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 EHA: RESULTS OF ASTRAL-1 STUDY, A PHASE 3 RANDOMIZED TRIAL OF GUADECITABINE (G) VS TREATMENT CHOICE (TC) IN TREATMENT NAÏVE ACUTE MYELOID LEUKEMIA (TN-AML) NOT ELIGIBLE FOR INTENSIVE CHEMOTHERAPY (IC)

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RESULTS OF ASTRAL-1 STUDY, A PHASE 3 RANDOMIZED TRIAL OF GUADECITABINE (G) VS TREATMENT CHOICE (TC) IN TREATMENT NAÏVE ACUTE MYELOID LEUKEMIA (TN-AML) NOT ELIGIBLE FOR INTENSIVE CHEMOTHERAPY (IC)

 

Background: Guadecitabine is a next generation hypomethylating agent (HMA) given subcutaneously (SC) which provides prolonged in vivo exposure to its active metabolite decitabine, thus offering potential clinical advantages over current HMAs. A multicenter phase 2 study reported a 38% CR rate, and a 54% composite CR (CR+CRp+CRi) rate using 5-day regimen at 60 mg/m2/d SC Q28 days in TN-AML not eligible for IC (Kantarjian et al, Lancet Oncology 2017). This led to ASTRAL-1 study, an international phase 3 randomized trial comparing guadecitabine to TC of azacitidine (AZA), decitabine (DEC) or Low Dose Ara-C (LDAC).
Aims: To report ASTRAL-1 study primary analyses results.
Methods: TN-AML not eligible for IC due to age ≥ 75 y or comorbidities including ECOG PS 3 were randomized 1:1 to either guadecitabine (60 mg/m2/d SC for 5-days Q28 days) or a preselected TC of AZA, DEC, or LDAC at standard regimens. AML diagnosis and response status were assessed by an independent central pathologist blinded to randomization assignment. CR and Overall Survival (OS) were co-primary endpoints.
Results: 815 patients were randomized to guadecitabine (408) or TC (407). Preselected TCs were DEC (43%), AZA (42%), and LDAC (15%). Baseline variables were balanced across the 2 arms. Median age 76 y for both arms, patients ≥75 y were 62% vs 62.4%, PS 2-3 in 50.5% vs 50.4% (including 10.8% vs 8.8% PS 3), poor risk cytogenetics 34.3% vs 34.6%, secondary AML 36.3% vs 36.9%, WBCs ≥20×109/L 15.2% vs 14.3%, and median BM blasts 56% vs 53% for G vs TC respectively. Median follow up was 25.5 m and median number of treatment cycles was 5 for both arms. Many patients (41.6%) received ≤ 3 cycles mainly due to early death or progression with no difference between the 2 arms (42.4% on G, and 40.8% on TC). The co-primary endpoints ITT analyses showed a CR rate of 19.4% vs 17.4% for G vs TC (p = 0.48). The median, 1-y, and 2-y survival were 7.1 m, 37%, and 18% for guadecitabine, and 8.4 m, 36%, and 14% for TC (Figure 1). OS HR was 0.91, 0.98, and 0.96 for G vs AZA, DEC, and LDAC respectively. Landmark survival analyses showed potential benefit of guadecitabine vs TC in patients who received >3 cycles (median, 1-y, and 2-y OS 15.6 m, 60% and 29% on guadecitabine vs 13 m, 52%, and 20% on TC; log-rank p value=0.02, HR 0.78, 95% CI 0.64-0.96), and those who achieved any CR (CR, CRp, or CRi): OS HR 0.72, 95% CI 0.50-1.05. Analyses of predefined clinical, cytogenetics, and molecular genetics variables assessed by PCR (Flt-3 ITD, CEBPA, NPM1, and TP53) did not show significant differences of primary outcomes between guadecitabine and TC in any subgroup except for TP53. Patients with identified baseline TP53 mutations did worse on G vs TC while those without identified TP53 mutations had a more favorable outcome on guadecitabine vs TC. Both treatment arms showed overall similar safety profiles with slightly higher but not significant serious AEs incidence (81% vs 75.5%) and Grade ≥ 3 AEs (91.5% vs 87.5%) on guadecitabine vs TC respectively. There was no difference in AEs leading to death (28.7% for guadecitabine vs 29.8% for TC).
Conclusions/Summary: The trial did not achieve its primary endpoints of statistically significant superiority of guadecitabine vs TC for CR or OS. However due to the large sample size and narrow 95% CI for OS difference, the trial suggests that G is an active drug with an overall similar efficacy and safety profiles to standard therapy. Potential benefit of guadecitabine vs TC was observed in patients who were able to receive adequate treatment (>3 cycles), and those who achieved any CR. The significance of TP53 mutations needs to be further explored.
Figure 1: Kaplan-Meier Survival Plot of guadecitabine vs TC

