T-dxd Resistant HER2-PositivePhase 1/2RAGENCT07785856
Study of Trastuzumab Deruxtecan (T-DXd) in Combination With a RAGE Inhibitor in Patients With T-DXd-Resistant HER2-Positive or HER2-Low Metastatic Breast Cancer
A Phase 1/2 study testing Azeliragon and T-DXd in people with T-dxd Resistant HER2-Positive and HER2 Low Metastatic Breast Cancer, run by The Methodist Hospital Research Institute.
Trial summary
This phase Ib/II trial aims to evaluate the safety and preliminary efficacy of combining Trastuzumab Deruxtecan (T-DXd) with Azeliragon, a receptor for advanced glycation end products (RAGE) inhibitor in patients with T-DXd-resistant HER2-positive or HER2-low metastatic breast cancer at Houston Methodist Neal Cancer… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- T-dxd Resistant HER2-Positive, HER2 Low Metastatic Breast Cancer
- What is being tested?
- Azeliragon and T-DXd
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 27 participants
- Where
- No sites listed yet
- Study dates
- Dec 2026to Dec 2029
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male or female ≥18 years of age at time of consent.
- Written informed consent is required before performing any trial-specific tests or procedures. Signing of the informed consent form can occur outside the 28-day screening period.
- Histologically confirmed HER2-positive or HER2-low or ultra low metastatic breast cancer.
- Prior systemic progression in metastatic setting on T-DXd and have measurable disease per RECIST v1.1 Criteria.
- ECOG performance status of 0-2 at time of consent.
- Hematology laboratory values of:
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- Absolute neutrophil count ≥ 1500 cells/mm3
- Platelets ≥100,000 cells/mm3
- Hemoglobin ≥9 g/dL
- White blood count ≥3000 cells/mm3.
- Hepatic laboratory values of aspartate transaminase (AST) or alanine aminotransferase (ALT):
- <5 × upper limits of normal (ULN) if the documented history of hepatic metastases; or
- <2.5 × ULN if no liver metastases are present.
- Serum albumin >2.8 g/dL.
- Total bilirubin <1.7 mg/dL × ULN.
- Prothrombin time (PT) or international normalized ratio (INR) <1.5 × ULN. Note: Patients receiving therapeutic doses of anticoagulant therapy may be considered eligible if PT and INR are within the acceptable institutional therapeutic limits.
- Serum creatinine or serum urea <1.5 × ULN.
- Estimated glomerular filtration rate >50 mL/min.
- Urine dipstick or urinalysis with protein <2+ or 24-hour urine protein <1.0 g/24-h. Subjects with 1+ proteinuria must undergo a 24-hour urine collection to assess urine protein level.
- Any CNS metastases allowed if stable. Brain metastases needing immediate local intervention allowed. Patients can still be included after local intervention like radiation or surgery if there are any other sites of systemic progressive metastases. Patients must wait for at least 2 weeks after intracranial SRS before beginning study treatment)
- Patients of childbearing potential must agree to use an adequate method of contraception during the study and for 30 days after the last dose of study treatment.
- Patients must be able to swallow oral capsules
- Willing to able to comply with study procedures.
Who cannot join
- Positive pregnancy test, pregnant, or breastfeeding for all women of child-bearing potential.
- Per treating physician's assessment, any other clinically significant laboratory abnormality that would compromise patient safety or the outcome of the study.
- Any clinically significant and/or uncontrolled pathologic cardiac-related abnormality that would compromise patient safety or the outcome of the study including, but not limited to:
- Symptomatic valvular disease
- Symptomatic congestive heart failure is classified by the New York Heart Association as Class III or IV
- Unstable angina pectoris.
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- Myocardial infarction within the past 6 months from consent.
- Active bleeding diathesis.
- Receiving chronic treatment with corticosteroids ≥20 mg of prednisone per day (or equivalent) or other systemic immunosuppressive agents. Topical or nasal corticosteroids are allowed.
- Uncontrolled hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus (HIV)-1 or HIV-2.
- History of galactose intolerance, deficiency of Lapp lactase, or glucose-galactose malabsorption.
- History of malignancy or active treatment for malignancy other than breast cancer (i.e., radiation or chemotherapy, including monoclonal antibodies) within 5 years. Note: Patients with squamous or basal cell carcinomas of the skin, carcinomas in situ of the cervix or uterus, ductal breast cancer in situ, resected low-grade prostate cancer, or other malignancies that in the opinion of the investigator are considered cured may participate.
