65 Participants Needed

Aza-TdC for Solid Tumors

AB
JH
DR
Overseen ByDTC Referral Coordinators
Age: 18+
Sex: Any
Trial Phase: Phase 1
Sponsor: National Cancer Institute (NCI)
No Placebo GroupAll trial participants will receive the active study treatment (no placebo)

Trial Summary

What is the purpose of this trial?

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

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must have completed any chemotherapy, radiation, or biologic therapy at least 4 weeks before starting the study. You can continue intravenous bisphosphonate treatment if you have bone metastases or hypercalcemia.

What data supports the effectiveness of the drug Aza-TdC for solid tumors?

Research shows that a similar drug, 5-aza-2'-deoxycytidine, is effective against certain cancers by reactivating genes that suppress tumors. This suggests that Aza-TdC, which is related, might also help treat solid tumors by a similar mechanism.12345

What safety data exists for Aza-TdC in humans?

Aza-TdC, also known as 5-azacytidine or 5-aza-2'-deoxycytidine, has been associated with significant side effects in humans, including blood-related issues (myelosuppression) and digestive problems. In some studies, serious complications like infections (sepsis) and bleeding in the brain (cerebral hemorrhage) have been reported, leading to fatalities.36789

What makes the drug Aza-TdC unique for treating solid tumors?

Aza-TdC is unique because it is an orally bioavailable drug that selectively depletes DNMT1, an enzyme involved in DNA methylation, with lower toxicity compared to similar drugs like decitabine. This means it can potentially be used at effective doses for longer durations with fewer side effects.810111213

Research Team

JH

James H Doroshow, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults over 18 with advanced solid tumors that have worsened after standard treatment or for which no effective therapy exists. They must be in relatively good health, able to swallow pills, and willing to use two forms of contraception. Excluded are pregnant or breastfeeding women, those with significant illnesses like uncontrolled infections or heart problems, known HIV requiring specific therapy, Hepatitis B/C, brain metastases unless stable and not on anti-seizure meds.

Inclusion Criteria

I can do most of my daily activities without help.
My blood, liver, and kidney functions are within normal ranges.
I have recovered from previous treatment side effects.
See 10 more

Exclusion Criteria

My brain metastases have been stable for at least 1 month after treatment.
I am taking medication for seizures.
I do not have any major health issues that would stop me from participating in the study.
See 3 more

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks
Multiple visits (in-person)

Treatment

Participants receive Aza-TdC orally once a day for 5 days a week for 2 weeks, with one week off, in 21-day cycles

21-day cycles
Weekly visits (in-person) for blood tests and scans every 6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks
2 visits (in-person)

Extension

Participants may continue treatment as long as the drug is tolerated and the cancer is stable or improving

Indefinite, based on patient response

Treatment Details

Interventions

  • Aza-TdC
Trial Overview The trial is testing the safety and appropriate dosage of a new drug called Aza-TdC taken orally by patients with advanced solid tumors. The drug is given in cycles: daily for five days followed by two days off in weeks one and two; no drug in week three. Treatment continues if tolerated well and cancer doesn't progress.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: 1Experimental Treatment1 Intervention
Aza-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

Find a Clinic Near You

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials
14,080
Recruited
41,180,000+

Findings from Research

The chemotherapeutic agent 5-aza-2'-deoxycitidine (5-aza-dC) induces cancer cell death primarily through its interaction with the DNA methyltransferases Dnmt3a and Dnmt3b, as shown in experiments with various Dnmt null mutant embryonic stem cells.
Dnmt3a-Dnmt3b double null cells were found to be highly resistant to 5-aza-dC, indicating that the presence of these enzymes is crucial for the drug's cytotoxic effects, suggesting that 5-aza-dC may be particularly effective in treating cancers that express Dnmt3.
De novo DNA methyltransferases Dnmt3a and Dnmt3b primarily mediate the cytotoxic effect of 5-aza-2'-deoxycytidine.Oka, M., Meacham, AM., Hamazaki, T., et al.[2023]
5-aza-2-deoxycytidine (ZdCyd) effectively inhibits the growth of bile duct cancer cells (QBC939) by inducing apoptosis and blocking the cell cycle, with effects that are both dose and time-dependent.
ZdCyd enhances the effectiveness of other chemotherapy drugs, showing potential for improved treatment outcomes in bile duct cancer when used in combination therapies.
Inhibitory effect of methylation inhibitor 5-aza-2-deoxycytidine on bile duct cancer cell line in vivo and in vitro.Tang, QB., Sun, HW., Zou, SQ.[2014]
5-Aza-2'-deoxycytidine (5-AZA-CdR) is an effective epigenetic drug that can reactivate tumor suppressor genes silenced by DNA methylation, showing promise in treating myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) based on preclinical and clinical data.
The drug has a short plasma half-life of about 20 minutes in humans, suggesting that combining it with a cytidine deaminase inhibitor could enhance its effectiveness, especially in achieving complete remissions in patients with cancer.
Pharmacokinetic and pharmacodynamic analysis of 5-aza-2'-deoxycytidine (decitabine) in the design of its dose-schedule for cancer therapy.Karahoca, M., Momparler, RL.[2022]

References

De novo DNA methyltransferases Dnmt3a and Dnmt3b primarily mediate the cytotoxic effect of 5-aza-2'-deoxycytidine. [2023]
Inhibitory effect of methylation inhibitor 5-aza-2-deoxycytidine on bile duct cancer cell line in vivo and in vitro. [2014]
Pharmacokinetic and pharmacodynamic analysis of 5-aza-2'-deoxycytidine (decitabine) in the design of its dose-schedule for cancer therapy. [2022]
Treatment of human cell lines with 5-azacytidine may result in profound alterations in clonogenicity and growth rate. [2019]
Comprehensive comparison between azacytidine and decitabine treatment in an acute myeloid leukemia cell line. [2022]
Phase II study of subcutaneously administered 5-azacytidine (NSC-102816) in patients with metastatic malignant melanoma. [2019]
[Effects and mechanisms of 5-aza-2'-deoxycytidine on endometrial cancer cell.]. [2018]
Pilot phase I-II study on 5-aza-2'-deoxycytidine (Decitabine) in patients with metastatic lung cancer. [2020]
Phase II study of 5-azacytidine in solid tumors. [2013]
10.United Statespubmed.ncbi.nlm.nih.gov
5-Aza-4'-thio-2'-deoxycytidine, a New Orally Bioavailable Nontoxic "Best-in-Class": DNA Methyltransferase 1-Depleting Agent in Clinical Development. [2022]
11.United Statespubmed.ncbi.nlm.nih.gov
Phase I and pharmacokinetic study of 5-aza-2'-deoxycytidine (NSC 127716) in cancer patients. [2018]
Pharmacological approach for optimization of the dose schedule of 5-Aza-2'-deoxycytidine (Decitabine) for the therapy of leukemia. [2018]
Pharmacological approach for optimization of the dose schedule of 5-Aza-2'-deoxycytidine (Decitabine) for the therapy of leukemia. [2019]