 

2019 EHA: ASTX660, a non-peptidomimetic antagonist of cIAP1/2 and XIAP, induces apoptosis in T cell lymphoma by enhancing immune mediated and death receptor dependent killing

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ASTX660, a non-peptidomimetic antagonist of cIAP1/2 and XIAP, induces apoptosis in T cell lymphoma by enhancing immune mediated and death receptor dependent killing

 

Abstract:

Background: ASTX660 is a potent, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which is currently being tested in a first in human phase I-II study in patients with advanced solid tumors and lymphomas (NCT02503423). IAP antagonists enhance tumor necrosis factor (TNF) receptor superfamily mediated apoptosis and are potent anti-tumor immune enhancers.

Aim: Herein, we describe the profile of ASTX660 in a range of T cell lymphoma (TCL) cell lines and evaluate ASTX660’s ability to enhance immune mediated killing of tumor cells.

Methods: A panel of human and mouse T-cell lymphoma cell lines were tested in proliferation (Alamar blue or CellTiterGlo) or apoptosis assays (activated caspase-3 substrate assays by IncuCyte or FACS) for sensitivity to ASTX660 alone or in combination with recombinant Death Receptor ligands (TNFa, FASL or TRAIL). Additionally, we used a novel co-culture system of tumor cell lines with anti-CD3 activated human peripheral blood mononuclear cells (PBMC) to assess ASTX660 effects on immune mediated cell killing. Target engagement and induction of apoptosis markers were analysed by Western blotting.

Results: ASTX660 antagonises IAPs in TCL cell lines, as indicated by a decrease in cIAP1 protein levels. This ASTX660-dependent decrease in cIAP was associated with an increase in TNFa-dependent apoptosis in the EL4 and L5178 TCL cell lines. Several T-cell lymphoma models, including HuT-78, HH and My-La expressed low levels of TNFR1 and therefore did not respond to ASTX660 in the presence of TNFa. However, in these cell lines, ASTX660 conferred a significant increase in FASL or TRAIL-dependent apoptosis, indicating that ASTX660 sensitises TCL cells to various death receptor ligands and response correlates with receptor expression levels. In addition to this direct effect on TCL cell lines, ASTX660 also enhances anti-CD3 stimulated PBMC-dependent killing of multiple tumour cell lines, including TCL lines, via induction of caspase activity. Additional preclinical experiments (both in vitro and in vivo) are underway to further characterise the mode of action of ASTX660 in TCL.

Conclusion: The combination of both direct and indirect effects of ASTX660 on TCL lines, described here, supports the ongoing clinical testing of ASTX660 in TCL (NCT02503423). Preliminary clinical efficacy and safety data of ASTX660 in relapsed/refractory (r/r) peripheral T cell lymphoma and cutaneous T cell lymphoma is the subject of a separate abstract.

 

2019 EHA: Preliminary Results of ASTX660, a Novel Non-Peptidomimetic cIAP1/2 and XIAP Antagonist, in Relapsed/Refractory Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma

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Background: ASTX660 is an oral, novel nonpeptidomimetic, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP). ASTX660 is currently being evaluated in a first-in-human phase 1‒2 study in patients (pts) with advanced solid tumors and lymphoma (ClinicalTrials.gov NCT02503423). In the phase 1 part of the study, the recommended phase 2 dose (RP2D) was identified with a favorable safety profile and initial evidence of clinical activity in a pt with mycoses fungoides (Mita et al, presented at the AACR-NCI-EORTC Conference 2017, abs #A091).

AIMS: Herein we report preliminary efficacy and safety data from the relapsed/refractory (r/r) peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) Phase 2 cohorts.

Methods: Pts receive treatment with ASXT660 at the RP2D 180mg/day on Days 1 to 7, and 15 to 22 in a 28-day cycle. The primary endpoint is response rate as assessed by the investigator according to either the Lugano criteria (PTCL) or Global Assessment (CTCL). Adverse events (AEs) are assessed per CTCAE V4.03.

