Aza-TdC for Solid Tumors

Overseen By DTC Referral Coordinators

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anti-seizure medications

Disqualifiers: Pregnancy, HIV, Hepatitis B, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 8

Duration: 21-day cycles

65 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new drug called Aza-TdC (also known as 5-Aza-4'-thio-2'-deoxycytidine) to determine if it can safely reactivate certain genes and slow tumor growth in people with advanced cancer. Participants will take the drug orally in cycles: 5 days a week for 2 weeks, followed by a week off. The trial seeks adults with solid tumors that have worsened after standard treatments or for which no effective therapy exists. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

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.

Is there any evidence suggesting that Aza-TdC is likely to be safe for humans?

Research has shown that Aza-TdC is generally safe for people. One study found that a dose of 32 mg of Aza-TdC was well-tolerated, with most participants not experiencing serious side effects at this level. The side effects resembled those of other approved drugs in the same category, suggesting that Aza-TdC is as safe as existing treatments.

However, as this is an early-stage trial, the primary goal is to determine the safest dose. Researchers will closely monitor participants to ensure their safety throughout the study. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike standard chemotherapy treatments for solid tumors, Aza-TdC is unique because it is administered orally, offering a more convenient option for patients compared to intravenous methods. Researchers are excited about Aza-TdC because it targets tumors with a novel mechanism of action, potentially increasing its effectiveness against cancer cells. Additionally, the treatment's schedule, with dosing for 5 days followed by a break, may help minimize side effects while maintaining effectiveness, which is a significant improvement over traditional treatments.

What evidence suggests that Aza-TdC might be an effective treatment for solid tumors?

Research has shown that Aza-TdC, the treatment under study in this trial, may effectively combat solid tumors. Studies in lab models have found that Aza-TdC can reduce levels of a protein called DNMT1, which is linked to cancer growth. This drug outperforms similar treatments in these models. Aza-TdC might help activate genes that slow tumor growth. Although this is early research, these findings offer hope for its effectiveness in treating advanced cancers. ^{1 3 5 6 7}

Who Is on the Research Team?

James H Doroshow, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: 1 Experimental Treatment 1 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

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Azacytidine (AzaC) and decitabine (AzadC) both reduce global DNA methylation and affect oncogene expression in acute myeloid leukemia cells, but only AzadC effectively induces apoptosis, highlighting a difference in their therapeutic efficacy.

The study found that the level of hydroxy-methyl-deoxycytidine (hmdC) is a potential biomarker for determining the effectiveness of AzaC and AzadC treatments, as higher hmdC levels correlated with increased cell death in leukemic cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive comparison between azacytidine and decitabine treatment in an acute myeloid leukemia cell line. Aumer, T., Gremmelmaier, CB., Runtsch, LS., et al.[2022]

5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) effectively depletes the DNMT1 enzyme in mouse tumor models, showing similar efficacy to the existing treatment 5-aza-2'-deoxycytidine (aza-dCyd) but with significantly lower toxicity.

Aza-T-dCyd has a larger therapeutic index compared to aza-dCyd, meaning it can selectively target DNMT1 without causing as many harmful side effects, making it a promising candidate for treating diseases linked to DNA methylation.

NCBI (Pubmed)

pubmed.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. Parker, WB., Thottassery, JV.[2022]

In a study involving 30 patients with advanced metastatic malignant melanoma who were resistant to previous treatments, 5-azacytidine was administered at a dosage of 100 mg/m2/day for 10 days.

The treatment resulted in significant toxicities, including hematologic, gastrointestinal, and cutaneous issues, but no antitumor activity was observed, indicating that 5-azacytidine may not be effective for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of subcutaneously administered 5-azacytidine (NSC-102816) in patients with metastatic malignant melanoma. Bellet, RE., Catalano, RB., Mastrangelo, MJ., et al.[2019]

5-Aza-2'-deoxycytidine (5-Aza-CdR) effectively inhibits the growth of endometrial cancer cells (HEC-1B) and induces apoptosis in a concentration- and time-dependent manner, demonstrating its potential as a therapeutic agent.

5-Aza-CdR treatment restores the expression of the RASSF1A gene by reversing its hypermethylation in HEC-1B cells, indicating a mechanism by which it may exert its anti-cancer effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects and mechanisms of 5-aza-2'-deoxycytidine on endometrial cancer cell.]. Zhang, YQ., Mao, XY., Ma, XL., et al.[2018]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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]

Treatment with 5-azacytidine (5-azaC) for 3 days was found to be nontoxic and nonmutagenic in three human cell lines, indicating its safety for potential therapeutic applications.

