2019 ACOP: A Semi-physiological Population Pharmacokinetic Model Developed Using Clinical Dose Escalation and Dose Confirmation Data for an Oral Fixed-Dose Combination of CDA Inhibitor Cedazuridine with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes

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A Semi-physiological Population Pharmacokinetic Model Developed Using Clinical Dose Escalation and Dose Confirmation Data for an Oral Fixed-Dose Combination of CDA Inhibitor Cedazuridine with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes

Abstract

Objectives:
Cytidine deaminase (CDA) rapidly degrades decitabine (DAC), an approved treatment for myelodysplastic syndromes, resulting in poor and variable bioavailability. Low doses of oral DAC co-administered with a novel and potent CDA inhibitor, cedazuridine (E7727), have been shown in clinic to produce exposures similar to IV DAC with acceptable inter-patient variability. The objective of this work was to further develop a semi-physiological population PK model ([1]) to characterize the PK enhancement of oral DAC when co-administered with cedazuridine and to identify potential covariates that impact the PK of DAC and/or cedazuridine.

Methods:
Model development utilized serial cedazuridine and DAC plasma concentration observations of IV DAC, oral DAC, and cedazuridine monotherapies and DAC+cedazuridine combinations. Observations from Phase 1/2 Study ASTX727-01 included dose escalation data (n=43; cohorts of 40:20, 60:20, 100:20, 100:40, and 100:30 mg cedazuridine:DAC with n=6 per cohort), dose confirmation data (n=42; 35:100 mg cedazuridine:DAC), and an FDC formulation extension (n=26). R was used for data processing, exploratory analysis, and visual predictive checks, while model development and parameter estimation utilized NONMEM. Covariate effects were explored using a full model approach.

Results:
Mono- and combination therapy data were sequentially integrated into a semi-physiological population PK model. Semi-physiological structural modeling elements included an IV DAC depot, oral DAC and cedazuridine transit compartment absorption, and portal vein, liver, central, and peripheral compartments. CDA metabolism of DAC primarily occurs in the liver compartment, with additional extra-hepatic metabolism. A maximum effect (Emax) inhibition model, dependent on local cedazuridine concentrations, described the drug effect of the oral ASTX727 combination therapy on CDA metabolism of DAC. IV DAC data were used to parameterize distribution and metabolism of DAC, while oral DAC monotherapy data was used to parameterize oral absorption. cedazuridine mono- and combination therapy data were used to parameterize cedazuridine PK parameters. Stratified individual-level random effects did not demonstrate systematic biases for any covariates, including weight-based effects.

Conclusions:
A semi-physiological population PK model was sequentially developed from mono- and combination therapy observations of plasma concentrations from the ASTX727-01 dose escalation and confirmation study. The analysis characterized the PK enhancement of oral DAC when co-administered with cedazuridine across a range of dose regimens and found no significant covariate effects, including weight-based effects. The resulting model will be used to interpret outcomes from an ongoing Phase 3 study (FDC ASTX727 of 35 mg DAC / 100 mg cedazuridine), while simulations will quantitatively inform future clinical development of ASTX727.

Savona et al., An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study

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Savona et al, “Savona et al., An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study”, The Lancet Haematology, Volume 6, Issue 4, e194 – e203  DOI:10.1016/S2352-3026(19)30030-4

Abstract

BACKGROUND:

Decitabine, a DNA methyltransferase 1 inhibitor or DNA hypomethylating compound, is not readily orally bioavailable because of rapid clearance by cytidine deaminase (CDA) in the gut and liver. This dose-escalation study, guided by pharmacokinetic and pharmacodynamic observations, evaluated whether simultaneous oral administration with the novel CDA inhibitor cedazuridine increases decitabine bioavailability for the treatment of myelodysplastic syndromes.METHODS:

