Azeliragon + Chemotherapy for Breast Cancer

(RAGE Trial)

Recruiting at 4 trial locations

Overseen By Lana Kheir

Age: 18+

Sex: Female

Trial Phase: Phase 1 & 2

Sponsor: Georgetown University

Must not be taking: Strong CYP2C8 inhibitors

Disqualifiers: Stage IV cancer, Neurodegenerative disease, others

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

Compensation: Varies

Number of Visits: Unknown

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

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a treatment called azeliragon, which might help reduce heart damage and memory issues caused by chemotherapy in breast cancer patients. Researchers seek to determine if adding azeliragon to various chemotherapy regimens can safely protect the heart and brain without interfering with cancer treatment. The trial seeks participants with early-stage breast cancer who have not undergone previous cancer therapies and are preparing to start chemotherapy.

As a Phase 1 and Phase 2 trial, this research focuses on understanding how azeliragon works in people and measuring its effectiveness in a smaller group, offering participants a chance to contribute to groundbreaking research.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that azeliragon is generally safe. In studies involving over 2,000 people, azeliragon was used for up to 18 months and was well-tolerated. Early results from Alzheimer's disease trials suggested that azeliragon may be safe for humans. Additionally, azeliragon has been tested in breast cancer studies, where it demonstrated a good safety record. These studies indicate that azeliragon, when combined with chemotherapy, might be safe for patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Azeliragon for breast cancer treatment because it offers a novel approach by targeting the RAGE (receptor for advanced glycation end products) pathway. This mechanism is different from standard chemotherapy agents like paclitaxel and doxorubicin, which directly attack cancer cells. Azeliragon's unique action may enhance the effectiveness of existing chemotherapy regimens by potentially reducing inflammation and tumor growth. This innovative combination could lead to more effective and personalized treatment options for patients with breast cancer.

What evidence suggests that this trial's treatments could be effective for reducing cardiac toxicity in breast cancer patients?

Research suggests that azeliragon, also known as TTP488, might help slow the spread of triple-negative breast cancer (TNBC), a very aggressive cancer form. Studies indicate that it blocks a pathway called RAGE, which contributes to the cancer's spread. Previous human trials for other conditions have shown azeliragon to be safe. While most current evidence comes from lab and animal studies, early results are promising for its use in breast cancer. In this trial, participants will receive azeliragon with different chemotherapy regimens to evaluate its effectiveness and potential to reduce heart-related side effects from chemotherapy. ^{3 6 7 8 9}

Who Is on the Research Team?

Candace Mainor, MD

Principal Investigator

Georgetown University

Are You a Good Fit for This Trial?

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 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.

No psychiatric disorders which could interfere with their ability to consent. (Allowed psychiatric disorders may include but are not limited to: anxiety, depression, obsessive compulsive disorder, ADHD; as long as the disorder does not affect the ability to consent). Any other psychiatric disorders should be discussed with the Principal Investigator (PI) and will be allowed at the discretion of the PI.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Azeliragon

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10344964/

RAGE inhibitor TTP488 (Azeliragon) suppresses metastasis in ... These results show that TTP488 impairs metastasis of TNBC and further clarifies the signaling and cellular mechanisms through which RAGE mediates metastasis.

2. aacrjournals.org aacrjournals.org/cancerres/article/83/5_Supplement/P4-08-10/717057/Abstract-P4-08-10-Azeliragon-TTP488-an-orally

Abstract P4-08-10: Azeliragon (TTP488), an orally- available ... Importantly, TTP488 displays a high safety profile in human trials and has previously undergone Phase 3 clinical trials for Alzheimer's disease.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05256745

Study Details | NCT05256745 | RAGE Inhibition to ... This is a pilot study to evaluate the effects of azeliragon to decrease cardiac toxicity from chemotherapy and the safety of azelirgaon when given with ...

4. lombardi.georgetown.edu lombardi.georgetown.edu/news-release/biology-behind-new-drug-used-to-treat-triple-negative-breast-cancer-uncovered/

Biology Behind New Drug Used to Treat Triple-Negative ... TTP488 (azeliragon), an experimental drug, impairs aggressive, triple-negative breast cancer from metastasizing has been uncovered at the cellular level.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0960894X21006715

Design, synthesis and anti-TNBC activity of Azeliragon ... A patent using Azeliragon for treating breast cancer was submitted due to the positive nature of the results obtained. Therefore we supposed ...

6. nature.com nature.com/articles/s41523-023-00564-9

RAGE inhibitor TTP488 (Azeliragon) suppresses ... TTP488 has shown excellent safety profiles in clinical trials of Alzheimer's disease, with initial Phase II data also showing that TTP488 may ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37443146/

RAGE inhibitor TTP488 (Azeliragon) suppresses ... RAGE inhibitor TTP488 (Azeliragon) suppresses metastasis in triple-negative breast cancer ... Importantly, as TTP488 displays a favorable safety ...

8. cantex.com cantex.com/2023/08/10/cantex-pharmaceuticals-announces-article-published-in-npj-breast-cancer-highlighting-potential-role-of-rage-inhibition-to-prevent-metastasis-in-triple-negative-breast-cancer/

Cantex Pharmaceuticals Clinical safety data from these trials, involving more than 2000 individuals dosed for periods up to 18 months, indicate that azeliragon is very ...

9. onclive.com onclive.com/view/fda-grants-orphan-drug-designation-to-azeliragon-for-pancreatic-cancer

FDA Grants Orphan Drug Designation to Azeliragon for ... The FDA has granted orphan drug designation to azeliragon (TTP488) as a potential therapeutic option for patients with pancreatic cancer.