RAGE Inhibition to Decrease Cardiotoxicity in Women With Early Breast Cancer

NCT05256745 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: STUDY00003782
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 3

Brief Summary

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 chemotherapy. The Investigators hypothesize that there will be no significant interaction with Azeliragon and chemotherapy and that targeting the RAGE pathway will decrease anthracycline related cardiotoxicity and chemotherapy related cognitive decline.

Conditions

Non-metastatic Breast Cancer; Cancer Related Cognitive Decline

Outcome Measures

Primary Outcomes (4)

• Incidence of unacceptable toxicity

  Any Adverse Event (AE) considered unrelated to chemotherapy, underlying disease, disease progression, intercurrent illness or concomitant medications/therapies resulting in the inability to tolerate the cycle of chemotherapy

  1 cycle (Cohort 1 and 4 each cycle is 14 days; Cohort 2 and 3 each cycle is 21 days)

• Incidence of severe AE graded according to the CTCAE v.5

  1 cycle (Cohort 1 and 4 each cycle is 14 days; Cohort 2 and 3 each cycle is 21 days)

• Incidence of chemotherapy dose interruption, dose modification, dose discontinuation

  1 cycle (Cohort 1 and 4 each cycle is 14 days; Cohort 2 and 3 each cycle is 21 days)

• Change in Troponin level

  • Change in troponin levels after administration of chemotherapy, in those treated with and without azeliragon.

  Cohort 1 and 4: cycle 3 and cycle 4, day 1 and day 2 of 14 day cycle; Cohort 2 and 3:cycle 5 and cycle 6, day 1 and day 2 of 21 day cycle]

Secondary Outcomes (6)

• Pharmacokinetic (PK) assessment: Cmax

  Cohort 1 and 4: cycle 3 and cycle 4, day 1 and day 2 of 14 day cycle; Cohort 2 and 3:cycle 5 and cycle 6, day 1 and day 2 of 21 day cycle

• Pharmacokinetic (PK) assessment: tmax

  Cohort 1 and 4: cycle 3 and cycle 4, day 1 and day 2 of 14 day cycle; Cohort 2 and 3:cycle 5 and cycle 6, day 1 and day 2 of 21 day cycle

• Pharmacokinetic (PK) assessment: AUC0-last

  Cohort 1 and 4: cycle 3 and cycle 4, day 1 and day 2 of 14 day cycle; Cohort 2 and 3:cycle 5 and cycle 6, day 1 and day 2 of 21 day cycle

• Pharmacokinetic (PK) assessment: AUC0-INF

  Cohort 1 and 4: cycle 3 and cycle 4, day 1 and day 2 of 14 day cycle; Cohort 2 and 3:cycle 5 and cycle 6, day 1 and day 2 of 21 day cycle

• Pharmacokinetic (PK) assessment: AUC0-tau

  Cohort 1 and 4: cycle 3 and cycle 4, day 1 and day 2 of 14 day cycle; Cohort 2 and 3:cycle 5 and cycle 6, day 1 and day 2 of 21 day cycle

Study Arms (4)

Cohort 1: TTP488 (Azeliragon) co-administered with dose dense paclitaxel (ddAC/ddT)

EXPERIMENTAL

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).

Drug: TTP488; Drug: ddAC/ddT

Cohort 2: TTP488 (Azeliragon) co-administered with TC

EXPERIMENTAL

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).

Drug: TTP488; Drug: TC

Cohort 3: TTP488 (Azeliragon) co-administered with TCHP

EXPERIMENTAL

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).

Drug: TTP488; Drug: TCHP

Cohort 4: TTP488 (Azeliragon) co-administered with chemotherapy regimen that includes ddAC

EXPERIMENTAL

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).

Drug: TTP488; Drug: Chemotherapy regimen that includes ddAC

Interventions

TTP488 DRUG

Each Azeliragon capsule is 5mg, and is to be taken in the morning with food as indicated in each cohort.

Also known as: Azeliragon

Cohort 1: TTP488 (Azeliragon) co-administered with dose dense paclitaxel (ddAC/ddT); Cohort 2: TTP488 (Azeliragon) co-administered with TC; Cohort 3: TTP488 (Azeliragon) co-administered with TCHP; Cohort 4: TTP488 (Azeliragon) co-administered with chemotherapy regimen that includes ddAC

ddAC/ddT DRUG

Dose dense doxorubicin plus cyclophosphamide followed by paclitaxel (ddAC/ddT) for 8 cycles, administered per USPI (Unites States Prescribing Information) Label

Also known as: Dose dense doxorubicin plus cyclophosphamide, dose dense paclitaxel