Results: As of 15 January 2019, 16 PTCL pts and 13 CTCL pts have received ASTX660. Pt characteristics: median (range) age: PTCL: 59 (39-81) years and CTCL: 57 (23-75) years; median prior therapies: PTCL: 3 (1-7) and CTCL: 3 (1-9). In the PTCL cohort the ORR is 28% (4/14); 2 pts have yet to reach their first assessment. Three responding pts remain on study drug for 7-10 months. Responses have been observed in pts with AITL and PTCL-NOS. In the CTCL cohort the global response is 25% (3/12); 1 pt has yet to reach their first assessment. Two responding pts remain on study drug for 4-6 months. Responses have been seen in pts with large cell transformation, sezary syndrome and visceral metastases. Among all pts, the most common related AEs of any grade (≥ 15%) were lipase elevation (38%), amylase elevation (34%), ALT elevation (28%), elevation (24%) and rash (24%). Related AEs ≥ Grade 3 occurring in ≥3 pts were rash (n=5) and lipase elevation (n=4). Accrual continues; updated efficacy and safety data will be presented at the meeting.

Conclusion: In ongoing Phase 2 cohorts ASTX660 has shown activity against PTCL and CTCL with manageable safety profile. These early data support continued development of ASXT660 for the treatment of r/r PTCL and CTCL. Correlative studies are aimed at identifying predictors of response.

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Preliminary Results of ASTX660, a Novel Non-Peptidomimetic cIAP1/2 and XIAP Antagonist, in Relapsed/Refractory Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma

2019 EHA: Characterization of a novel, potent small molecule MDM2 antagonist which activates wild-type p53 and induces apoptosis in AML

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Background: In the presence of various stress signals, p53 acts as a tumor suppressor by regulating the expression of a multitude of genes to elicit cellular responses such as cell cycle arrest and apoptosis. The activity of p53 is tightly regulated by MDM2, an E3 ubiquitin ligase that acts as a primary inhibitor of p53 function by, for example, targeting p53 for proteasomal degradation. Early studies have demonstrated that blocking the MDM2-p53 interaction in tumors carrying wild-type p53 prevents p53 degradation and reactivates it. Small molecule MDM2 antagonists that inhibit the MDM2-p53 interaction, therefore, present a promising strategy for cancer therapy and a number of these compounds are in clinical development.
Aims: Herein, we describe the characterization of a novel, potent small molecule MDM2 antagonist in AML in vitro and in vivo pre-clinical models and in patient-derived AML blast cells.
Methods: A panel of p53 wild-type AML cell lines was tested for reduction in cell proliferation using Alamar Blue assay following treatment with the compound. Induction of apoptosis was measured by flow cytometry using a fluorescent caspase-3 substrate or Annexin V. Target engagement was analyzed by Western Blotting and TaqMan qRT-PCR. The MV-4-11 mouse systemic model was used to test in vivo sensitivity to the compound. Primary AML blasts were isolated from patients using combinations of antibodies against CD34, CD33, CD45, and CD117.
Results: We have applied structure-based design to develop a novel, potent, orally bioavailable MDM2 antagonist. The compound exhibits EC50 <1 nM against the full-length MDM2 protein in a cell-free ELISA and increases p53 levels in a wide range of p53 wild-type cells (e.g. EC50=10 nM for p53 induction in SJSA-1 osteosarcoma cells).
When tested in a panel of p53 wild-type AML cell lines, the compound exerted a strong anti-proliferative effect with GI50 values of <30 nM being observed in 9 out of 11 cell lines. In contrast, the compound had little effect on p53 mutant KG-1 cells (GI50 >10 M). In addition, many of the p53 wild-type AML cell lines showed a strong induction of apoptosis in response to treatment with the compound. Activation of p53 was evident by an increase in the expression of p53 and that of its well-known transcriptional targets such as p21 and MDM2. Consistent with these findings, a detailed study of gene expression changes in MV-4-11 confirmed clear transcriptional activation of several p53 target genes (CDKN1A, MDM2, BBC3, FAS, GADD45, BAX) 2-6 hours after addition of the compound.
In accordance with its potent activity in vitro, the compound displayed significant in vivo efficacy in the MV-4-11 mouse systemic model of AML. Here, QDx14 oral dosing at well tolerated doses demonstrated a clear reduction in tumor burden. Furthermore, p53 activation by the compound triggered apoptosis when tested in primary AML blast cells isolated from patients.
Summary/Conclusion: Taken together, our findings demonstrate that the compound exhibits potent activity against AML cells that retain wild-type p53, thus meriting further clinical investigations.