- Receipt of live, attenuated vaccine (e.g., intranasal influenza, measles, mumps, rubella, varicella) or close contact with someone who has received a live, attenuated vaccine within the past 1 month from consent. Note: Influenza vaccine will be allowed if administered >21 days.
- Receipt of any investigational agent or study treatment within the past 30 days from consent for a condition other than breast cancer.
- Receipt of any protein or antibody-based therapeutic agents (e.g., growth hormones or monoclonal antibodies) within the past 3 months from consent for a condition other than breast cancer.
- Active infection requiring treatment (patients can be included as soon as they are off antibiotics; no wash-out period)
- Adults unable to consent
- Intracranial oligo progression alone (if patient is only progressing in the brain and not systemically, he/she cannot be included in the study)
About this study
Official title: A Phase Ib/II Study of Trastuzumab Deruxtecan (T-DXd) in Combination With a RAGE Inhibitor in Patients With T-DXd-Resistant HER2-Positive or HER2-Low Metastatic Breast Cancer
This phase Ib/II trial aims to evaluate the safety and preliminary efficacy of combining Trastuzumab Deruxtecan (T-DXd) with Azeliragon, a receptor for advanced glycation end products (RAGE) inhibitor in patients with T-DXd-resistant HER2-positive or HER2-low metastatic breast cancer at Houston Methodist Neal Cancer Center (HMNCC). Adults, 18 years of age or older, with histologically confirmed HER2-positive or HER2-low metastatic breast cancer with prior progression on T-DXd will be eligible to participate in the study.
Read the detailed description
This phase Ib/II trial aims to evaluate the safety and preliminary efficacy of combining Trastuzumab Deruxtecan (T-DXd) with Azeliragon, a receptor for advanced glycation end products (RAGE) inhibitor in patients with T-DXd-resistant HER2-positive or HER2-low metastatic breast cancer at Houston Methodist Neal Cancer Center (HMNCC). Adults, 18 years of age or older, with histologically confirmed HER2-positive or HER2-low metastatic breast cancer with prior progression on T-DXd will be eligible to participate in the study.
In phase Ib part of the study, 12 patients will be administered standard T-DXd (5.4 mg/kg intravenously [IV] every 3 weeks [q3w]) plus escalating oral doses of the RAGE inhibitor Azeliragon (starting dose 5, 10, 20 mg, orally, daily) in a BOIN design to determine the recommended phase II dose (RP2D) of T-DXd and Azeliragon. In phase II part of the study, 15 patients will receive T-DXd (5.4 mg/kg IV q3w) plus the RP2D of Azeliragon. If patients are on a lower dose of T-DXd prior to trial enrollment due to adverse events the same low dose can be continued for the trial. HER2 ultra-low patients can be included as well.
The doses for Azeliragon are as follows:
- Starting Dose Level 1: Loading Dose for 6 Days is 15mg once daily; Maintenance Dose for days 7 and onward 5mg once daily
- Dose level 2: Loading dose for 6 days is 15mg twice daily; maintenance dose for days 7 and onward is 10mg once daily
- Dose level 3: Loading dose for 6 days is 30 mg twice daily; maintenance dose for days 7 and onward is 20mg once daily
In phase II part of the study, 15 patients will receive T-DXd (5.4 mg/kg IV q3w) plus the RP2D of Azeliragon. If patients are on a lower dose of T-DXd prior to trial enrollment due to adverse events the same low dose can be continued for the trial. The total study duration will be 2 years. The primary endpoint of phase Ib will be the assessment of the safety, tolerability, and RP2D of T-DXd plus a RAGE inhibitor (e.g. Azeliragon). The primary endpoint of phase II will be the evaluation of the objective response rate (ORR) of the combination therapy in patients with documented T-DXd resistance. Secondary endpoints will include assessment of progression-free survival (PFS), duration of response (DoR), Quality of life (QOL), PFS2, overall survival (OS) and intracranial response rate in patients with brain metastases. This single-arm, open-label, phase Ib/II study conducted at HMNCC aims to evaluate the safety and preliminary efficacy of combining T-DXd with a RAGE inhibitor in patients with T-DXd-resistant metastatic breast cancer, with the goal of overcoming drug resistance and improving clinical outcomes.
