Azeliragon + Chemotherapy for Breast Cancer

(RAGE Trial)

Recruiting at2 trial locations

Overseen by Candace Mainor, MD

Age: 18+

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Georgetown University

Must not be taking: Strong CYP2C8 inhibitors

Disqualifiers: Stage IV cancer, Neurodegenerative disease, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing azeliragon, a drug that may reduce heart and brain damage caused by chemotherapy. It targets patients receiving anthracycline chemotherapy, which can harm the heart and cause cognitive decline. Azeliragon works by blocking a pathway involved in inflammation and cell damage. It is being studied as a potential treatment to slow disease progression in patients with mild Alzheimer's Disease.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take strong CYP2C8 inhibitors. If you are on such medications, you must stop them at least 5 days before starting the trial.

How does the drug Azeliragon differ from other breast cancer treatments?

Azeliragon is unique because it is being studied in combination with chemotherapy for breast cancer, potentially offering a new approach by targeting specific pathways involved in cancer cell survival and growth, which may differ from standard chemotherapy alone. ^{1 2 3 4 5}

Research Team

Candace Mainor, MD

Principal Investigator

Georgetown University

Eligibility Criteria

This trial is for women with early-stage breast cancer (stage I-III) who are about to start chemotherapy and have not had previous treatments for any cancer. They must be over 18, have good organ function, no severe neurological or psychiatric conditions that could affect consent, and agree to use contraception. HIV-positive patients on effective therapy can join.

Inclusion Criteria

I am 18 years old or older.

I have not had chemotherapy, radiotherapy, or systemic therapy for early stage breast cancer or any other cancer.

I have no history of stroke, head injury, or diseases like Alzheimer's.

Exclusion Criteria

I do not have any serious illnesses that would stop me from following the study's requirements.

I am not taking any strong CYP2C8 inhibitors, or have stopped them as required.

I have had chemotherapy, radiotherapy, systemic therapy, or hormonal therapy before.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive azeliragon co-administered with chemotherapy to evaluate its effects on cardiac toxicity and safety

6 cycles (Cohort 2 and 3: 21 days per cycle; Cohort 1 and 4: 14 days per cycle)

Multiple visits per cycle for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including changes in troponin levels and pharmacokinetic assessments

4 weeks

Treatment Details

Interventions

• Azeliragon (RAGE Inhibitor)

Trial Overview The study tests azeliragon's ability to reduce heart damage from certain chemotherapies (TCHP, ddAC/ddT, TC) and its safety when combined with these treatments. It aims to see if blocking the RAGE pathway lessens heart toxicity and cognitive decline caused by chemotherapy.

Participant Groups

Group I: Cohort 4: TTP488 (Azeliragon) co-administered with chemotherapy regimen that includes ddAC Experimental Treatment 2 Interventions

given at the end of the chemotherapy plan \[can include: (1)weekly carboplatin + paclitaxel + pembrolizumab followed by pembrolizumab + dose dense doxorubicin and cyclophosphamide; (2) weekly carboplatin + paclitaxel followed by dose dense doxorubicin and cyclophosphamide; (3) weekly or dose dense paclitaxel followed by dose dense doxorubicin and cyclophosphamide\] Cohort 4: On day 7 of cycle 3, twelve capsules of azeliragon taken daily for 6 days, and then four capsules of Azeliragon each day continuously through the end of that cycle of chemotherapy, extending into Cycle 4 Day 2 (C4D2).

Group II: Cohort 3: TTP488 (Azeliragon) co-administered with TCHP Experimental Treatment 2 Interventions

TCHP: docetaxel, carboplatin, trastuzumab, and pertuzumab Cohort 3: Cycle 5 Day 14 (C5D14), take twelve capsules of azeliragon daily for 6 days, then four capsules of Azeliragon each day continuously through the end of that cycle of chemotherapy, extending into Cycle 6 Day 2 (C6D2).

Group III: Cohort 2: TTP488 (Azeliragon) co-administered with TC Experimental Treatment 2 Interventions

TC: docetaxel and cyclophosphamide Cohort 2a (6 cycles): Cycle 5 Day 14 (C5D14), take twelve capsules of azeliragon daily for 6 days, then four capsules of Azeliragon each day continuously through the end of that cycle of chemotherapy, extending into Cycle 6 Day 2 (C6D2). Cohort 2b (4 cycles): Cycle 3 Day 14 (C3D14), take twelve capsules of azeliragon daily for 6 days, then four capsules of Azeliragon each day continuously through the end of that cycle of chemotherapy, extending into Cycle 4 Day 2 (C4D2).

