BRIDGET: Secondary BRain metastases prevention after Isolated intracranial progression on Trastuzumab/Pertuzumab or T-DM1 in patients with aDvanced human epidermal Growth factor receptor 2+ brEast cancer with the addition of Tucatinib

Protocol # :
Brain Metastases
Human Epidermal Growth Factor 2 Positive Carcinoma of Breast
Advanced Breast Cancer
Disease Sites
Brain and Nervous System
Principal Investigator
Sammons, Sarah
Site Research Nurses
Bowers, Jordan
Campbell, Margaret
Cung, Connie
Dishman, Rachel, C.
Ficociello, Samantha
Jeon, Maryangel, H.
Kasparian, Elizabeth
Loeser, Wendy
Orechia, Meghan
Patel, Nikita
Roche, Kathleen, A.

Trial Description

Patients with advanced HER2+ breast cancer on maintenance trastuzumab/pertuzumab or T-DM1
with 1st or 2nd intracranial disease event (brain metastases) and stable extracranial disease
will be enrolled. They will receive local therapy with stereotactic radiosurgery ± surgical
resection if indicated followed by enrollment. Patients will continue standard of care
trastuzumab/pertuzumab or T-DM1 with the addition of tucatinib. Hormone receptor positive
patients requiring endocrine therapy should continue. Study treatment will continue until
disease progression or intolerable side effects. Patients on trial with extracranial disease
progression with stable intracranial disease should continue tucatinib into next line of

Eligibility Requirements

Inclusion Criteria:

Subject must meet all of the following applicable inclusion criteria to participate in this

- Written informed consent and HIPAA authorization for release of personal health
information prior to registration. NOTE: HIPAA authorization may be included in the
informed consent or obtained separately.

- Age ≥ 18 years at the time of consent.

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.

- Locally advanced/unresectable or metastatic breast cancer with presence of brain
metastases (Stage IV).

- Histologically confirmed HER2+ breast carcinoma by ASCO-CAP guidelines, with HER2+
defined by in situ hybridization (ISH), immunohistochemistry (IHC), or fluorescence in
situ hybridization (FISH) methodology on most recent biopsy.

- Currently receiving: (1) first-line trastuzumab/pertuzumab OR (2) second-line T-DM1 in
the metastatic setting OR (3) adjuvant trastuzumab-based therapy or T-DM1 with
isolated intracranial recurrence. Patients with de novo metastatic disease and brain
metastases or isolated intracranial recurrence can enter upon initiation of
maintenance trastuzumab/pertuzumab after chemotherapy if deemed necessary by treating
oncologist and meeting other inclusion criteria.

- Systemic disease otherwise stable per RECIST 1.1 or no evidence of extracranial

- Adequate hepatic and renal function and hematologic parameters:

- Absolute neutrophil count (ANC) ≥ 1.0 × 109/L

- Platelets ≥ 100 × 109/L

- Hemoglobin ≥ 9 g/dL

- Total serum bilirubin ≤ 1.5 times upper limit of normal (ULN)

- Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤
2.5 × ULN (or ≤ 5 × ULN if liver metastases are present)

- Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 50 mL/min as
calculated using the Cockcroft-Gault (CG) equation

- Left ventricular ejection fraction (LVEF) ≥ 50%.

- Central nervous system inclusion - Based on screening brain magnetic resonance imaging
(MRI), patients must have ALL of the following:

- Adequate local therapy to existing brain lesions ≥ 5mm including surgical
resection and/or stereotactic radiosurgery

- Limited to first or second intracranial progression. Third intracranial
progression would be considered if > 12 month interval between second and third
intracranial progression.

- Time since stereotactic radiosurgery (SRS) is ≥ 7 days prior to first dose of
study treatment.

- Time since surgical resection is ≥ 14 days prior to first dose of study

- Time since local therapy < 8 weeks. Patients with de novo metastastic breast
cancer presenting with brain metastases may enter following cessation of
chemotherapy if within 12 weeks of local therapy to the brain.

NOTE: Relevant records of any CNS treatment including radiation must be available to allow
for classification of target and non-target lesions

- Females of childbearing potential must have a negative serum pregnancy test at
screening. NOTE: Females are considered of child bearing potential unless they are
surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) or they are naturally postmenopausal for at least 12
consecutive months.

- Females of childbearing potential and males must be willing to abstain from
heterosexual intercourse or to use contraception as outlined in the protocol.

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:

- Previously been treated with: Lapatinib, neratinib, afatinib, tucatinib or other
investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase
inhibitor (TKI) at any time previously (patients treated with adjuvant neratinib
allowed if relapse > 12 months after last dose).

- Clinically significant cardiopulmonary disease.

- Clinically significant acute infection requiring systemic antibacterial, antifungal,
or antiviral therapy including:

- tuberculosis (clinical evaluation that includes clinical history, physical
examination, and radiographic findings, and TB testing in line with local

- hepatitis B (known positive HBV surface antigen (HBsAg) result),

- hepatitis C, or

- human immunodeficiency virus (positive HIV 1/2 antibodies)

NOTE: Patients with a past or resolved HBV infection (defined as the presence of hepatitis
B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for
HCV RNA. Subjects with HIV/AIDS with adequate antiviral therapy to control viral load would
be allowed if they are stable and have been on treatment for ≥ 4 weeks prior to first dose
of study drug(s). Subjects with viral hepatitis with controlled viral load would be allowed
while on suppressive antiviral therapy. Testing not required.

- Unable for any reason to undergo MRI of the brain

- Use of a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the
inhibitor, or a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of
study treatment. See protocol.

- Central nervous system exclusion - Based on screening brain MRI, patients must not
have any of the following:

- Ongoing use of systemic corticosteroids for control of symptoms of brain
metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent)

- Diffuse leptomeningeal disease or positive CSF cytology; however, discreet
dural-based metastases are allowed

- Poorly controlled seizures. Defined as seizures that continue to occur despite
optimal anticonvulsant medications based on investigator discretion.

- History of whole brain radiation therapy

- Any untreated brain lesions ≥ 5 mm

- Active infection requiring intravenous systemic therapy.

- Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study).

- Patients with a prior or concurrent malignancy within last 3 years whose natural
history or treatment has the potential to interfere with the safety or efficacy
assessment of the investigational regimen, per treating physician discretion, are not
eligible for this trial.

- Treatment with any investigational drug within 30 days prior to registration.