- Being tested
- Azeliragon, T-DXd
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzeliragonDrug
- Starting Dose Level 1: Loading Dose for 6 Days is 15mg once daily; Maintenance Dose for days 7 and onward 5mg once daily
- Dose level 2: Loading dose for 6 days is 15mg twice daily; maintenance dose for days 7 and onward is 10mg once daily
- Dose level 3: Loading dose for 6 days is 30 mg twice daily; maintenance dose for days 7 and onward is 20mg once daily
T-DXdDrug
5.4 mg/kg IV q3w
| Study group | Role | What they receive |
|---|---|---|
| Azeliragon | Experimental | In phase Ib part of the study, 12 patients will be administered standard T-DXd (5.4 mg/kg intravenously [IV] every 3 weeks [q3w]) plus escalating oral doses of the RAGE inhibitor Azeliragon (starting dose 5, 10, 20 mg, orally, daily) in a BOIN design to determine the recommended phase II dose (RP2D) of T-DXd and Azeliragon. In phase II part of the study, 15 patients will receive T-DXd (5.4 mg/kg IV q3w) plus the RP2D of Azeliragon. If patients are on a lower dose of T-DXd prior to trial enrollment due to adverse events the same low dose can be continued for the trial. HER2 ultra-low patients can be included as well. Receives: Drug: Azeliragon; Drug: T-DXd |
What is being measured
The primary outcome is the main question the study is designed to answer.
RP2D of Azeligaron
Phase Ib (Dose Escalation): To assess the safety, tolerability (according to the NCI CTCAE (v6.0)) and to determine the RP2D of T-DXd plus a RAGE inhibitor (Azeliragon) in patients with T-DXd-resistant HER2-positive or HER2-low metastatic breast cancer.
Measured: From time of enrollment to end of cycle 1 (3 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Aug 2026
- Study startDec 2026 (estimated)
- Primary completionDec 2028 (estimated)
- Study completionDec 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for T-dxd Resistant HER2-PositiveStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 27 participants (estimated)
Sponsor and investigators
- Lead sponsor
- The Methodist Hospital Research Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, AkshjotP, The Methodist Hospital Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07785856
- Sponsor's protocol ID
- PRO00043008 (HMCC-BR25-003)
- Acronym
- RAGE
- Status last verified
- Aug 2026
- First submitted
- 21 Aug 2026
- Last updated
- 25 Aug 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 25 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase Ib/II Study of Trastuzumab Deruxtecan (T-DXd) in Combination With a RAGE Inhibitor in Patients With T-DXd-Resistant HER2-Positive or HER2-Low Metastatic Breast Cancer
- ClinicalTrials.gov ID
- NCT07785856
- Acronym / sponsor ID
- RAGE / PRO00043008 (HMCC-BR25-003)
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 27 participants (estimated)
- Lead sponsor
- The Methodist Hospital Research InstituteUniversity, hospital or other
- Study start
- Dec 2026 (estimated)
- Primary completion
- Dec 2028 (estimated)
- Study completion
- Dec 2029 (estimated)
- First posted
- 25 Aug 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This phase Ib/II trial aims to evaluate the safety and preliminary efficacy of combining Trastuzumab Deruxtecan (T-DXd) with Azeliragon, a receptor for advanced glycation end products (RAGE) inhibitor in patients with T-DXd-resistant HER2-positive or HER2-low metastatic breast cancer at Houston Methodist Neal Cancer Center (HMNCC). Adults, 18 years of age or older, with histologically confirmed HER2-positive or HER2-low metastatic breast cancer with prior progression on T-DXd will be eligible to participate in the study.
Detailed description
This phase Ib/II trial aims to evaluate the safety and preliminary efficacy of combining Trastuzumab Deruxtecan (T-DXd) with Azeliragon, a receptor for advanced glycation end products (RAGE) inhibitor in patients with T-DXd-resistant HER2-positive or HER2-low metastatic breast cancer at Houston Methodist Neal Cancer Center (HMNCC). Adults, 18 years of age or older, with histologically confirmed HER2-positive or HER2-low metastatic breast cancer with prior progression on T-DXd will be eligible to participate in the study.
In phase Ib part of the study, 12 patients will be administered standard T-DXd (5.4 mg/kg intravenously [IV] every 3 weeks [q3w]) plus escalating oral doses of the RAGE inhibitor Azeliragon (starting dose 5, 10, 20 mg, orally, daily) in a BOIN design to determine the recommended phase II dose (RP2D) of T-DXd and Azeliragon. In phase II part of the study, 15 patients will receive T-DXd (5.4 mg/kg IV q3w) plus the RP2D of Azeliragon. If patients are on a lower dose of T-DXd prior to trial enrollment due to adverse events the same low dose can be continued for the trial. HER2 ultra-low patients can be included as well.
