4'-Thio-2'-Deoxycytidine (TdCyd) / National Cancer Institute - LARVOL DELTA

5-aza-4'-Thio-2'-Deoxycytidine (Aza-TdC) in People With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=65 | Recruiting | Sponsor: National Cancer Institute (NCI) | N=50 ➔ 65

Enrollment change • Metastases • Oncology • Solid Tumor

5-aza-4'-Thio-2'-Deoxycytidine (Aza-TdC) in People With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=50 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2024 ➔ Sep 2026 | Trial primary completion date: Sep 2024 ➔ Sep 2026

Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Upregulation of TET2 and Resistance to DNA Methyltransferase (DNMT) Inhibitors in DNMT1-Deleted Cancer Cells. (PubMed, Diseases) - "DNMT1 gene deletion made cancer cells prone to TET2 upregulation and activation of tumor suppressor expression upon DNMT inhibitor challenge. TET2 augmentation is concomitant with resistance to DNMT inhibitors in a DNMT1-deleted state."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Solid Tumor • ANXA5 • CDKN2A • DNMT1 • TET2

Phase I Trial of 4'-Thio-2'-Deoxycytidine (TdCyd) in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=27 | Suspended | Sponsor: National Cancer Institute (NCI) | Trial completion date: Aug 2024 ➔ May 2028 | Trial primary completion date: Aug 2024 ➔ May 2027

Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

The DNA methyltransferase inhibitor 5-aza-4'-thio-2'-deoxycytidine induces C>G transversions and acute lymphoid leukemia development. (PubMed, Cancer Res) - "Deletion of Dck, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C>G transversions. Taken together, these findings demonstrate a highly penetrant mutagenic and leukemogenic phenotype associated with ATC."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor • Transplantation • NF1 • NOTCH1 • PAX5 • PTEN • TP53

5-aza-4'-Thio-2'-Deoxycytidine (Aza-TdC) in People With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=50 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial primary completion date: Sep 2023 ➔ Sep 2024

Metastases • Trial primary completion date • Oncology • Solid Tumor • CTCs

DNA damage, demethylation and anticancer activity of DNA methyltransferase (DNMT) inhibitors. (PubMed, Sci Rep) - "The gene deletion markedly attenuated cytotoxicity and growth inhibition mediated by decitabine, azacitidine and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) in colon and breast cancer cells. Thus, DNMT1 deletion confers resistance to DNMTi, and their anti-cancer activity is determined by DNA damage effects. Patients with DNMT1 gene deletions may not respond to DNMTi treatment."

Journal • Bladder Cancer • Breast Cancer • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CDKN2A • CDKN2B

[VIRTUAL] Preclinical development of NSC-801845, a new cytidine analog, in comparative cell culture and xenograft studies with the clinical candidates T-dCyd and aza-T-dCyd (AACR-II 2020) - P1 | "4'-thio-2'-deoxycytidine (T-dCyd) and 5-aza-4’-thio-2’-deoxycytidine (aza-T-dCyd) are two cytidine analogs that deplete DNMT1 both in vitro and in vivo in tumor cells...NCI-Frederick is accredited by AAALACi and follows the Public Health Service Policy on the Care and Use of Laboratory Animals. These studies were conducted on an approved Institutional Animal Care and Use Committee approved protocol."

Bladder Cancer • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Hematological Malignancies • Leukemia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Thoracic Cancer • Urothelial Cancer • DNMT1

Comparison of thio-deoxy-cytidine (TdCyd) and aza-thio-deoxy-cytidine (Aza-TdCyd) in solid and liquid tumor cell lines and PPTC pediatric xenografts (AACR 2019) - P1; "Aza-TdCyd was, in general, a more active antitumor agent than TdCyd. In cell culture, after 7-days exposure Aza-TdCyd was 3-to 4-fold more potent than TdCyd in 10 solid tumor lines (IC50 1.2 vs 3.7 uM) and similarly more potent in 6 liquid tumor lines (0.03 vs 0.11 uM). TdCyd and Aza-TdCyd were tested in Ewing sarcoma, rhabdoid tumor, rhabdomyosarcoma, osteosarcoma, and pediatric acute lymphoblastic leukemia (ALL) patient-derived xenografts."

Phase I Trial of 4'-Thio-2'-Deoxycytidine (TdCyd) in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=27 | Suspended | Sponsor: National Cancer Institute (NCI) | Trial completion date: Apr 2023 ➔ Aug 2024 | Trial primary completion date: Apr 2023 ➔ Aug 2024

Trial completion date • Trial primary completion date • Oncology • Solid Tumor

5-aza-4'-Thio-2'-Deoxycytidine (Aza-TdC) in People With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=50 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2022 ➔ Sep 2024 | Trial primary completion date: Sep 2022 ➔ Sep 2023

Trial completion date • Trial primary completion date • Oncology • Solid Tumor • CTCs

Phase I Trial of 4'-Thio-2'-Deoxycytidine (TdCyd) in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=27; Suspended; Sponsor: National Cancer Institute (NCI); Trial completion date: Apr 2022 ➔ Apr 2023; Trial primary completion date: Apr 2022 ➔ Apr 2023

Clinical • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Trial in progress abstract phase I trial of 5-aza-4-thio-2-deoxycytidine (Aza-TdC) in patients with advanced solid tumors. (ASCO 2019) - P1; "The DNMT1 inhibitors decitabine and 5-azacytdine are currently FDA-approved for use in myelodysplastic syndromes and are also used in patients with acute myeloid leukemia. HHSN261200800001E. Clinical trial information: NCT03366116"

Clinical • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

5-Aza-4'-thio-2'-deoxycytidine, a new orally bioavailable non-toxic "best-in-class" DNMT1 depleting agent in clinical development. (PubMed, J Pharmacol Exp Ther) - "Two DNMT1 depleting agents aza-dCyd (5-aza-2'-deoxycytidine, decitabine) and aza-Cyd (5-aza-cytidine, azacitidine) are currently used for the treatment of myelodysplastic syndromes and acute myeloid leukemia, and have also been investigated for non-oncology indications such as sickle cell disease. Although similar in structure to decitabine (aza-dCyd) its metabolism and mechanism of action is different than that of aza-dCyd, resulting in less off target activity and less toxicity. The larger therapeutic index of aza-T-dCyd (DNMT1 depletion vs toxicity) in mice suggests that it would be a better clinical candidate to selectively deplete DNMT1 from target cells and determine whether or not depletion of DNMT1 is an effective target for various diseases."

