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

• Trastuzumab Deruxtecan (Drug), also known as T-DXd: 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.
• Stereotactic Radiosurgery (Radiation), also known as SRS: 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 outcomes

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

Secondary outcomes

• Intracranial Progression-free survival (PFS) at 6 months (PFS-6) [6 months]: Intracranial PFS-6 will be defined as the time from first dose of study drug until intracranial disease progression (i.e., progression within the skull) or death from any cause using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) at 6 months post-treatment. Progression is defined as at least 20% increase in the sum of the longest diameters of the target lesions, appearance of any new lesions, or unequivocable progression of any non-target lesions. For participants whose disease has not progressed at the time of the analysis, censoring will be performed using the date of the last valid disease assessment.
• Extracranial PFS-6 [6 months]: Extracranial PFS-6 will be defined as the time from first dose of study drug until extracranial disease progression (i.e., progression outside of the skull) or death from any cause using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) at 6 months post-treatment. Progression is defined as at least 20% increase in the sum of the longest diameters (LD) of the target lesions compared to the smallest recorded LD since treatment started, appearance of any new lesions, or unequivocable progression of any non-target lesions. For participants whose disease has not progressed at the time of the analysis, censoring will be performed using the date of the last valid disease assessment.
• Overall survival (OS) [2 years]: Median OS will be defined as the time from the beginning of study drug treatment until death due to any cause at the end of the study (\~2 years). For participants who have not died at the time of the analysis, censoring will be performed using the date the participant was last known to be alive.
• Objective response rate (ORR) [2 years]: ORR will be defined as the proportion of participants achieving a complete response (CR) or partial response (PR) using RECIST v1.1 as their best overall response by the end of the study (\~2 years). Participants with CR or PR will be counted as successes and all other participants (including those with missing response information) will be counted as failures. CR is defined as disappearance of all target and non-target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. All lymph nodes must be non-pathological in size (<10 mm short axis). PR is defined as at least 30% decrease in the sum of the LD of target lesions compared to baseline. There can be no appearance of new lesions.
• Intracranial PFS-6 comparison to historical data [6 months]: Intracranial PFS-6 as defined in Outcome 3 will be compared to historical data.
• Extracranial PFS-6 comparison to historical data [6 months]: Extracranial PFS-6 as defined in Outcome 4 will be compared to historical data.
• OS comparison to historical data [2 years]: Median OS as defined in Outcome 5 will be compared to historical data.
• ORR comparison to historical data [2 years]: ORR as defined in Outcome 6 will be compared to historical data.

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

1. Histologically confirmed HER-2-positive breast cancer with newly diagnosed brain metastases.
2. ECOG Performance Status (PS) of 0, 1, 2.
3. 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.
4. Age ≥ 18 years
5. Signed written informed consent by patient or legally authorized representative. A signed informed consent must be obtained prior to any study-specific procedures.
6. Life expectancy of at least 12 weeks.
7. Any number of prior systemic therapies will be allowed, except T-DXd.
8. Hemoglobin ≥ 9 g/dL, White blood count ≥ 3.0 × 109/L, Absolute Neutrophil count ≥ 1.5 × 109/L and platelet count ≥ 100 × 109/L.
9. Serum bilirubin ≤ 1.5 × upper limit of normal (ULN).
10. AST and/or ALT ≤ 2 × ULN (≤ 5 × ULN when clearly attributable to the presence of liver metastases).
11. Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance > 60 mL/min.
12. Ability to comply with study procedures and monitoring.
13. For individuals of childbearing potential, a negative pregnancy test should be obtained within 7 days prior to the start of therapy.
14. 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).
15. 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:

1. Participants with leptomeningeal metastases documented by MRI or CSF evaluation.
2. Evidence of intra-tumoral or peri-tumoral hemorrhage deemed clinically significant by the treating physician.
3. Brain metastases within 5 mm of the optic chiasm or optic nerve.
4. 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.
5. 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.
6. Unable to undergo brain MRI.
7. Screen for human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C. HIV/HBV/HCV testing per institutional practice.
8. All toxicities from prior therapies must have resolved to CTCAE v5.0 grade 1 or better by the time of study enrollment.
9. 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.
10. Currently receiving other investigational cancer therapy (with the exception of continuing therapy with GnRH analogues) within 4 weeks prior to start of study treatment.
11. Mean QT interval corrected heart rate (QTc) ≥ 470 ms calculated from 3 electrocardiograms using Fredericia's Correction, calculated as: 8.22 ∛(RR interval)
12. LVEF <50%.
13. Ineligible for treatment with T-DXd.
14. Ineligible for treatment with SRS.
15. Active or prior documented ILD/pneumonitis or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
16. History of hypersensitivity to T-DXd.
17. History and/or confirmed corneal ulceration.
18. Pregnant or breast feeding. The patients should not breast feed for 7 months after stopping the drug.
19. Use of anthracyclines will be prohibited while on the protocol.
20. Prior cranial radiation is not allowed.

• Manmeet Ahluwalia, Principal investigator, Baptist Health Herbert Wertheim Cancer Institute