Low Dose Azacitidine for Early Stage Breast Cancer

(BRE-04 Trial)

Overseen By Mercedes Carrasquillo, BS

Age: 18+

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Illinois at Chicago

Disqualifiers: Breast implants, Active infection, HIV/AIDS, others

No Placebo Group

Prior Safety Data

Approved in 5 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing if low dose azacitidine can help the immune system fight high-risk early stage breast cancer. The treatment aims to increase immune cells that attack cancer cells. It targets patients whose cancer is more likely to return or spread.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the drug Azacitidine for early stage breast cancer?

Research shows that Azacitidine, a drug used for blood disorders, has been effective in reducing tumor burden and increasing survival in preclinical models of brain metastasis from breast cancer. This suggests potential benefits for breast cancer treatment. ^{1 2 3 4 5}

Is azacitidine safe for humans?

Azacitidine, also known as Vidaza, has been used safely in patients with certain blood disorders like myelodysplastic syndromes and acute myeloid leukemia. It is generally well-tolerated, with the most common side effect being low blood cell counts. ^{2 6 7 8 9}

How is the drug Azacitidine unique for treating early-stage breast cancer?

Azacitidine is unique because it is a hypomethylating agent, originally used for blood cancers like myelodysplastic syndromes and acute myeloid leukemia, and it works by altering the DNA in cancer cells to stop their growth. Its use in early-stage breast cancer is novel, as it is not a standard treatment for this condition, and it is being explored for its potential to target cancer cells differently than traditional breast cancer therapies. ^{2 6 7 8 10}

Research Team

Vijayakrishna Krishnamurthy Gadi, MD, PhD

Principal Investigator

University of Illinois at Chicago

Eligibility Criteria

This trial is for adults with high-risk early stage breast cancer that hasn't spread far and hasn't been treated yet. Eligible patients have tumors over 1cm, are not pregnant or breastfeeding, and can follow the study plan. They should be in good health overall without serious illnesses that could interfere with the trial.

Inclusion Criteria

I can follow the study's procedures as explained to me.

I am 18 years old or older.

I can take care of myself and am up and about more than half of my waking hours.

Exclusion Criteria

Any mental or medical condition that prevents the patient from giving informed consent or participating in the trial unless a Legal Authorized Representative (LAR) is in place to sign on behalf of the patient

I have had treatments like chemotherapy or radiation for my current breast cancer.

Pregnant or nursing

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Treatment

Participants receive low dose azacitidine therapy for 5 consecutive days

1 week

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Long-term Follow-up

Participants are monitored for overall survival and disease-free survival

2 years

Treatment Details

Interventions

• Azacitidine (Anti-metabolites)

Trial Overview The trial tests low dose Azacitidine's effect on immune cells within breast tumors. Researchers will compare these immune cell counts before and after treatment to see if there's a change.

Participant Groups

Group I: Single arm with previously untreated high risk early stage breast cancer Experimental Treatment 1 Intervention

All participants will receive azacitidine 50mg/m2 SC daily for five consecutive days.

Azacitidine is already approved in Canada, Japan for the following indications:

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

University of Illinois at Chicago

Lead Sponsor

Trials

653

Recruited

1,574,000+

Findings from Research

5-azacytidine (5-aza-CR) and 5-aza-2'-deoxycytidine (5-aza-dC) are both DNA methyltransferase inhibitors that trigger distinct molecular responses in cancer cells, which is crucial for developing effective combination therapies.

In vitro and in vivo studies showed that 5-aza-dC induces p53-dependent senescence and DNA damage, while 5-aza-CR promotes apoptosis through caspase activation, highlighting their different mechanisms of action despite their structural similarities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential induction of apoptosis and senescence by the DNA methyltransferase inhibitors 5-azacytidine and 5-aza-2'-deoxycytidine in solid tumor cells. Venturelli, S., Berger, A., Weiland, T., et al.[2020]

Azacitidine is an effective and well-tolerated treatment for patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), including older patients who are ineligible for stem cell transplants, as demonstrated in pivotal phase 3 trials.

It is the only approved hypomethylating agent that has been shown to prolong overall survival compared to conventional care, making it the recommended first-line treatment for most patients with higher-risk MDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. Scott, LJ.[2022]

In the phase III AZA-001 study, azacitidine significantly improved overall survival in patients with higher-risk myelodysplastic syndromes compared to conventional care, with a hazard ratio of 0.58, indicating a 42% reduction in the risk of death.

