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

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. ^{1 2 3 4 5}

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. ^{3 6 7 8 9}

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. ^{8 10 11 12 13}

Research Team

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.

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

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

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+

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.

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]

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]

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]

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) 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 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]

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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

De novo DNA methyltransferases Dnmt3a and Dnmt3b primarily mediate the cytotoxic effect of 5-aza-2'-deoxycytidine. [2023]

2. Singapore 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. [2014]

3. Germany 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. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Treatment of human cell lines with 5-azacytidine may result in profound alterations in clonogenicity and growth rate. [2019]

5. Germany pubmed.ncbi.nlm.nih.gov

Comprehensive comparison between azacytidine and decitabine treatment in an acute myeloid leukemia cell line. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Phase II study of subcutaneously administered 5-azacytidine (NSC-102816) in patients with metastatic malignant melanoma. [2019]

7. China pubmed.ncbi.nlm.nih.gov

[Effects and mechanisms of 5-aza-2'-deoxycytidine on endometrial cancer cell.]. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Pilot phase I-II study on 5-aza-2'-deoxycytidine (Decitabine) in patients with metastatic lung cancer. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Phase II study of 5-azacytidine in solid tumors. [2013]

10. United States 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. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic study of 5-aza-2'-deoxycytidine (NSC 127716) in cancer patients. [2018]

12. England pubmed.ncbi.nlm.nih.gov

Pharmacological approach for optimization of the dose schedule of 5-Aza-2'-deoxycytidine (Decitabine) for the therapy of leukemia. [2018]

13. England pubmed.ncbi.nlm.nih.gov

Pharmacological approach for optimization of the dose schedule of 5-Aza-2'-deoxycytidine (Decitabine) for the therapy of leukemia. [2019]