Group IV: Cohort 1: TTP488 (Azeliragon) co-administered with dose dense paclitaxel (ddAC/ddT) Experimental Treatment 2 Interventions

Cohort 1: On day 7 of cycle 3, twelve capsules of azeliragon taken daily for 6 days, and then four capsules of Azeliragon each day continuously through the end of that cycle of chemotherapy, extending into Cycle 4 Day 2 (C4D2).

Who Is Running the Clinical Trial?

Georgetown University

Lead Sponsor

Trials

355

Recruited

142,000+

Dr. Ivica Labuda

Georgetown University

Chief Executive Officer since 2022

PhD in Biochemistry and Molecular & Cellular Biology from Slovak Academy of Sciences, University of Graz, and Rutgers University

Dr. Richard Ascione

Georgetown University

Chief Medical Officer since 2023

MD from Georgetown University Medical School

Findings from Research

In a study of 33 patients with metastatic breast cancer who had previously failed multiple chemotherapy regimens, AZQ treatment resulted in only two partial responses, indicating limited efficacy.

The treatment was associated with dose-limiting myelosuppression, primarily thrombocytopenia, while other side effects were mild, suggesting that while AZQ has some safety concerns, it is unlikely to be an effective option for refractory breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II clinical evaluation of AZQ in metastatic breast cancer. Yap, HY., Bedikian, AY., Schell, FC., et al.[2014]

The ATR inhibitor AZD6738 effectively inhibits the growth of human breast cancer cells, particularly in HER2-positive cell lines, with IC50 values below 1 μmol/L in nine out of thirteen tested cell lines.

AZD6738 induces apoptosis and S phase arrest in sensitive breast cancer cells by reducing CHK1 expression, leading to DNA damage accumulation, and shows potential for synergistic effects when combined with cisplatin, suggesting a promising avenue for future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells. Kim, HJ., Min, A., Im, SA., et al.[2021]

The combination of AZD0156, an ATM inhibitor, with irinotecan showed enhanced anti-proliferative effects in colorectal cancer cell lines, particularly by increasing G2/M cell cycle arrest, suggesting a potential for improved efficacy in chemotherapy regimens.

In preclinical models, the combination therapy resulted in greater tumor growth inhibition compared to single-agent treatments, indicating that AZD0156 may enhance the effectiveness of irinotecan in treating colorectal cancer, although results varied based on the DNA damage response mutation profiles of the models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ATM kinase inhibitor AZD0156 in combination with irinotecan and 5-fluorouracil in preclinical models of colorectal cancer. Davis, SL., Hartman, SJ., Bagby, SM., et al.[2022]

In a study involving 17 patients with metastatic breast cancer who had not responded to previous chemotherapy, treatment with intravenous AZQ showed no therapeutic responses.

The main side effect observed was myelosuppression, which limited the dosage, and one patient experienced a serious liver infarction potentially linked to the treatment, indicating safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of metastatic breast cancer with AZQ: a phase II trial. Martino, S., Ratanatharathorn, V., Samal, BA., et al.[2019]

AZD6738 is a new ATR kinase inhibitor that can induce cell death and senescence in non-small cell lung cancer (NSCLC) cell lines, showing promise as a cancer treatment.

Surprisingly, AZD6738 is well-tolerated in mice over 14 days and enhances the effectiveness of cisplatin, particularly in ATM-deficient NSCLC, leading to the resolution of tumors in xenograft models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo. Vendetti, FP., Lau, A., Schamus, S., et al.[2022]

References

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

Phase II clinical evaluation of AZQ in metastatic breast cancer. [2014]

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

Anti-tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells. [2021]

3. England pubmed.ncbi.nlm.nih.gov

ATM kinase inhibitor AZD0156 in combination with irinotecan and 5-fluorouracil in preclinical models of colorectal cancer. [2022]

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

Treatment of metastatic breast cancer with AZQ: a phase II trial. [2019]

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

The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo. [2022]