5-aza-4'-Thio-2'-Deoxycytidine (Aza-TdC) in People With Advanced Solid Tumors

Neoplasms Clinical Trial

Official title: Phase I Trial of 5-aza-4'-Thio-2'-Deoxycytidine (Aza-TdC) in Patients With Advanced Solid Tumors

Status Recruiting

Clinical Trial Summary

Background:

Blood, tissue, and tumor cells contain genes. Genes are made up of DNA. DNA is the instruction book for each cell. In some people with cancer, the genes that might have slowed the growth of their tumor were turned off. Researchers want to see if a new drug can turn the genes back on and slow the tumor growth. The drug is called Aza-TdC.

Objective:

To test the safety of Aza-TdC, and to find out the dose of this drug that can be safely given to humans.

Eligibility:

People ages 18 and older who have advanced cancer that has gotten worse after standard treatment, or for which no effective therapy exists

Design:

Participants will be screened with:

Medical history

Blood and urine tests

Scans to measure their tumors

Test to measure the electrical activity of the heart

Participants will take the study drug by mouth. The drug is given in cycles. Each cycle is 21 days (3 weeks) long.

Week 1 and week 2: participants will take the study drug once a day for 5 days. Then they will have 2 days without the drug. Week 3: no study drug is taken. This completes one cycle of treatment.

For cycle 1, participants will repeat the screening tests several times. For all other cycles, participants will have blood tests and pregnancy tests. They will have scans of their tumor every 6 weeks.

The cycle will be repeated as long as the participant tolerates the drug and the cancer is either stable or gets better.

Sponsoring Institute: National Cancer Institute

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 5-aza-4 -thio-2 -deoxycytidine (Aza-TdC) 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 re-activation of tumor suppressor genes.

Data suggest a correlation between Aza-TdC activity in solid tumor xenograft models and decreased levels of DNMT1.

Aza-TdC offers an improvement over traditional DNA methyltransferase inhibitors by virtue of a higher incorporation rate into DNA at lower levels of cytotoxicity; Aza-TdC has greater antitumor activity than another recently developed DNMT1 inhibitor, TdCyd, in some solid tumor xenograft models. Treatment with Aza-TdC 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.

Primary Objective:

To establish the safety, tolerability, and MTD of oral Aza-TdC 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 Aza-TdC

To document preliminary evidence of Aza-TdC activity

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

To determine the effects of Aza-TdC on DNA damage response (DDR) signaling and on genome-wide DNA methylation in tumor biopsy tissue

Exploratory Objective:

To determine the effects of Aza-TdC on global RNA expression and on levels of DNMT1, DNMT3a, DNMT3b, and other select proteins in tumor biopsy tissue

To examine genomic alterations in circulating tumor DNA (ctDNA) that may be associated with Aza-TdC response or resistance

Eligibility:

Patients >= 18 years of age must have histologically documented solid tumors whose disease has progressed on standard therapy or for which there is no available standard therapy

Study Design:

Aza-TdC 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.

Up to 21 patients will be accrued to a PD expansion cohort at the MTD to further assess pharmacodynamic endpoints in tumor and blood. ;

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumors

• NCT number: NCT03366116
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: DTC Referral Coordinators
• Phone: (240) 781-3499
• Email: dtcreferralcoordinators@nih.gov
• Status: Recruiting
• Phase: Phase 1
• Start date: November 5, 2018
• Completion date: September 30, 2024