The doses for Azeliragon are as follows:
- Starting Dose Level 1: Loading Dose for 6 Days is 15mg once daily; Maintenance Dose for days 7 and onward 5mg once daily
- Dose level 2: Loading dose for 6 days is 15mg twice daily; maintenance dose for days 7 and onward is 10mg once daily
- Dose level 3: Loading dose for 6 days is 30 mg twice daily; maintenance dose for days 7 and onward is 20mg once daily
In phase II part of the study, 15 patients will receive T-DXd (5.4 mg/kg IV q3w) plus the RP2D of Azeliragon. If patients are on a lower dose of T-DXd prior to trial enrollment due to adverse events the same low dose can be continued for the trial. The total study duration will be 2 years. The primary endpoint of phase Ib will be the assessment of the safety, tolerability, and RP2D of T-DXd plus a RAGE inhibitor (e.g. Azeliragon). The primary endpoint of phase II will be the evaluation of the objective response rate (ORR) of the combination therapy in patients with documented T-DXd resistance. Secondary endpoints will include assessment of progression-free survival (PFS), duration of response (DoR), Quality of life (QOL), PFS2, overall survival (OS) and intracranial response rate in patients with brain metastases. This single-arm, open-label, phase Ib/II study conducted at HMNCC aims to evaluate the safety and preliminary efficacy of combining T-DXd with a RAGE inhibitor in patients with T-DXd-resistant metastatic breast cancer, with the goal of overcoming drug resistance and improving clinical outcomes.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Azeliragon | Experimental | Drug: Azeliragon, Drug: T-DXdIn phase Ib part of the study, 12 patients will be administered standard T-DXd (5.4 mg/kg intravenously [IV] every 3 weeks [q3w]) plus escalating oral doses of the RAGE inhibitor Azeliragon (starting dose 5, 10, 20 mg, orally, daily) in a BOIN design to determine the recommended phase II dose (RP2D) of T-DXd and Azeliragon. In phase II part of the study, 15 patients will receive T-DXd (5.4 mg/kg IV q3w) plus the RP2D of Azeliragon. If patients are on a lower dose of T-DXd prior to trial enrollment due to adverse events the same low dose can be continued for the trial. HER2 ultra-low patients can be included as well. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- Male or female ≥18 years of age at time of consent.
- Written informed consent is required before performing any trial-specific tests or procedures. Signing of the informed consent form can occur outside the 28-day screening period.
- Histologically confirmed HER2-positive or HER2-low or ultra low metastatic breast cancer.
- Prior systemic progression in metastatic setting on T-DXd and have measurable disease per RECIST v1.1 Criteria.
- ECOG performance status of 0-2 at time of consent.
Key exclusion criteria (18 listed)
- Positive pregnancy test, pregnant, or breastfeeding for all women of child-bearing potential.
- Per treating physician's assessment, any other clinically significant laboratory abnormality that would compromise patient safety or the outcome of the study.
- Any clinically significant and/or uncontrolled pathologic cardiac-related abnormality that would compromise patient safety or the outcome of the study including, but not limited to:
- Myocardial infarction within the past 6 months from consent.
- Active bleeding diathesis.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Azeliragon* Starting Dose Level 1: Loading Dose for 6 Days is 15mg once daily; Maintenance Dose for days 7 and onward 5mg once daily * Dose level 2: Loading dose for 6 days is 15mg twice daily; maintenance dose for days 7 and onward is 10mg once daily * Dose level 3: Loading dose for 6 days is 30 mg twice daily; maintenance dose for days 7 and onward is 20mg once daily | Drug | Azeliragon |
| T-DXd5.4 mg/kg IV q3w | Drug | Azeliragon |
Primary outcome
RP2D of Azeligaron
Time frame: From time of enrollment to end of cycle 1 (3 weeks)
Phase Ib (Dose Escalation): To assess the safety, tolerability (according to the NCI CTCAE (v6.0)) and to determine the RP2D of T-DXd plus a RAGE inhibitor (Azeliragon) in patients with T-DXd-resistant HER2-positive or HER2-low metastatic breast cancer.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Aug 2026.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
The record lists no contact. Use the official record to reach the sponsor.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Azeliragon and T-DXd in people with T-dxd Resistant HER2-Positive and HER2 Low Metastatic Breast Cancer, run by The Methodist Hospital Research Institute.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 23 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 25 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
RP2D of Azeligaron (time frame: From time of enrollment to end of cycle 1 (3 weeks)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Aug 2026.