Some subclones of the treated cell lines exhibited significantly enhanced growth properties, with population-doubling times reduced to 12-14 hours and cloning efficiencies exceeding 50%, suggesting that 5-azaC can activate genes that promote rapid cell proliferation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of human cell lines with 5-azacytidine may result in profound alterations in clonogenicity and growth rate. Olsson, L., Due, C., Diamant, M.[2019]

5-Aza-2'-deoxycytidine (5-Aza-CdR) is an effective treatment for leukemia that works by demethylating DNA, potentially reactivating tumor suppressor genes, but its effectiveness is influenced by the dosing schedule due to its short half-life and S phase specificity.

The major side effect of 5-Aza-CdR is granulocytopenia, and strategies such as using hematopoietic growth factors or gene therapy to enhance drug resistance in normal cells are being explored to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological approach for optimization of the dose schedule of 5-Aza-2'-deoxycytidine (Decitabine) for the therapy of leukemia. Momparler, RL., Côté, S., Eliopoulos, N.[2019]

5-Aza-2'-deoxycytidine (5-AZA-CdR) demonstrated a potent antineoplastic effect in laboratory studies and showed potential clinical activity in a phase I-II study with 15 patients suffering from stage IV non-small cell lung carcinoma, resulting in a median survival of 6.7 months for those treated.

The main side effect observed was hematopoietic toxicity, which necessitated a recovery period of 5-6 weeks before subsequent treatment cycles, indicating a need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot phase I-II study on 5-aza-2'-deoxycytidine (Decitabine) in patients with metastatic lung cancer. Momparler, RL., Bouffard, DY., Momparler, LF., et al.[2020]

In a phase I trial involving 21 patients with advanced solid tumors, 5-aza-2'-deoxycytidine (5-aza-dCyd) showed a dose-limiting toxicity of myelosuppression, indicating that while the drug has potential, careful monitoring of blood cell levels is necessary during treatment.

The study observed one partial response in a patient and recommended a dosing schedule of 75 mg/m2 in three infusions every 5 weeks for future phase II trials, suggesting that this regimen may be effective for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic study of 5-aza-2'-deoxycytidine (NSC 127716) in cancer patients. van Groeningen, CJ., Leyva, A., O'Brien, AM., et al.[2018]

5-Aza-2'-deoxycytidine (5-Aza-CdR) is an effective treatment for leukemia that works by demethylating DNA, potentially reactivating tumor suppressor genes, but its effectiveness is influenced by the dosing schedule due to its short half-life and S phase specificity.

The major side effect of 5-Aza-CdR is granulocytopenia, and strategies such as using hematopoietic growth factors or gene therapy to enhance drug resistance in normal cells are being explored to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological approach for optimization of the dose schedule of 5-Aza-2'-deoxycytidine (Decitabine) for the therapy of leukemia. Momparler, RL., Côté, S., Eliopoulos, N.[2018]

In a phase II study of 5-azacytidine involving 191 eligible patients with solid tumors, only 2.6% showed partial regression of their tumors, indicating limited efficacy.

The treatment was associated with significant toxicities, including myelosuppression and gastrointestinal issues, leading to 13 deaths due to drug-related complications, highlighting safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of 5-azacytidine in solid tumors. Quagliana, JM., O'Bryan, RM., Baker, L., et al.[2013]

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03366116

NCT03366116 | 5-aza-4'-Thio-2'-Deoxycytidine (Aza-TdC) ...

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

2.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.3088

Phase I trial of 5-aza-4'-thio-2'-deoxycytidine (Aza-TdC) in ...

Aza-TdC has also shown improved preclinical antitumor activity compared to other hypomethylating agents in some solid tumor xenograft models. In ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9164309/

5-Aza-4′-thio-2′-deoxycytidine, a New Orally ...

Although active against heme malignancies, these agents are much less effective in solid tumors. ... deoxycytidine (aza-TdC) in patients with advanced solid ...

4.

trialx.com

trialx.com/clinical-trials/listings/254354/5-aza-4-thio-2-deoxycytidine-aza-tdc-in-people-with-advanced-solid-tumors/

Thio-2'-Deoxycytidine (Aza-TdC) in ...

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

5.

trialfinder.panfoundation.org

trialfinder.panfoundation.org/en-US/trial/listing/161258

Deoxycytidine (Aza-TdC) in People With Advanced Solid Tumors

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 ...

6.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.TPS3148

Trial in progress abstract phase I trial of 5-aza-4'-thio-2'

This study seeks to evaluate the safety and maximum tolerated dose (MTD) of oral Aza-TdC in patients with advanced solid tumors.

7.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03366116

NCT03366116 | 5-aza-4'-Thio-2'-Deoxycytidine (Aza-TdC) ...

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