Ferraris et al., “Design, Synthesis, and Pharmacological Evaluation of Fluorinated Tetrahydrouridine Derivatives as Inhibitors of Cytidine Deaminase.” Journal of Medicinal Chemistry, 2014

Abstract:

Several 2′-fluorinated tetrahydrouridine derivatives were synthesized as inhibitors of cytidine deaminase (CDA). (4R)-2′-Deoxy-2′,2′-difluoro-3,4,5,6-tetrahydrouridine (7a) showed enhanced acid stability over tetrahydrouridine (THU) 5 at its N-glycosyl bond. As a result, compound 7a showed an improved oral pharmacokinetic profile with a higher and more reproducible plasma exposure in rhesus monkeys compared to 5. Co-administration of 7a with decitabine, a CDA substrate, boosted the plasma levels of decitabine in rhesus monkeys. These results demonstrate that compound 7a can serve as an acid-stable alternative to 5 as a pharmacoenhancer of drugs subject to CDA-mediated metabolism.

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Ferraris et al., “Design, Synthesis, and Pharmacological Evaluation of Fluorinated Tetrahydrouridine Derivatives as Inhibitors of Cytidine Deaminase.” J.MedChem. ,2014, 57 (6), pp 2582–2588 DOI: 10.1021/jm401856k

 

 

2018: ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNFα-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth.

Abstract

Because of their roles in the evasion of apoptosis, inhibitor of apoptosis proteins (IAP) are considered attractive targets for anticancer therapy. Antagonists of these proteins have the potential to switch prosurvival signaling pathways in cancer cells toward cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single-agent efficacy. ASTX660 is a potent, non-peptidomimetic antagonist of cIAP1/2 and XIAP, discovered using fragment-based drug design. The antagonism of XIAP and cIAP1 by ASTX660 was demonstrated on purified proteins, cells, and in vivo in xenograft models. The compound binds to the isolated BIR3 domains of both XIAP and cIAP1 with nanomolar potencies. In cells and xenograft tissue, direct antagonism of XIAP was demonstrated by measuring its displacement from caspase-9 or SMAC. Compound-induced proteasomal degradation of cIAP1 and 2, resulting in downstream effects of NIK stabilization and activation of noncanonical NF-κB signaling, demonstrated cIAP1/2 antagonism. Treatment with ASTX660 led to TNFα-dependent induction of apoptosis in various cancer cell lines in vitro, whereas dosing in mice bearing breast and melanoma tumor xenografts inhibited tumor growth. ASTX660 is currently being tested in a phase I–II clinical trial (NCT02503423), and we propose that its antagonism of cIAP1/2 and XIAP may offer improved efficacy over first-generation antagonists that are more cIAP1/2 selective. Mol Cancer Ther; 17(7); 1–11. ©2018 AACR.

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Ward et al. “ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNFα-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth.” Mol Cancer Ther. June 14, 2018, doi: 10.1158/1535-7163.MCT-17-0848

2017 ASH: Predictors of Response and Survival in 206 AML Patients Treated with Guadecitabine in a Phase 2 Study

Summary
Background: Guadecitabine is a next generation hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a prospective phase 2 study testing different schedules of guadecitabine in 206 AML patients. We present here the results of multiple logistic regression, and Cox regression analyses of predictors of composite Complete Response or CRc (CR+CRp+CRi) and overall survival (OS).

Methods: Multiple logistic regression analysis of response (CRc), and Cox regression analysis of OS were conducted with inclusion of the following baseline variables: disease state (relapsed/refractory (r/r) vs. treatment naïve (TN) AML); guadecitabine schedule (10day vs. 5day); age (<75 vs. ≥75); ECOG PS (01 vs. ≥2); Cytogenetics (others vs. poor risk); baseline BM blasts (≤40% vs. >40%); baseline Peripheral blood (PB) blasts (≤30% vs. >30%); baseline WBCs count (<20,000/μL vs. ≥20,000/μL); Flt3 ITD, NPM, and TP53 mutations (each present vs. not detected). Cutoff values for blasts % for BM and PB were chosen based on the median or mean values respectively, and cutoff value for WBCs count was chosen as a common cutoff used for proliferative AML. Backward elimination method with alpha =0.05 was used to reach the final models.

Results: We treated 206 AML patients (103 patients each for TN or r/r AML); 101 with 5day schedule and 105 with 10day schedule. There were 91 patients (44%) ≥75 y; 53 (26%) with ECOG PS≥2; 85 (41%) with poor risk cytogenetics; 99 (48%) with baseline BM blasts >40%; 65 (32%) with baseline PB blasts >30%; 20 (9.7%) with WBCs ≥20,000/μL. Flt3, NPM, and TP53 mutations were present in 8%, 9%, and 4% of patients respectively. The final logistic regression model indicated that patients with ECOG PS 01 and those with baseline PB blasts ≤ 30% have twofold higher odds of response than those with ECOG PS ≥2 and PB blasts >30% (Odds ratio 2.18; and 2.03 respectively; p<0.05 for both). Patients with TN AML had fivefold higher odds of response to guadecitabine than r/r AML (Odds ratio of response for r/r AML 0.22; p <0.0001). The final Cox regression model showed that both ECOG PS 01 and PB blasts ≤30% retained their significance for OS (HR 0.69 with p=0.03; and 0.61 with p=0.004 respectively). However disease state (r/r AML vs TN AML) lost significance for OS while cytogenetics risk level (others vs poor risk) became significant with a HR for OS of 0.68, p=0.016.

Summary/Conclusions: In a prospective series of AML patients treated with guadecitabine in a phase 2 study, better ECOG PS 01 and lower baseline PB blasts ≤30% were associated with a significantly higher likelihood of response and a longer OS. Patients with TN AML had significantly higher likelihood of response than those with r/r AML but this was not a significant factor for OS when other factors are present in the model such as ECOG PS, cytogenetics risk and PB blasts. On the other hand, the presence of poor risk cytogenetics did not alter the likelihood of response to guadecitabine but still had shorter survival compared to patients with other cytogenetics risk levels. Other variables such as age, baseline BM blasts %, and baseline WBCs count did not significantly impact response or OS in AML patients treated with guadecitabine when all other factors are present in the models. The analysis of genetic mutations was limited by the small number of patients where these mutations were present. The analysis of the treatment schedule is limited by the different effect of the schedule on r/r AML compared to TN AML where the 10day schedule did better than the 5day schedule in r/r AML but not in TN AML patients.

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Predictors of Response and Survival in 206 AML Patients Treated with Guadecitabine in a Phase 2 Study

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)

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

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

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

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 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

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)

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.

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