Low Dose Azacitidine for Early Stage Breast Cancer

(BRE-04 Trial)

Overseen By Mercedes Carrasquillo, BS

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: University of Illinois at Chicago

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

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 1 week

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a medication called azacitidine to determine if it can help the body's immune cells, known as tumor infiltrating lymphocytes, combat early-stage breast cancer. The focus is on patients who have not yet received any treatment for their high-risk early-stage breast cancer. Suitable candidates include individuals with breast cancer that hasn't spread to other parts of the body and have specific cancer types, such as TNBC (triple-negative breast cancer) or HER2 positive. Participants will receive azacitidine as a daily injection for five days. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that azacitidine is likely to be safe for humans?

Research has shown that azacitidine, the treatment used in this trial, has been tested for safety in other conditions. In studies with patients who have myelodysplastic syndromes (MDS), a type of blood disorder, azacitidine's safety remained consistent even at different doses, meaning the side effects were manageable and stable across doses.

The treatment has also been well-tolerated in other cancer studies. For instance, when combined with another drug in advanced breast cancer cases, patients experienced expected and manageable side effects. While every treatment carries potential risks, azacitidine has a history of being well-tolerated in various situations. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for breast cancer?

Azacitidine is unique because it offers a new approach to treating early-stage breast cancer by potentially reactivating tumor suppressor genes through its role as a hypomethylating agent. Unlike traditional treatments like surgery, radiation, or chemotherapy, which directly target cancer cells, azacitidine works on an epigenetic level, modifying the expression of genes involved in cancer growth. Researchers are excited because this method could lead to more personalized and effective treatments, especially for high-risk patients who haven't responded well to conventional therapies.

What evidence suggests that low dose azacitidine might be an effective treatment for early stage breast cancer?

Research suggests that azacitidine could be promising for treating high-risk early-stage breast cancer. In this trial, all participants will receive azacitidine. One study showed that patients who responded well to azacitidine, either fully or partially, had a 95% lower risk of death compared to those receiving standard treatments. Another study examined azacitidine's effect on immune cells in tumors, known as tumor infiltrating lymphocytes (TILs), and found changes in their numbers after treatment. These findings indicate that azacitidine might improve patient outcomes by influencing the immune environment in tumors. ^{1 2 3 6 7}

Who Is on the Research Team?

Vijayakrishna Krishnamurthy Gadi, MD, PhD

Principal Investigator

University of Illinois at Chicago

Are You a Good Fit for This Trial?

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

My breast cancer is confirmed and at an early to mid-stage, without distant spread.

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine

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.

How Is the Trial Designed?

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 European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

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+

Published Research Related to This Trial

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]

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]

In a study of 149 patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), azacitidine treatment resulted in a median progression-free survival (PFS) of 10.9 months and an overall survival (OS) of 14.1 months, demonstrating its effectiveness in a real-world clinical setting.

The safety profile of azacitidine was consistent with previous clinical trials, and factors such as Eastern Cooperative Oncology Group (ECOG) performance status and red blood cell transfusion prior to treatment were identified as predictive factors for better PFS.

NCBI (Pubmed)

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). Wehmeyer, J., Zaiss, M., Losem, C., et al.[2019]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5457329/

Combination Epigenetic Therapy in Advanced Breast ... We did not observe any clinical response in the first stage of 13 patients with TNBC, and this cohort was closed to further accrual. At a median ...

2. withpower.com withpower.com/trial/phase-3-breast-neoplasms-9-2021-ff578

Low Dose Azacitidine for Early Stage Breast Cancer Achieving an Overall Response (complete or partial remission) with azacitidine drastically reduced the risk of death by 95% compared to conventional treatments, ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04891068

Study Details | NCT04891068 | BRE-04: Window of ... Change in tumor infiltrating lymphocytes (TILs) count in primary tumors from patients with high-risk early stage breast cancer following low-dose azacitidine ...

4. aacrjournals.org aacrjournals.org/clincancerres/article/23/11/2691/79781/Combination-Epigenetic-Therapy-in-Advanced-Breast

Combination Epigenetic Therapy in Advanced Breast Cancer ... In a multicenter phase II study, we have demonstrated that the combination of epigenetic modifiers, 5-azacitidine and entinostat, was well tolerated in patients ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7225776/

Hypomethylating Agent Azacitidine Is Effective in Treating ... Collectively, in vitro results support the hypothesis that AZA is effective in treating brain metastasis of breast cancer in vivo. The BBB acts ...

6. onclive.com onclive.com/view/dr-daver-on-initial-efficacy-and-safety-data-with-bexmarilimab-plus-azacitidine-in-higher-risk-mds

Dr Daver on Initial Efficacy and Safety Data With ... Naval G. Daver, MD, discusses early efficacy and safety data for bexmarilimab plus azacitidine in patients with higher-risk myelodysplastic syndrome.

7. cancernetwork.com cancernetwork.com/view/safety-profile-of-oral-azacitadine-remains-consistent-in-lower-risk-mds

Safety Profile of Oral Azacitadine Remains Consistent in ... The safety profile of oral azacitadine was shown to be similar across the 200-mg and 300-mg arms in patients with lower- to intermediate-risk MDS.