Achieving an Overall Response (complete or partial remission) with azacitidine drastically reduced the risk of death by 95% compared to conventional treatments, highlighting its efficacy even in patients who only achieved hematologic improvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial. Gore, SD., Fenaux, P., Santini, V., et al.[2022]

In a study of 687 patients with higher-risk myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML) treated with 5-azacytidine (5-AZA), factors such as the revised International Prognostic Scoring System (IPSS-R), Eastern Cooperative Oncology Group Performance Status (ECOG PS), and high baseline serum ferritin levels were found to independently predict response to treatment and overall survival.

The study developed new modified risk classification systems (H-PSS and H-PSS-R) that better predict overall survival and leukemia-free survival in patients treated with 5-AZA, demonstrating improved predictive power compared to previous models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serum ferritin and ECOG performance status predict the response and improve the prognostic value of IPSS or IPSS-R in patients with high-risk myelodysplastic syndromes and oligoblastic acute myeloid leukemia treated with 5-azacytidine: a retrospective analysis of the Hellenic national registry of myelodysplastic and hypoplastic syndromes. Papageorgiou, SG., Kotsianidis, I., Bouchla, A., et al.[2022]

The hypomethylating agent azacitidine (AZA) shows promise as a novel treatment for brain metastases in breast cancer, demonstrating a significantly lower IC50 in brain-colonizing cells compared to parental cells, indicating higher sensitivity to the drug.

In preclinical mouse models, AZA treatment significantly reduced tumor burden and increased survival rates, while also promoting apoptosis and inhibiting key pathways associated with cancer progression, suggesting its potential efficacy in managing brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypomethylating Agent Azacitidine Is Effective in Treating Brain Metastasis Triple-Negative Breast Cancer Through Regulation of DNA Methylation of Keratin 18 Gene. Butler, C., Sprowls, S., Szalai, G., et al.[2023]

The Vidaza Access Program in Belgium successfully facilitated access to azacitidine treatment for 175 patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) by streamlining the approval process for patient dossiers.

Out of the 175 patient dossiers submitted, 163 were approved by Celgene, demonstrating the program's effectiveness in ensuring timely treatment initiation without financial risk to hospitals, which is crucial for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. Meers, S., Selleslag, D., Potier, H., et al.[2018]

Azacitidine (Vidaza) is the only drug approved in the EU that significantly prolongs survival in adults with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), making it a crucial treatment option for patients not eligible for stem cell transplantation.

The treatment is associated with a lower risk of AML progression and higher rates of remission and blood transfusion independence, while maintaining an acceptable safety profile, with peripheral cytopenias being the most common side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. Keating, GM.[2021]

In a real-life study of 49 patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), azacitidine demonstrated a clinically acceptable safety profile, with 67.3% of patients experiencing treatment-related adverse events.

Efficacy results showed that 41.4% of MDS and CMML patients achieved a complete or partial response, and 43.8% of transfusion-dependent patients became transfusion-independent, with a median overall survival of 490 days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. Beguin, Y., Selleslag, D., Meers, S., et al.[2015]

Azacitidine significantly improves response rates and overall survival in patients with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), with a median survival increase of 9.4 months compared to conventional care in higher-risk patients.

The treatment is generally well tolerated, with peripheral cytopenias being the most common side effect, along with gastrointestinal issues and injection-site reactions, making it a viable option for elderly patients as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia. Keating, GM.[2022]

References

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

Differential induction of apoptosis and senescence by the DNA methyltransferase inhibitors 5-azacytidine and 5-aza-2'-deoxycytidine in solid tumor cells. [2020]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. [2022]

3. Italy pubmed.ncbi.nlm.nih.gov

A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Serum ferritin and ECOG performance status predict the response and improve the prognostic value of IPSS or IPSS-R in patients with high-risk myelodysplastic syndromes and oligoblastic acute myeloid leukemia treated with 5-azacytidine: a retrospective analysis of the Hellenic national registry of myelodysplastic and hypoplastic syndromes. [2022]

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

Hypomethylating Agent Azacitidine Is Effective in Treating Brain Metastasis Triple-Negative Breast Cancer Through Regulation of DNA Methylation of Keratin 18 Gene. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). [2019]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. [2015]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia. [2022]