In this phase 1 study, we enrolled patients aged 18 years or older with myelodysplastic syndromes or chronic myelomonocytic leukaemia. Eligible patients were assigned to cohorts to receive escalating oral doses of decitabine and cedazuridine. The starting dose was decitabine 20 mg and cedazuridine 40 mg. Treatment cycles lasted 28 days, with 5 days of drug administration. In cycle 1, each patient received a cohort-defined dose of oral decitabine on day -3, a 1-h intravenous infusion of decitabine 20 mg/m2 on day 1, and cohort-defined doses of oral decitabine plus cedazuridine on days 2-5. In cycles 2 and beyond, the oral decitabine and cedazuridine were given on days 1-5. The dose of cedazuridine was escalated first and decitabine was escalated once CDA inhibition by cedazuridine approached the maximum effect. The drug dose was escalated if mean decitabine area under the curve (AUC) of the oral drug was less than 90% of that for intravenous decitabine in the cohort and if no dose-limiting toxicity was observed. Dose-limiting toxicity was defined as a grade 3 or greater non-haematologic toxicity or grade 4 haematologic toxicity lasting more than 14 days and unrelated to the underlying disease. Once the decitabine AUC target range set as the primary endpoint, and established with intravenous decitabine, was reached at a dose deemed to be safe, the cohort that most closely approximated intravenous decitabine exposure was expanded to 18 evaluable patients. The primary objectives were to assess the safety of decitabine plus cedazuridine, and to determine the dose of each drug needed to achieve a mean AUC for decitabine exposure similar to that for intravenous decitabine exposure. This study is registered with ClinicalTrials.gov, number NCT02103478.

FINDINGS:

Between Oct 28, 2014, and Nov 13, 2015, we enrolled 44 eligible patients (of 75 screened) with previously treated or newly diagnosed myelodysplastic syndromes or chronic myelomonocytic leukaemia; 43 of the enrolled patients were evaluable. Participants were treated in five cohorts: cohorts 1-4 included six evaluable patients each; cohort 5 included 19 patients in a 13-patient expansion. Dose-dependent increases in decitabine AUC and peak plasma concentration occurred with each cohort dose escalation. There was no evident increase in toxicity compared with that reported for intravenous decitabine. Decitabine 30 mg and 40 mg plus cedazuridine 100 mg produced mean day-5 decitabine AUCs (146 ng × h/mL for decitabine 30 mg, and 221 ng × h/mL for decitabine 40 mg) closest to the mean intravenous-decitabine AUC (164 ng × h/mL). The most common grade 3 or more adverse events were thrombocytopenia (18 [41%] of 44 patients), neutropenia (13 [30%]), anaemia (11 [25%]), leukopenia (seven [16%]), febrile neutropenia (seven [16%]), and pneumonia (seven [16%]). Four (9%) patients died because of adverse events, none of which was considered drug related, and three (7%) patients died more than 30 days after discontinuing treatment because of progressive disease (two [5%]) and respiratory failure (one [2%]).

INTERPRETATION:

Oral decitabine plus cedazuridine emulated the pharmacokinetics of intravenous decitabine, with a similar safety profile and dose-dependent demethylation. Clinical responses were similar to intravenous decitabine treatment for 5 days. Further study of decitabine plus cedazuridine as an alternative to parenteral therapy or in combination with other new oral agents for myeloid disorders is warranted.

 

de Witte, Effective oral hypomethylating drugs in intermediate-risk or high-risk myelodysplasia: a breakthrough?

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“Effective oral hypomethylating drugs in intermediate-risk or high-risk myelodysplasia: a breakthrough?” The Lancet Haematology, Volume 6, Issue 4, PE170-E171, DOI 10.1016/S2352-3026(19)30025-0•

 

Curative treatment options for patients with intermediate-risk or high-risk myelodysplasia are intensive chemotherapy and allogeneic stem cell transplantation, but most patients with myelodysplasia are too frail to be treated with these demanding interventions because of advanced age and comorbidities. Alternative treatment approaches are either ineffective or result in short response durations with little survival benefit.

 

 

2019 ICTXV: Nonclinical Development of Cedazuridine, a Novel Cytidine Deaminase Inhibitor for use in Combination with Decitabine to Enable Oral Administration to Patients with Myelodysplastic Syndromes (MDS)

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Nonclinical Development of Cedazuridine, a Novel Cytidine Deaminase Inhibitor for use in Combination with Decitabine to Enable Oral Administration to Patients with Myelodysplastic Syndromes (MDS)

Abstract:

Cedazuridine (E7727) is a synthetic nucleoside analog derived from tetrahydrouridine (THU) and designed as a potent inhibitor of cytidine deaminase (CDA) with improved stability over THU. It is currently being developed in combination with hypomethylating agent decitabine (ASTX727) as an oral option for treatment of MDS and CMML. Concomitant administration of cedazuridine enhances oral bioavailability of decitabine and achieves therapeutic AUC exposures in the clinic at low doses of decitabine (similar to IV dose, in mg) that are well tolerated.

