Combining targeted therapy and radiation for brain metastases in HER2-positive breast cancer

Phase 1 Trial of Tucatinib, Trastuzumab, and Capecitabine With Stereotactic Radiosurgery (SRS) in Patients With Brain Metastases From HER-2 Positive Breast Cancer

This study is testing if combining a special type of radiation with three targeted drugs can help people with HER2-positive breast cancer that has spread to the brain.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 40 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Baptist Health South Florida (Academic / other)
• Drugs / interventions: trastuzumab, tucatinib, Chemotherapy, radiation
• Locations: 1 site (Miami, Florida)
• Trial ID: NCT05553522 on ClinicalTrials.gov

What this trial studies

This study evaluates the effectiveness of combining stereotactic radiosurgery (SRS) with three therapeutic agents—tucatinib, trastuzumab, and capecitabine—in controlling brain metastases from HER-2 positive breast cancer. The approach is investigational and aims to determine how well this combination can manage the disease in patients with newly diagnosed brain metastases. Eligible participants will have a limited number of brain metastases and will be monitored for treatment response and safety.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with histologically confirmed HER-2 positive breast cancer and 1-10 brain metastases measuring 3 cm or less.

Not a fit: Patients with brain metastases larger than 3 cm or those who have previously received tucatinib or capecitabine may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could improve control of brain metastases and overall outcomes for patients with HER-2 positive breast cancer.

How similar studies have performed: While the combination of SRS with these specific agents is investigational, similar approaches in treating brain metastases have shown promise in other studies.

Eligibility criteria

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. Patients with 1-10 brain metastases will be candidates for tucatinib, capecitabine, and trastuzumab with SRS at the discretion of the treating radiation oncologist. Intra-cranial brain metastasis must measure 3 cm or less in the greatest dimension
4. Age 18 years or greater and being willing and able to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures
5. Life expectancy at least 12 weeks
6. Any number of prior systemic therapies will be allowed, except tucatinib and capecitabine.
7. Hemoglobin ≥ 9g/dL, White blood count ≥3.0 × 10\^9/ L , Absolute Granulocyte count ≥1.5x 10\^9/ L and platelet count ≥100 × 10\^9/ L.
8. Serum bilirubin ≤ 1.5 × ULN
9. AST and / or ALT \<= 2 × ULN (≤ 5 × ULN when clearly attributable to the presence of liver metastases)
10. Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance \> 60mL/min
11. Ability to comply with study procedures and monitoring
12. For women of childbearing potential, a negative pregnancy test should be obtained within one week prior to the start of therapy
13. Male or female patients 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 tucatinib, capecitabine and trastuzumab.

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 woman 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 women under 50
* 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. Patients with leptomeningeal metastases documented by MRI or CSF evaluation
2. Evidence of intra-tumoral or peri-tumoral hemorrhage deemed 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. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C
8. All toxicities from prior therapies must have resolved to CTCAE v 5.0 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 within 4 weeks prior to start of study treatment with the exception of continuing therapy with GnRH analogues
11. Mean QT interval corrected heart rate (QTc) ≥ 470ms calculated from 3 electrocardiograms using Frediricia's Correction
12. Left ventricular ejection fraction (LVEF) \<50%
13. Concomitant use of strong cytochrome P450 (CYP)3A inhibitors including macrolide antibiotics (e.g., Telithromycin), antifungals (e.g., Itraconazole), antivirals (e.g., ritonavir), and Nefazodone
14. Concomitant use of strong CYP2C8 inhibitor within 5 half-lives of the inhibitor
15. Concomitant use of strong CYP3A4 inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John's Wort) within 5 days prior to the first dose of study treatment
16. Concomitant use of a strong CYP2C8 inducer within 5 days prior to the first dose of study treatment
17. History of hypersensitivity to tucatinib, capecitabine, and trastuzumab, or any of its excipients
18. History and/or confirmed corneal ulceration
19. Pregnant or breast feeding
20. Use of anthracyline will be prohibited on the protocol

Where this trial is running

Miami, Florida

• Miami Cancer Institute at Baptist Health, Inc. — Miami, Florida, United States (Recruiting)

Study contacts

• Principal investigator: Manmeet Ahluwalia, M.D., MBA — Miami Cancer Institute/Baptist Health South Florida
• Study coordinator: Manmeet Ahluwalia, M.D., MBA

Conditions Brain Metastases; HER2-positive Breast Cancer; brain metastases; HER2-positive breast cancer