Trastuzumab Deruxtecan + Stereotactic Radiosurgery (SRS) in HER2+ Breast Cancer Brain Metastases

NCT07454668 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 2025-AHL-001
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

A phase I clinical trial (a type of research study) for people with human epidermal growth factor receptor 2 (HER-2) positive breast cancer with metastasis to the brain. This research study will evaluate how well brain metastases can be controlled using a type of radiation therapy known as stereotactic radiosurgery (SRS) when combined with the therapeutic agent Trastuzumab Deruxtecan (T-DXd). The combined use of SRS with T-DXd is considered investigational.

Conditions

Breast Cancer; HER2-positive Breast Cancer; Brain Metastases; Cancer; Cancer Metastatic

Outcome Measures

Primary Outcomes (2)

• Incidence of dose-limiting toxicities (DLTs)

  DLTs will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5.0 starting from the first dose of T-DXd through 3 weeks after SRS. DLT is defined as the appearance of side effects during treatment that are severe enough to prevent continuation of treatment at a participant's assigned dose. Any of the following events will be considered a DLT if treatment-related: * ≥ Grade 4 non-hematologic toxicity except nausea and vomiting (if manageable with supportive care measures), alopecia, drug-related fever, and toxicities secondary to neutropenia and sepsis * ≥ Grade 3 neurologic toxicity (sensory or autonomic) * Grade 4 platelet count (\<25,000/mm³) 50 days beyond the start of the most recent chemotherapy (not related to recurrent leukemia) * Grade 4 neutropenia 50 days beyond the start of the most recent chemotherapy (not related to recurrent leukemia) * Grade 3 non-hematologic toxicity (excluding alopecia or toxicities secondary to neutropenia

  3 weeks

• Determination of the maximum tolerated dose (MTD) of T-DXd in combination with SRS

  The MTD will be determined using a standard 3+3 dose de-escalation design across predefined dose levels of T-DXd (5.4 mg/kg, 4.4 mg/kg, and 3.2 mg/kg IV every 21 days), based on the number of participants who experience a DLT at each dose level.

  3 weeks

Secondary Outcomes (8)

• Intracranial Progression-free survival (PFS) at 6 months (PFS-6)

  6 months

• Extracranial PFS-6

  6 months

• Overall survival (OS)

  2 years

• Objective response rate (ORR)

  2 years

• Intracranial PFS-6 comparison to historical data

  6 months

Study Arms (1)

T-DXd + SRS

EXPERIMENTAL

All participants will receive SRS and the drug T-DXd. The goal is to evaluate safety and determine an appropriate dose.

Drug: Trastuzumab Deruxtecan; Radiation: Stereotactic Radiosurgery

Interventions

Trastuzumab Deruxtecan DRUG

T-DXd will be given as an IV infusion every 21 days. This Phase 1 study will use predefined dose levels (5.4 mg/kg, 4.4 mg/kg, and 3.2 mg/kg) to evaluate safety and tolerability. Participants may continue treatment until disease progression, unacceptable side effects, or withdrawal.

Also known as: T-DXd

T-DXd + SRS

Stereotactic Radiosurgery RADIATION

Participants will receive SRS to intact brain metastases. Typical dosing is 20-24 Gy in a single fraction for lesions \<20 mm, or 27 Gy in 3 fractions for lesions ≥20 mm. Exact dosing will be based on the treating radiation oncologist's clinical judgment.

Also known as: SRS

T-DXd + SRS

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed HER-2-positive breast cancer with newly diagnosed brain metastases.
• ECOG Performance Status (PS) of 0, 1, 2.
• Participants with 1-10 brain metastases will be candidates for T-DXd with SRS at the discretion of the treating radiation oncologist. Intra-cranial metastasis must measure 3 cm or less in the greatest dimension.
• Age ≥ 18 years
• Signed written informed consent by patient or legally authorized representative. A signed informed consent must be obtained prior to any study-specific procedures.
• Life expectancy of at least 12 weeks.
• Any number of prior systemic therapies will be allowed, except T-DXd.
• Hemoglobin ≥ 9 g/dL, White blood count ≥ 3.0 × 109/L, Absolute Neutrophil count ≥ 1.5 × 109/L and platelet count ≥ 100 × 109/L.
• Serum bilirubin ≤ 1.5 × upper limit of normal (ULN).
• AST and/or ALT ≤ 2 × ULN (≤ 5 × ULN when clearly attributable to the presence of liver metastases).
• Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance \> 60 mL/min.
• Ability to comply with study procedures and monitoring.
• For individuals of childbearing potential, a negative pregnancy test should be obtained within 7 days prior to the start of therapy.
• Participants must have left ventricular ejection fraction (LVEF) ≥ 50% by either an echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within 28 days before enrollment (to be assessed as clinically indicated).
• Male or female participants of reproductive potential need to employ two highly effective and acceptable forms of contraception throughout their participation in the study and for 7 months after last dose of T-DXd.

You may not qualify if:

• Participants with leptomeningeal metastases documented by MRI or CSF evaluation.
• Evidence of intra-tumoral or peri-tumoral hemorrhage deemed clinically significant by the treating physician.
• Brain metastases within 5 mm of the optic chiasm or optic nerve.
• Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom, e.g., Crohn's disease, malabsorption, or CTCAE grade \> 2 diarrhea of any etiology at baseline.
• History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction, arrhythmia, New York Heart Association (NYHA) functional classification of 3 or 4.
• Unable to undergo brain MRI.
• Screen for human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C. HIV/HBV/HCV testing per institutional practice.
• All toxicities from prior therapies must have resolved to CTCAE v5.0 grade 1 or better by the time of study enrollment.
• Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active, or uncontrolled infection, uncontrolled diabetes, second active malignancy) that could cause unacceptable safety risks or compromise compliance with the protocol.
• Currently receiving other investigational cancer therapy (with the exception of continuing therapy with GnRH analogues) within 4 weeks prior to start of study treatment.
• Mean QT interval corrected heart rate (QTc) ≥ 470 ms calculated from 3 electrocardiograms using Fredericia's Correction, calculated as: 8.22 ∛(RR interval)
• LVEF \<50%.
• Ineligible for treatment with T-DXd.
• Ineligible for treatment with SRS.
• Active or prior documented ILD/pneumonitis or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.

Sponsors & Collaborators

• Baptist Health South Florida: lead
• National Brain Tumor Society: collaborator

Study Sites (1)

Miami Cancer Institute at Baptist Health, Inc.

Miami, Florida, 33176, United States

Location

Related Links

• Miami Cancer Institute

MeSH Terms

Conditions

Breast Neoplasms; Brain Neoplasms; Neoplasms; Neoplasm Metastasis

Interventions

trastuzumab deruxtecan; Radiosurgery

Condition Hierarchy (Ancestors)

Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Manmeet Ahluwalia

  Miami Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Manmeet Ahluwalia, M.D.

CONTACT

786-596-2000; ManmeetA@baptisthealth.net

Carla Munevar Sumarriva

CONTACT

786-596-2000; Carla.MunevarSumarriva@baptisthealth.net

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a phase 1 multi-site, open-label, single-arm dose de-escalation study in participants with HER-2 positive breast cancer with 1-10 brain metastases.

Study Record Dates

• First Submitted: February 16, 2026
• First Posted: March 6, 2026
• Study Start: June 1, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2029
• Last Updated: March 6, 2026

Record last verified: 2026-03

Locations

US (1)