Nonclinical development of cedazuridine included full toxicological and DMPK evaluation. Cedazuridine is well tolerated in mice and monkeys (tox species) over 1-cycle of 7 days dosing, (followed by recovery), with NOAEL at 1000 mg/kg and 200 mg/kg, respectively. Subchronic studies of 13-weeks duration with multi-cycles (28 days/cycle with dosing on days 1-7) resulted in NOAEL of 100/300 mg/kg in mice (females/males) and 60 mg/kg in cynomolgus monkeys. The highest non-severely toxic dose (HNSTD) in multi-cycle study was 200 mg/kg/dose in monkeys. Target organs at the NOAEL were lymph nodes in mice and GI mucosa and bone marrow (RBC parameters) in monkeys. These dose levels offer a large safety margin over the clinical dose (and systemic exposures) used for cedazuridine (100 mg fixed dose, in combination with 35 mg decitabine). Cedazuridine in mouse in vivo micronucleus study was negative at up to 2000 mg/kg and was negative in in vitro Ames and chromosome aberration tests at concentrations that were not cytotoxic.

Co-administration with decitabine in mice and monkeys resulted in significant increase in systemic exposures compared with decitabine administered alone. Cedazuridine is metabolically stable in liver microsomes and hepatocytes, does not inhibit major human CYP enzymes, and is not a substrate and/or inhibitor of major human drug transporters. It does not accumulate in tissues and is excreted mainly renally. The main metabolite was its epimer, to which it partially converts in acidic environment in the stomach prior to absorption.

In summary, cedazuridine has been well characterized in nonclinical toxicology and DMPK studies and its nonclinical data profile supports late-stage clinical development.

2019 MDSF: Development of an oral hypomethylating agent (HMA) as a fixed dose combination (FDC) of decitabine and CDA inhibitor cedazuridine

Summary:

Background: Hypomethylating agents azacitidine and decitabine are not readily bioavailable orally due to their degradation in the gut and liver by CDA. We developed a selective, potent, and safe CDA inhibitor cedazuridine. The combination of cedazuridine with decitabine delivered orally as an FDC tablet is developed to achieve an equivalent AUC exposure to IV decitabine.

Methods: A phase 1-2 study was conducted in 124 patients eligible to receive IV decitabine. The phase 1 dose escalation (n=44 patients) established a recommended dose for both oral decitabine (35 mg), and cedazuridine (100 mg) likely to achieve a decitabine AUC exposure equivalent to decitabine IV at 20 mg/m2. The phase 2 (n=80 patients) was conducted using a randomized cross-over design comparing IV decitabine to oral ASTX727 to confirm intra-patient decitabine AUC exposure equivalence between standard IV decitabine and the selected ASTX727 FDC doses (35/100 mg decitabine/cedazuridine).

Results: In the phase 2 patients were randomized to either decitabine IV 20 mg/m2/d x5 or oral ASTX727 (decitabine/cedazuridine 35/100 mg/d) x5 Q 28 days in Cycle 1 and crossed over to the other arm in Cycle 2. All patients continued to receive oral ASTX727 from Cycle 3 onwards until progression or treatment discontinuation for other reasons. The median age was 69.7 years, median weight was 82.7 Kg (range 40-122), and median BSA was 1.99 m2 (range 1.3-2.4). The MDS-IPSS status of the patients was Int-1 in 44%, Int-2 in 24%, and HR in 11%, with 21% having CMML. No differences were observed between the 2 randomized arms. The decitabine AUC0-t (h*ng/mL) 5-Day geometric mean estimate was 745 from decitabine IV and 727 from the oral FDC tablet resulting in an oral/IV AUC ratio of 97.6% (80% CI of 80, 118%). Hypomethylating activity as measured by LINE-1 demethylation, and safety were comparable between decitabine IV and oral ASTX727 in the first 2 randomized cycles. Of note is the absence of grade 3 or higher GI AEs related to ASTX727. Overall response rate in the phase 2 population was 65% including 18% CR by the IWG 2006 MDS response criteria

Conclusions: ASTX727 FDC oral tablet at the selected doses (35/100 mg decitabine/cedazuridine) with no body weight or BSA adjustment achieved an equivalent decitabine AUC exposure to IV decitabine 20 mg/m2 over the 5-day cycle. LINE-1 demethylation and safety in the 2 randomized cycles were comparable and overall response rate was consistent with expected decitabine IV clinical response

 

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2019_ASTX727_Poster_MDSF_abst_MDSF19-0166_Garcia-Manero-Final