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

Official title

Phase 1 Trial of Trastuzumab Deruxtecan With Stereotactic Radiosurgery (SRS) in Participants With Brain Metastases From HER-2 Positive Breast Cancer

Overview

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.

Interventions

• Drug Trastuzumab Deruxtecan
  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.
• Radiation Stereotactic Radiosurgery
  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.

Primary outcome measures

• Incidence of dose-limiting toxicities (DLTs) [Time frame: 3 weeks]
• Determination of the maximum tolerated dose (MTD) of T-DXd in combination with SRS [Time frame: 3 weeks]

Secondary outcome measures (8)

• Intracranial Progression-free survival (PFS) at 6 months (PFS-6) [Time frame: 6 months]
• Extracranial PFS-6 [Time frame: 6 months]
• Overall survival (OS) [Time frame: 2 years]
• Objective response rate (ORR) [Time frame: 2 years]
• Intracranial PFS-6 comparison to historical data [Time frame: 6 months]
• Extracranial PFS-6 comparison to historical data [Time frame: 6 months]
• OS comparison to historical data [Time frame: 2 years]
• ORR comparison to historical data [Time frame: 2 years]

Eligibility criteria

Inclusion criteria

• 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.

Highly effective and acceptable forms of contraception are:

• Male condom plus spermicide
• Cap plus spermicide
• Diaphragm plus spermicide
• Copper T
• Progesterone T
• Levonorgestrel-releasing intrauterine system (e.g., Mirena®)
• Implants
• Hormone shot or injection
• Combined pill
• Mini-pill
• Patch

Postmenopausal individuals on the study (that will not need contraception) is defined as:

• Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments.
• LH and FSH levels in the postmenopausal range for individuals < 50 years.
• Radiation-induced oophorectomy with last menses > 1 year ago.
• Chemotherapy-induced menopause with > 1 year interval since last menses.
• Surgical sterilization (bilateral oophorectomy or hysterectomy).

Men and women and members of all races and ethnic groups are eligible for this trial.

Exclusion criteria

• 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.
• History of hypersensitivity to T-DXd.
• History and/or confirmed corneal ulceration.
• Pregnant or breast feeding. The patients should not breast feed for 7 months after stopping the drug.
• Use of anthracyclines will be prohibited while on the protocol.
• Prior cranial radiation is not allowed.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Miami Cancer Institute at Baptist Health, Inc. — Miami

Identifiers

NCT: NCT07454668 · 2025-AHL-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