Clinical • Journal • Acute Myelogenous Leukemia • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Sickle Cell Disease • DNMT1

5-aza-4'-Thio-2'-Deoxycytidine (Aza-TdC) in People With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=46; Recruiting; Sponsor: National Cancer Institute (NCI); Trial completion date: Sep 2021 ➔ Sep 2022; Trial primary completion date: Sep 2021 ➔ Sep 2022

Clinical • Trial completion date • Trial primary completion date • Oncology • Solid Tumor • CTCs

TET2 and DNMT3A mutations and exceptional response to 4'-thio-2'-deoxycytidine in human solid tumor models. (PubMed, J Hematol Oncol) - "Cell and animal models with concurrent mutations in TET2 and DNMT3A were sensitive to T-dCyd treatment. The mutations were detectable in human solid tumors and frequently occur in some hematological malignancies."

Journal • Preclinical • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Kidney Cancer • Leukemia • Lymphoma • Melanoma • Oncology • Peripheral T-cell Lymphoma • Renal Cell Carcinoma • Solid Tumor • T Cell Non-Hodgkin Lymphoma • CDKN1A • DNMT3A • TET2

Phase I Trial of 4'-Thio-2'-Deoxycytidine (TdCyd) in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=27; Suspended; Sponsor: National Cancer Institute (NCI); Trial completion date: Apr 2021 ➔ Apr 2022; Trial primary completion date: Mar 2021 ➔ Apr 2022

Clinical • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

The development of β-selective glycosylation reactions with benzyl substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides: enabling practical multi-gram syntheses of 4'-Thio-2'-deoxycytidine (T-dCyd) and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) to support clinical development. (PubMed, Nucleosides Nucleotides Nucleic Acids) - "Furthermore, we describe the development of reaction conditions for β-selective glycosylation reactions of benzyl substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides with both N4-benzoylcytosine and 5-aza-cytosine to enable the practical multi-gram syntheses of the clinical candidates 4'-thio-2'-deoxycytidine (T-dCyd) and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd). Taken together, these new synthetic developments have made possible the preclinical and early clinical development of these important anticancer agents at the National Cancer Institute."

Clinical • Journal • Oncology

[VIRTUAL] Synthesis, identification, and preclinical characterization of NSC-801845 as a new chemotherapeutic agent for the treatment of cancer (ACS-Fall 2020) - P1 | "4'-Thio-2'-deoxycytidine (T-dCyd) and 5-aza-4’-thio-2’-deoxycytidine (aza-T-dCyd) are two cytidine analogs that deplete DNMT1 both in vitro and in vivo in tumor cells...Similarly, complete tumor regression was observed in the HL-60 leukemia xenograft when mice were dosed with NSC-801845 (10 mg/kg IP, QDx5 for 3 cycles). In the BL-0382 bladder study, oral dosing of NSC-801845 (8 mg/kg PO, QDx5, for 3 cycles) produced a regressions that showed tumor regrowth 10-days post dosing."

Preclinical • Bladder Cancer • Colon Cancer • Colorectal Cancer • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer • DNMT1

[VIRTUAL] TET2/DNMT3A mutations and exceptional response to novel epigenetic agent in human malignancies (AACR-II 2020) - "Cancer cells and animal models examined with TET2 and DNMT3A-mutant genotype are sensitive to T-dCyd treatment."

Late-breaking abstract • Genito-urinary Cancer • Leukemia • Lymphoma • Melanoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • Renal Cell Carcinoma • Squamous Cell Carcinoma • CDKN1A • DNMT3A • TET2

Phase I Trial of 4'-Thio-2'-Deoxycytidine (TdCyd) in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=24; Suspended; Sponsor: National Cancer Institute (NCI); Trial completion date: Apr 2020 ➔ Apr 2021; Trial primary completion date: Mar 2020 ➔ Mar 2021

Clinical • Trial completion date • Trial primary completion date

Phase I Trial of 4'-Thio-2'-Deoxycytidine (TdCyd) in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=24; Suspended; Sponsor: National Cancer Institute (NCI); N=46 ➔ 24

Clinical • Enrollment change

Phase I Trial of 4'-Thio-2'-Deoxycytidine (TdCyd) in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=46; Suspended; Sponsor: National Cancer Institute (NCI); Recruiting ➔ Suspended

Clinical • Trial suspension

Restoration of p16INK4A expression in circulating tumor cells in patients with advanced solid tumors treated with deoxycytidine analogs and associated dynamic EMT phenotypic changes (AACR-NCI-EORTC 2019) - "We demonstrated in vitro re-expression of p16 by Western blot and whole cell immunofluorescence in EJ-6 cells treated with decitabine, 4-thio-2’-deoxycytidine (TdCyd) and 5-fluoro-2’-deoxyctidine (FdC) but not in the p16-deleted line A549. Funded by NCI Contract No. HHSN261200800001E, and Cooperative Agreements U01CA062505 and UM1CA186717."

Circulating Tumor Cells • Clinical