Entries by Renee Hansen


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 […]

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

 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 […]

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

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 […]

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

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 […]

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

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. […]

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

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 […]

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 […]

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

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 […]

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 […]

Astex Pharmaceuticals and Otsuka announce results of the phase 3 ASTRAL-1 study of guadecitabine (SGI-110) in treatment-naïve AML patients ineligible to receive intense induction chemotherapy

Astex Pharmaceuticals and Otsuka announce results of the phase 3 ASTRAL-1 study of guadecitabine (SGI-110) in treatment-naïve AML patients ineligible to receive intense induction chemotherapy Guadecitabine did not meet the co-primary endpoints of complete response (CR) rate or overall survival (OS) in the ASTRAL-1 study Astex continues to focus on completing the phase 3 ASTRAL-2 and […]