Cohort 1: TTP488 (Azeliragon) co-administered with dose dense paclitaxel (ddAC/ddT)

TC DRUG

Docetaxel plus cyclophosphamide (TC) for 4-6 cycles, administered per USPI (Unites States Prescribing Information) Label

Also known as: Docetaxel plus cyclophosphamide

Cohort 2: TTP488 (Azeliragon) co-administered with TC

TCHP DRUG

Docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP)for 6 cycles, administered per USPI (Unites States Prescribing Information) Label

Also known as: Docetaxel, carboplatin, trastuzumab, and pertuzumab

Cohort 3: TTP488 (Azeliragon) co-administered with TCHP

Chemotherapy regimen that includes ddAC DRUG

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, administered per USPI (Unites States Prescribing Information) Label

Also known as: Dose dense doxorubicin plus cyclophosphamide

Cohort 4: TTP488 (Azeliragon) co-administered with chemotherapy regimen that includes ddAC

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have clinical or pathologic stage I-III, histologically confirmed breast cancer, with any ER (estrogen-receptor), PR (progesterone receptors), or HER2 (human epidermal growth factor receptor 2) status who are planned to receive chemotherapy in the adjuvant or neoadjuvant setting.
• a. Chemotherapy regimens administered per USPI (United States Prescribing Information) label: i. Dose dense doxorubicin plus cyclophosphamide followed by paclitaxel (ddAC/ddT) for 8 cycles ii. Docetaxel plus cyclophosphamide (TC) for 4-6 cycles iii. Docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP)for 6 cycles iv. Chemotherapy regimen that includes ddAC, given at the end of the chemotherapy plan \[can include: (1)weekly carboplatin + paclitaxel + pembrolizumab followed by pembrolizumab + dose dense doxorubicin and cyclophosphamide; (2) weekly carboplatin + paclitaxel followed by dose dense doxorubicin and cyclophosphamide; (3) weekly or dd paclitaxel followed by dose dense doxorubicin and cyclophosphamide\]
• Patients must have had no prior chemotherapy/radiotherapy/or systemic therapy for early stage breast cancer, or any other malignancy
• Age ≥18 years.
• ECOG (Eastern Cooperative Oncology Group) performance status ≤2 (Karnofsky ≥60%, see Appendix D).
• Patients must have normal organ and marrow function as defined below:
• Leukocytes ≥3,000/mcL (microliter)
• Absolute neutrophil count ≥1,500/mcL
• Platelets ≥100,000/mcL
• Total bilirubin ≤ 2.0 x institutional upper limit of normal (ULN)
• AST(SGOT) (aspartate transaminase)/ALT(SGPT) (alanine aminotransferase) ≤1.5 × institutional ULN
• Glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial. If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated. If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load.
• No pre-existing neurodegenerative disease or impairment, including history of CVA (cerebrovascular accident), or head injury.
• 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.

You may not qualify if:

• Patients who have had prior chemotherapy, radiotherapy, systemic therapy, or hormonal therapy
• Patients with Stage IV breast cancer
• Patients who are receiving any other investigational agents.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to azeliragon, or the standard of care chemotherapy assigned, including: docetaxel, cyclophosphamide, carboplatin, doxorubicin, paclitaxel, trastuzumab, pertuzumab, pembrolizumab.
• Patients receiving any medications or substances that are strong CYP2C8 inhibitors are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product. Subjects who discontinue a strong CYP2C8 inhibitor must have discontinued the drug for at least 5 days or 5 half-lives of the drug, whichever is longer, before the first dose of study drug.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, neurogenerative disease/impairment, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study as the risks of azeliragon to a fetus are unknown. There is unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with azeliragon; breastfeeding should be discontinued if the mother is treated with azeliragon. These potential risks may also apply to other agents used in this study.
• History of cancer within the last 5 years except adequately treated cervical carcinoma-in-situ, or cutaneous basal cell or squamous cell cancer.

Sponsors & Collaborators

• Georgetown University: lead

Study Sites (3)

Georgetown Lombardi Comprehensive Cancer Center

Washington D.C., District of Columbia, 20007, United States

RECRUITING

Medstar Washington Hospital Center

Washington D.C., District of Columbia, 20010, United States

RECRUITING

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

RECRUITING

MeSH Terms

Interventions

azeliragon; Cyclophosphamide; Docetaxel; Carboplatin; Trastuzumab; pertuzumab

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Diterpenes; Terpenes; Coordination Complexes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Candace Mainor, MD

  Georgetown University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lana Kheir

CONTACT

202-687-9016; lk814@georgetown.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 3, 2022
• First Posted: February 25, 2022
• Study Start: June 6, 2023
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: December 24, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)