day cycle. In another part of the phase 2 expansion, it was administered daily for 10 days (1-5 and 8-12) of a 28-day cycle.
The PK data included full concentration-time profiles of parent SGI-110 and its active metabolite, decitabine obtained after the first dose and after dose on day 5 (for regimen 1 and expansion), day 8 (for regimen 2a) or day 12 (for expansion 10-day regimen) of cycle 1.
The abstract reported results of the population PK analysis of data from 98 patients. Since the time the abstract was submitted, more data became available, and the model was updated. This poster describes the population PK modeling of data using an updated dataset from 124 patients.

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2017 ACCP: Population Pharmacokinetics Analysis for Guadecitabine (SGI-110) and Decitabine after Subcutaneous Dosing with SGI-110 in Patients with Relapsed/Refractory AML and 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 14th Intl. Symposium on MDS: Randomized Phase 2 Study of Guadecitabine in Patients with HMA-Naïve Higher Risk Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML)

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Summary
Guadecitabine (formerly SGI-110) is a next generation subcutaneous (SC) small volume dinucleotide HMA which results in prolonged in vivo exposure to active metabolite decitabine, and clinical activity reported in phase 1 in MDS and AML patients (Issa et al, Lancet Oncology 2015).

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2017 14th Int. Symposium in MDS: Randomized Phase 2 Study of Guadecitabine in Patients with HMA-Naïve Higher Risk Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML)

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

2016 ASH: Successful Emulation of IV Decitabine Pharmacokinetics with an Oral Fixed-Dose Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with Oral Decitabine, in Subjects with Myelodysplastic Syndromes (MDS): Final Data of Phase 1 Study

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Summary

Patients with International Prognostic Scoring System (IPSS) intermediate 1 and 2 (Int) and high risk (HR) MOS benefit from therapy with hypomethylating agents (HMAs) decitabine (DAC) and azacitidine (AZA). Treatment requires 5 or 7 daily parenteral doses every month while the patient is benefitting. An oral HMA taken at home would provide patient convenience, and potentially enhance adherence to treatment particularly for long-term responders. Neither DAC nor AZA is readily bioavailable in oral form due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDAi, is orally bioavailable with a large safety margin in preclinical models. We report here the final results of a Phase 1 study including an extension arm of a PK-guided first in human dose escalation trial of ASTX727 (the combination of oral DAC and E7727).

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2016 ASH: Successful Emulation of IV Decitabine Pharmacokinetics with an Oral Fixed-Dose Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with Oral Decitabine, in Subjects with Myelodysplastic Syndromes (MDS): Final Data of Phase 1 Study

2016 ASH: Genetic Determinants of Response to Guadecitabine (SGI-110) in AML

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Summary

Guadecitabine is a next generation hypomethylating drug with improved pharmacokinetics and pharmacodynamics compared to decitabine and demonstrated clinical activity in both treatment naïve (tn) and relapsed-refractory (rr) AML. Previous studies reported similar response rates to guadecitabine in different cytogenetic subsets but it remains unknown whether this extends to genetic changes.

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2016 ASH: Genetic Determinants of Response to Guadecitabine (SGI-110) in AML