Phase I Trial of 4'-Thio-2'-Deoxycytidine (TdCyd) in Patients With Advanced Solid Tumors

NCT02423057 | Completed Phase 1 FDA Drug

• 2 other identifiers: 15011615-C-0116
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- Genes are made up of DNA and are the instruction book for cells. When people have cancer, some of the genes that might have slowed the growth of tumor cells were turned off. Researchers think a drug called TdCyd might help to turn these genes back on. This may slow the growth of tumors in people with cancer. Objectives: \- To test the safety of TdCyd and to find out how it works. Also, to find out the dose of the drug that can be safely given to humans. Eligibility: \- Adults 18 years and older who have advanced cancer that has progressed after standard treatment, or for which no effective therapy exists. Design:

• Participants will take TdCyd by mouth. The drug is given in 21-day cycles. TdCyd is taken once a day during week 1 for 5 days. Then for 2 days participants do not take the drug. Then they take it for 5 days during week 2. No TdCyd is taken during week 3.
• Participants will keep a diary of their study drug doses.
• Participants will have tests about every 3 weeks to see how the study drugs are affecting their body. They will have blood and urine tests, a medical history, and physical exams. They may have computed tomography (CT) scans to measure their tumors. They may have an electrocardiogram, which measures the heart electrical activity.
• If participants develop any side effects, they may be asked to visit more often.
• Participants will stay in the study as long as they are tolerating TdCyd and their tumors are either stable or getting better. One month after stopping the drug, they will have a follow-up phone call.

Conditions

Neoplasms; Solid Tumors

Keywords

Pharmacodynamics; DNA Methylation; Pharmacokinetics; Nucleoside Analog; Epigenetics

Outcome Measures

Primary Outcomes (1)

• To determine the safety, tolerability, and MTD of oral TdCyd administered daily for 5 days a week for 2 weeks, with one week off, q 21-day cycles

  To determine the safety, tolerability, and MTD of oral TdCyd administered daily for 5 days a week for 2 weeks, with one week off, q 21-day cycles

  Cycle 1

Secondary Outcomes (1)

• To document preliminary evidence of TdCyd activity

  Cycle 1 and 2

Study Arms (1)

1

EXPERIMENTAL

TdCyd will be administered orally once a day for 5 days of each week for 2 weeks, with one week off, in 21-day cycles

Drug: TdCyd

Interventions

TdCyd DRUG

Methylation-mediated silencing of genes is an epigenetic mechanism implicated in carcinogenesis; agents that inhibit this mechanism are of clinical interest because of their potential to re-activate silenced tumor suppressor genes. The nucleoside analog 4'-thio-2'-deoxycytidine (TdCyd) is incorporated into DNA 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 offers an improvement over current DNMT inhibitors by virtue of a higher incorporation rate into DNA at lower levels of cytotoxicity; treatment with TdCyd is anticipated to result in the inhibition of tumor growth due to DNMT1 depletion at oral doses that are well tolerated in extended dosing schedules.

1

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically documented solid tumors whose disease has progressed on standard therapy or for which there is no available standard therapy.
• Patients must have measurable or evaluable disease.
• Age greater than or equal to 18 years of age.
• ECOG performance status less than or equal to 2.
• Life expectancy \> 3 months.
• Patients must have normal organ and marrow function as defined below:
• absolute neutrophil count greater than or equal to 1,500/mcL
• platelets greater than or equal to 100,000/mcL
• total bilirubin less than or equal to 1.5 times institutional upper limit of normal
• AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of normal
• creatinine less than or equal to 1.5 times institutional upper limit of normal
• e. creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above 1.5 times institutional normal
• Because nucleoside analogs are known to be teratogenic, women of child-bearing potential and men must agree to use two forms of contraception (hormonal or barrier method of birth control; abstinence; sterilization) prior to study entry, for the duration of study participation, and for 3 months after completing study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use two forms of contraception prior to the study, for the duration of study participation, and for 3 months after completion of administration of TdCyd.
• Patients must have completed any chemotherapy, radiation therapy, or biologic therapy greater than or equal to 4 weeks or 5 half-lives (whichever is shorter) (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. Patients must be greater than or equal to 2 weeks since any prior administration of a study drug in a phase 0 or equivalent study and be greater than or equal to 2 weeks since any prior palliative radiation or cyberknife therapy. Patients must have recovered to grade 1 from prior toxicity or adverse events. Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment prior to study entry may continue this treatment.
• Ability to understand and the willingness to sign a written informed consent document.

You may not qualify if:

• Patients who are receiving any other investigational agents.
• Pregnant women and women who are breastfeeding are excluded from this study.
• Patients with clinically significant illnesses which would compromise participation in the study, including, but not limited to active or uncontrolled infection, immune deficiencies, known HIV infection requiring protease inhibitor therapy, Hepatitis B, Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for greater than or equal to 1 month after treatment of the brain metastases. Patients should not be on anti-seizure medications. These patients may be enrolled at the discretion of the Principal Investigator.
• Malabsorption syndrome or other conditions that would interfere with intestinal absorption.
• Both men and women of all races and ethnic groups are eligible for this trial.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Cowan LA, Talwar S, Yang AS. Will DNA methylation inhibitors work in solid tumors? A review of the clinical experience with azacitidine and decitabine in solid tumors. Epigenomics. 2010 Feb;2(1):71-86. doi: 10.2217/epi.09.44.

  PMID: 22122748 BACKGROUND

• Thottassery JV, Sambandam V, Allan PW, Maddry JA, Maxuitenko YY, Tiwari K, Hollingshead M, Parker WB. Novel DNA methyltransferase-1 (DNMT1) depleting anticancer nucleosides, 4'-thio-2'-deoxycytidine and 5-aza-4'-thio-2'-deoxycytidine. Cancer Chemother Pharmacol. 2014 Aug;74(2):291-302. doi: 10.1007/s00280-014-2503-z. Epub 2014 Jun 8.

  PMID: 24908436 BACKGROUND

• Kumar S, Horton JR, Jones GD, Walker RT, Roberts RJ, Cheng X. DNA containing 4'-thio-2'-deoxycytidine inhibits methylation by HhaI methyltransferase. Nucleic Acids Res. 1997 Jul 15;25(14):2773-83. doi: 10.1093/nar/25.14.2773.

  PMID: 9207024 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Neoplasms

Study Officials

• James H Doroshow, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 18, 2015
• First Posted: April 22, 2015
• Study Start: May 18, 2015
• Primary Completion: March 19, 2019
• Study Completion: July 21, 2025
• Last Updated: April 24, 2026

Record last verified: 2026-01-16

Locations

US (1)