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Characterization of a novel, potent small molecule MDM2 antagonist which activates wild-type p53 and induces apoptosis in AML

2019 MDSF: Long Term Survival Results and Prognostic Factors Results of Higher Risk MDS and CMML treated with guadecitabine

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Long Term Survival Results and Prognostic Factors Results of Higher Risk MDS and CMML treated with guadecitabine

 

Abstract:

Background: Guadecitabine SC (SGI-110) is a dinucleotide next generation hypomethylating agent (HMA) resistant to degradation by cytidine deaminase resulting in extended in vivo exposure to its active metabolite decitabine.

 Methods: Int, or HR MDS, and CMML patients who were either treatment-naïve (TN) or relapsed/refractory (r/r) to other HMAs were randomized to either 60 mg/m2 or 90 mg/m2 QDx5 every 28 days.

 Results: We randomized 102 patients with a median follow up of 3.2 years: 53 to 60 mg/m2 and 49 patients to 90 mg/m2 QDx5. Of those, 53 patients were TN and 49 patients were r/r MDS/CMML. Median age was 71 and 72 years for TN MDS and r/r respectively. Most baseline patient characteristics were well balanced between the 2 treatment dose groups except that more CMML patients were randomized to the 60 mg/m2 group (28%) vs. 14% in the 90 mg/m2 group, and more patients with baseline BM blasts >5% were in the 90 mg/m2 group (67%) vs. 38% in the 60 mg/m2 group. Most patients were RBC transfusion-dependent at baseline (57%). In the r/r MDS cohort, most patients (77%) received ≥6 months of prior HMA treatment.

In the TN MDS cohort the median Overall Survival (OS) was 23.4 months (25.7 months for 60 mg/m2 dose group and 18.6 months for 90 mg/m2 dose group). In the r/r MDS cohort, the median OS was 11.7 months. No statistically significant difference in response or OS was observed between the 2 dose groups. In the overall population of 102 TN and r/r MDS patients there were no major differences in OS based on DNMT3A or TET2 mutation status while patients with TP53 mutations had worse median OS (7.4 months) compared to those without TP53 mutations (22.6 months). Other baseline prognostic factors associated with worse OS were BM blasts >5%; RBC transfusion-dependence; IPSS High Risk; and ECOG Performance Status of 2 or higher.

Conclusions: The median OS of 23.4 months (25.7 months for the 60 mg/m2 dose group) in TN MDS, and 11.7 months in r/r MDS signals a promising clinical activity of guadecitabine in the treatment of higher risk MDS/CMML. A phase 3 trial (ASTRAL-3) of guadecitabine vs Physician Treatment Choice in r/r MDS and CMML patients previously treated with other HMAs is actively enrolling (ClinicalTrials.gov ID: NCT02907359).

2018 EBF: Development and validation of an LC-MS/MS method for the simultaneous quantitation of cedazuridine (E7727), epimer of cedazuridine and decitabine in THU-stabilized K2EDTA human Plasma

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Summary

Abstract:

Cedazuridine is a novel cytidine deaminase inhibitor that inhibits the in vivo metabolic degradation of decitabine when administered orally in combination with decitabine (known as ASTX727) in clinical trials. Cedazuridine inhibits degradation of decitabine by inhibiting cytidine deaminase in the gut and liver thereby increasing oral bioavailability of decitabine. To support clinical trial pharmacokinetic studies for ASTX727, a sensitive LC-MS/MS method for the simultaneous quantitation of decitabine and cedazuridine, as well as the epimer of cedazuridine, in human plasma was developed and validated. Decitabine is known for its instability in human plasma over time as well as a previously observed chromatographic interference in certain subjects that was inseparable using reverse-phase chromatography. To stabilize decitabine, tetrahydrouridine (THU) was mixed with the human plasma samples. Chromatographic interference was resolved using normal phase chromatography. In-house synthesized stable-label internal standards for all three analytes were employed to ensure assay robustness. Stability of cedazuridine and cedazuridine-epimer were carefully evaluated and extensive experiments were conducted to ensure no inter-conversion occurs. As a result, a 3-in-1 method (single sample extraction) for the quantitation of cedazuridine, cedazuridine epimer and decitabine has been developed and fully validated. Protein precipitation (PPT) was used to extract all analytes from THU-stabilized human plasma samples. The analytes were separated on two different HPLC columns (reverse phase for cedazuridine and cedazuridine epimer and normal phase for decitabine). The method has been applied for clinical studies to evaluate the pharmacokinetics of cedazuridine, cedazuridine-epimer and decitabine in human.

 

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2018 ASTX727 Poster presented at EBF

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

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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