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

Savona, Michael R.; Odenike, Olatoyosi; Amrein, Philip C.; Steensma, David P.; DeZern, Amy E.; Michaelis, Laura C.; Faderl, Stefan; Harb, Wael A.; Kantarjian, Hagop M.; Lowder, James N.; Oganesian, Aram; Azab, Mohammad; Garcia‐Manero, Guillermo

doi:10.1016/s2352-3026(19)30030-4

Cited by 104 publications

(103 citation statements)

References 24 publications

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“…Consistent with previous preclinical and clinical studies with DEC + CDZ (ASTX727) [16], oral AZA approximated bioavailability in mice and monkeys and had comparable pharmacodynamic and anti-tumor activity to i.p. AZA when given with the CDAi CDZ.…”

Section: Discussionsupporting

confidence: 85%

“…In a recent dose-escalation study (NCT02103478), the simultaneous oral administration of the novel CDAi cedazuridine (CDZ) together with DEC approximated the pharmacokinetics of i.v. DEC in patients [16]. Global levels of demethylation as measured by bisulfate sequencing in long interspersed nuclear element-1 (LINE-1) demethylation assays revealed similar reduction [16].…”

Section: Introductionmentioning

confidence: 91%

“…DEC in patients [16]. Global levels of demethylation as measured by bisulfate sequencing in long interspersed nuclear element-1 (LINE-1) demethylation assays revealed similar reduction [16]. In a phase III, randomized study, an oral fixeddose combination (FDC) of DEC + CDZ 35 mg/100 mg (ASTX727) confirmed DEC systemic exposure equivalence with body-surface-area-adjusted i.v.…”

Section: Introductionmentioning

confidence: 94%

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Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model

Ramsey

Oganesian²,

Gorska

et al. 2020

Targ Oncol

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Background DNA methyltransferase inhibitors (DNMTis) improve survival for patients with myelodysplastic syndromes (MDS) and those with acute myeloid leukemia (AML) unable to receive standard cytotoxic chemotherapy and are, accordingly, the backbone of standard-of-care treatment for these conditions. Standard regimens with DNMTIs, decitabine (DEC) or azacitidine (AZA) include daily subcutaneous (s.c.) or intravenous (i.v.) administration for 5-7 consecutive days. Attempts to provide the therapy orally have been limited given rapid clearance of the agents by the enzyme cytidine deaminase (CDA), which is ubiquitous in the gut and liver as part of first-pass metabolism. Recently, cedazuridine (CDZ), an oral inhibitor of CDA, was successfully combined with DEC to approximate the pharmacokinetics of i.v. DEC in patients. Objective To determine if an oral dosing strategy might be feasible in the clinic with AZA, we attempted to increase the bioavailability of oral AZA through the use of CDZ, in a murine model. Methods Following pharmacokinetic and pharmacodynamic assessment of oral AZA dosed with CDZ in murine and monkey models, we tested this regimen in vivo with a human cell line-derived xenograft transplantation experiment (CDX). Following this we combined the regimen with venetoclax (VEN) to test the efficacy of an all-oral regimen in a patient-derived xenograft (PDX) model. Results Parenteral AZA and oral AZA + CDZ exhibited similar pharmacokinetic profiles, and efficacy against human AML cells. Tumor regression was seen with AZA + CDZ in MOLM-13 CDX and PDX models. Conclusions We conclude that oral AZA when combined with CDZ achieves successful tumor regression in both CDX and PDX models. Furthermore, the combination of AZA + CDZ with VEN in a PDX model emulated responses seen with VEN + AZA in the clinic, implying a potential all-oral VEN-based therapy opportunity in myeloid diseases. Key PointsOral azacitidine + cedazuridine achieved similar dosedependent responses to those achieved with intraperitoneal azacitidine.The addition of venetoclax to oral azacitidine + cedazuridine resulted in significant decreases in tumor expansion in an acute myeloid leukemia patient-derived xenograft model.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 94%

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Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model

