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

Neoplasms Clinical Trial

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

Status Suspended

Clinical Trial 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.

Clinical Trial Description

Background:

• 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. Two DNA hypomethylating nucleosides, 5-azacytidine (azacytidine) and 5-aza-2'-deoxycytidine (decitabine) have been approved by the FDA for the treatment of patients with myelodysplastic syndromes and certain leukemias.

• 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. DNMT1 can become trapped in a covalent complex with DNA, thus depleting free enzyme and inhibiting the normal maintenance methylation of CpG sites, resulting in reactivation of tumor suppressor genes.

• Data generated at Southern Research Institute and the NCI suggest a correlation between TdCyd activity in solid tumor xenograft models and decreased levels of DNMT1.

• TdCyd offers an improvement over current DNA methyltransferase 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.

• Two patients on dose levels 6 and 7 developed Pneumocystis jiroveci pneumonia (PJP) so all patients will be administered PJP prophylaxis.

Primary Objective:

-To establish 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 patients with refractory solid tumors

Secondary Objectives:

• To determine the pharmacokinetics of oral TdCyd

• To document preliminary evidence of TdCyd activity

• To determine effect of study treatment on re-expression of select genes silenced by methylation in circulating tumor cells

Eligibility:

-Patients must have histologically documented solid tumors whose disease has progressed on standard therapy or for which there is no available standard therapy

Study Design:

• 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.

• The trial will follow an accelerated titration design, changing to a traditional 3+3 dose escalation design (3-6 patients per cohort) once specified toxicity criteria are met. Intrapatient dose escalation will be allowed.

• Blood samples will be obtained for pharmacokinetic analysis and to isolate circulating tumor cells to assess re-expression of genes silenced by methylation. ;

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumors

• NCT number: NCT02423057
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Suspended
• Phase: Phase 1
• Start date: May 18, 2015
• Completion date: May 28, 2028