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

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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 ASH: Long term results of a randomized phase 2 dose-response study of guadecitabine, a novel subcutaneous (SC) hypomethylating agent (HMA), in 102 patients with Intermediate or High Risk Myelodysplastic syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML)

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Long term results of a randomized phase 2 dose-response study of guadecitabine, a novel subcutaneous (SC) hypomethylating agent (HMA), in 102 patients with Intermediate or High Risk Myelodysplastic syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML)</>

Background: Guadecitabine SC (SGI-110) is a dinucleotide next generation HMA resistant to degradation by cytidine deaminase resulting in extended in vivo exposure to its active metabolite decitabine. A Phase 1 established 60 mg/m2 QDx5 as the biologically effective dose (BED), and 90 mg/m2 QDx5 as the Maximum tolerated dose (MTD) in MDS patients given in 28-day cycles (Issa et al, 2015, Lancet Oncology). Phase 2 is conducted to evaluate dose response between the BED and MTD in both untreated MDS patients, and patients previously treated with other HMAs.

 Methods: Int, or HR MDS, and CMML patients who were either treatment-naïve (TN) or relapsed/refractory to other HMAs (r/r) were randomized to either 60 mg/m2 or 90 mg/m2 QDx5 every 28 days. Efficacy was evaluated by the clinical responses of CR, PR, marrow CR (mCR), and Hematological Improvement (HI) based on the International Working Group Criteria 2006, as well as transfusion-independence, and overall survival (OS). Adverse events (AEs) were graded by the CTCAE v4 criteria.

 Results: The study completed target enrolment with 102 patients: 53 r/r MDS, and 49 TN MDS. Fifty three patients were randomized to 60 mg/m2 and 49 patients to 90 mg/m2 QDx5 with a median follow up of 3.2 years (IQR 2.8-3.5 years). Median age was 72 and 71 years for r/r and TN MDS 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 (58%) received their last HMA treatment <3 month before enrolment, and most of them received ≥6 months of prior HMA treatment (77%).

Median number of treatment cycles was 5 for both r/r and TN MDS (range 1-37 in r/r MDS and 1-49 in TN MDS). In the TN MDS cohort CR was achieved in 11 (22%) of patients with no major difference between the 2 dose groups (19% in the 60 mg/m2 group vs 27% in the 90 mg/m2 group). Overall CR+mCR was achieved in 18 patients (37%) in TN MDS patients and median OS was 23.4 months. In the r/r MDS cohort, CR was achieved in 4% of patients in each of the 2 dose groups. Overall CR+mCR in the r/r MDS cohort was achieved in 17 patients (32%), with a median duration of response of 7.9 months, and median OS of 11.7 months. No significant difference in response or OS between the 2 dose groups was observed. In patients who were RBC transfusion-dependent at baseline, transfusion independence for at least 8 weeks was achieved in 42% of TN MDS, and 15% in r/r MDS patients. 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 for worse OS were BM blasts >5%; RBC transfusion-dependence; IPSS High Risk; and ECOG Performance Status of >1.

Overall incidence of Grade ≥3 AEs regardless of relationship to treatment was reported in 83 vs. 96% for 60 and 90 mg/m2 dose groups respectively. There was a slightly higher but non-significant difference in Grade ≥3 thrombocytopenia (57 vs 41.5%); neutropenia (51 vs 39.6%); febrile neutropenia (43% vs 32%); and pneumonia (32.7 vs. 26.4%) for the 90 mg/m2 compared to 60 mg/m2 dose group. Early 30, 60, and 90-day all-cause mortality was observed in 0, 3.7%, and 5.7% in the 60 mg/m2 dose group respectively; and in 2%, 4%, and 12% in the 90 mg/m2 dose group respectively.

Conclusions: Guadecitabine at both dose groups is a well-tolerated novel HMA with clinical activity in the treatment of both TN and r/r Int and HR MDS, and CMML patients. In TN MDS patient CR rate of 22% and median OS of 23.4 months compare well with first generation HMA efficacy (Fenaux et al, 2009, Lancet Oncology). Activity in r/r MDS who previously failed prior HMAs is particularly promising (CR+mCR in 32% of patients with median duration of response and overall survival of almost 8 and 12 months respectively). A phase 3 trial (ASTRAL-3) of guadecitabine vs Physician Treatment Choice in r/r MDS and CMML patients previously treated with azacitidine or decitabine is actively enrolling (ClinicalTrials.gov ID: NCT02907359).

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.

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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

2018 AACR: A novel ERK1/2 inhibitor has potent activity in KRAS-mutant non-small cell lung cancer models

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Summary
Non-small cell lung cancer (NSCLC) molecular profiling is a key factor in treatment selection. Although, patients with NSCLC tumors harboring EGFR or ALK mutations can benefit from personalized therapies, there are currently no approved targeted therapies for KRAS mutant tumors which occur in 25% to 30% of patients with NSCLC. The constitutive activation of the MAPK pathway in these tumors provides a rationale for targeting effectors such as MEK1/2 (MEK) or ERK1/2 (ERK). Inhibitor of MEK kinase have been tested clinically in KRAS-mutant NSCLC but results have been disappointing, possibly because compensatory signalling such as the reactivation of ERK is triggered following the inhibition of MEK, leading to cancer cell survival. Therefore, targeting ERK directly represents an attractive therapeutic approach. As previously described, we have developed a novel, potent and selective ERK inhibitor identified by fragment-based drug discovery which has potent activity in vitro and in vivo. Here, we demonstrate the activity of this lead compound in KRAS-mutant NSCLC models.
Our novel ERK inhibitor was tested in a panel of 440 human cancer cell lines of which the KRAS NSCLC population was identified as particularly sensitive. 62% of the KRAS-mutant NSCLC cell lines tested, exhibited antiproliferative IC50s ranging from 1 nM to 500 nM. This lead compound also inhibited ERK downstream signalling in KRAS NSCLC models both in vitro and in vivo. Indeed, the phosphorylation level of the ERK substrate, RSK, was strongly decreased in HCC-44 and Calu-6 xenograft tumors 2h after the oral administration of the lead compound at 50 mg/kg. Levels of pRSK remained below those of untreated tumors for up to 16h in HCC-44 tumors and 24h in Calu-6 tumors. We also confirmed that, the ERK inhibitor conferred a decrease in phosphorylation of ERK itself in both models. The inhibition of ERK signalling corresponded to significant anti-tumour activity in these models with a daily oral administration of 50 mg/kg compound leading to significant tumor regression in subcutaneous models of HCC-44 (18.3% T/C) and Calu-6 (8.9% T/C) xenograft tumors.
This work demonstrates the in vitro and in vivo activity of a novel, highly potent, selective ERK inhibitor in models of KRAS-mutant NSCLC. These data support the further optimisation of this series of compounds for clinical development.

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A novel ERK1/2 inhibitor has potent activity in KRAS-mutant non-small cell lung cancer models

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

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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)

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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.