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Poster display

1661 - First-in-human trial of 4'-thio-2'-deoxycytidine (TdCyd) in patients with advanced solid tumors

Date

10 Oct 2016

Session

Poster display

Presenters

Geraldine O'Sullivan Coyne

Citation

Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368

Authors

G. O'Sullivan Coyne1, A. Chen1, S. Kummar2, J.M. Collins3, R.S. Meehan1, M. Suto4, L. Rubinstein5, R. Kinders6, N. Moore7, R. Parchment6, Y. Horneffer1, L. Juwara7, M. Difilippantonio3, R. Piekarz1, J. Doroshow3

Author affiliations

  • 1 Developmental Therapeutics Clinic, Division Of Cancer Treatment And Diagnosis, National Cancer Institute, 20892 - Bethesda/US
  • 2 Phase I Clinical Research, Division Of Oncology, Stanford University, Palo Alto/US
  • 3 Division Of Cancer Treatment And Diagnosis, National Cancer Institute, 20892 - Bethesda/US
  • 4 Drug Discovery Division, Southern Research Institute, 35205 - Birmingham/US
  • 5 Biometric Research Program, National Cancer Institute, 20892 - Bethesda/US
  • 6 Applied/developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick/US
  • 7 Clinical Monitoring Research Program, Leidos Biomedical Research, 20892 - Bethesda/US
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Resources

Abstract 1661

Background

Methylation-mediated silencing of genes is an epigenetic mechanism implicated in tumorigenesis. Hypermethylation of cytosines at CpG sites in the regulatory sequences of tumor suppressor genes silences them in a manner akin to inactivating mutations. Agents that inhibit methylation are of clinical interest because of their potential to re-activate silenced tumor suppressor genes, and two DNA hypomethylating nucleosides have been approved by the FDA for the treatment of patients (pts) with hematologic malignancies. The nucleoside analog 4'-thio-2'-deoxycytidine (TdCyd, NSC764276) is a cytidine analog in which the 4'-O moiety in deoxyribose has been replaced with sulfur where it engages the active site of DNA methyltransferase I (DNMT1), a maintenance methyltransferase that contributes to the hypermethylation and silencing of tumor suppressor genes. TdCyd and its active metabolites are phosphorylated and incorporated into the DNA of human cells in culture and in xenografts at rates exceeding those of the natural nucleoside or ara-analogs. Growth inhibition and tumor shrinkage were found during TdCyd dosing in several human tumour xenografts. Depletion of DNMT1 was observed also in certain xenograft models.

Trial design

We are conducting an open label phase 1 first-in-human trial of TdCyd, following an accelerated titration design. TdCyd is administered PO qd x 5 days of each week for 2 weeks in 21-day cycles; the primary objective of the study is to establish its safety, tolerability, maximum tolerated dose, and recommended phase 2 dose. The secondary objectives of the study of oral TdCyd include preliminary efficacy assessment, pharmacokinetic (PK) characterization and exploratory pharmacodynamic (PD) evaluation of re-expression of select genes silenced by methylation in circulating tumor cells (CTCs). Eligibility criteria: solid tumor pts whose disease has progressed on standard therapy, ECOG ≤ 2, and normal organ function. Blood samples for PK/PD analyses and gene expression in CTCs are being evaluated. Currently, we are enrolling at DL5 in the escalation portion of the trial.

Clinical trial identification

NCT02423057

Legal entity responsible for the study

Division of Cancer Treatment and Diagnosis, National Cancer Institute

Funding

National Cancer Institute

Disclosure

All authors have declared no conflicts of interest.

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