Ramsey

Oganesian²,

Gorska

et al. 2020

Targ Oncol

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“…Therefore, lowdose HMAs can not only avoid excessive cytotoxicity, but also inhibit tumor growth by regulating the epigenetic state (14)(15)(16). Due to the rapid clearance of cytidine deaminase in the gut and liver, the oral bioavailability of HMAs is very low, which is one of the reasons for the poor oral effect of HMAs (17). Therefore, intravenous infusion of low-dose decitabine may be more helpful to sensitize PD-1 antibodies against tumors under low toxicity.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Low-Dose Decitabine Plus Anti-PD-1 Inhibitor Camrelizumab for Previously Treated Advanced Metastatic Non-Small Cell Lung Cancer

Yan

Zhao²,

Liu

et al. 2020

Front. Oncol.

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Background: Although the programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors have markedly changed the strategies of cancer treatment, most patients with advanced non-small cell lung cancer (NSCLC) do not respond to PD-1/PD-L1 monotherapy. Epigenetic drugs have been hypothesized to possess the potential to sensitize PD-1/PD-L1 inhibitors. Case Presentation: Three patients with advanced metastatic NSCLC failed to respond to first-line systemic therapy and had a low tumor mutation burden, low tumor neoantigen burden, low microsatellite instability, and HLA loss of heterozygosity according to their target lesion biopsies, all of which were considered unfavorable factors for PD-1/PD-L1 blockage. However, all three patients responded to low-dose decitabine, an epigenetic drug, in combination with camrelizumab (anti-PD-1 antibody), with only controllable adverse events, indicating that low-dose decitabine can sensitize PD-1/PD-L1 inhibitors. Summary: We report a novel therapy with low-dose decitabine plus camrelizumab for advanced NSCLC on the basis of successful treatment of three patients, emphasizing the potential of epigenetic drugs to regulate PD-1/PD-L1 inhibitors in advanced NSCLC.

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“…The hematological responses obtained are often not durable, and are associated with significant changes in DNA methylation arguing for an epigenetic restoration of normal hematopoiesis, without significantly altering disease biology or progression to AML . Second generation HMA such as Guadecitabine (SGI‐110) and the novel oral formulation of decitabine and the cytidine deaminase inhibitor (E7727‐cedazuridine) are also being developed and tested in MDS/CMML …”

Section: Risk Adapted Therapymentioning

confidence: 99%

Chronic Myelomonocytic leukemia: 2020 update on diagnosis, risk stratification and management

2019

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Disease overview: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (~15% over 3-5 years). Diagnosis: Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 10 9 /L; monocytes ≥10%), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in~30% of patients, while >90% have gene mutations. Mutations involving TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%) and the oncogenic RAS pathway (~30%) are frequent; while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact over-all survival. Risk stratification: Molecularly integrated prognostic models include; the Groupe Français des Myélodysplasies (GFM), Mayo Molecular Model (MMM) and the CMML specific prognostic model (CPSS-Mol). Risk factors incorporated into the MMM include presence of nonsense or frameshift ASXL1 mutations, absolute monocyte count>10 × 10 9 /L, hemoglobin <10 g/dL, platelet count <100 × 10 9 /L and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into four groups; high (≥3 risk factors), intermediate-2 (2 risk factors), intermediate-1 (1 risk factor) and low (no risk factors), with median survivals of 16, 31, 59 and 97 months, respectively.Risk-adapted therapy: Hypomethylating agents such as 5-azacitidine and decitabine are commonly used, with overall response rates of~40%-50% and complete remission rates of~7%-17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option, but is associated with significant morbidity and mortality.

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

Cited by 104 publications

References 24 publications

Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model

Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model

Case Report: Low-Dose Decitabine Plus Anti-PD-1 Inhibitor Camrelizumab for Previously Treated Advanced Metastatic Non-Small Cell Lung Cancer

Chronic Myelomonocytic leukemia: 2020 update on diagnosis, risk stratification and management

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