Inclusion Criteria:
- - Age ≥18 years at the time of consent.
- - Patients with HER2+ metastatic breast cancer with at least one progressive or new
brain metastasis measuring >5mm; prior local therapy to other intracranial lesions
allowed.
- - At least 1 prior standard of care therapy for metastatic disease.
- - Must have previously received T-DXd and Tucatinib.
If a patient has not received
T-DXd or Tucatinib as part of standard early line therapy due to allergies or
intolerability, the requirement of prior T-DXd and Tucatinib treatment is waived.
- - Participants must have adequate treatment washout period when applicable before
enrollment, defined as:
- >4 weeks from any major surgery.
- - >1 week from any cranial radiation treatment.
- - For cytotoxic containing agents, 5 half-lives or at least 21 days (whichever is
shorter)
- For weekly chemotherapy regimens, >2 weeks from chemotherapy; for every 3
weekly regimens, >3 weeks from chemotherapy.
At least 2 weeks from other
systemic or targeted or investigational therapies (other than endocrine
therapy) for breast cancer. No washout is required for endocrine therapy (e.g.
aromatase inhibitors, tamoxifen, fulvestrant) but patients should discontinue
prior to start of protocol therapy.
- - Patients on ovarian suppression are allowed (but not required) to continue
ovarian suppression at the discretion of their treating provider.
- - Adequate organ function and bone marrow reserve as determined by the investigator.
- - Adequate hepatic and renal function and hematologic parameters:
- Absolute neutrophil count (ANC) ≥ 1.0 × 109/L.
- - Platelets ≥ 100 × 109/L.
- - 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%.
- - Females of childbearing potential must have a negative pregnancy test (serum or
urine) at screening.
If a pregnancy test using either method is positive or cannot
be confirmed as negative, a second testing using the other method will be required
for confirmation.
- - Females of childbearing potential and males must be willing to abstain from
heterosexual intercourse or to use highly effective contraception.
- - Can enroll with intracranial disease only; extracranial disease can be absent or
non-measurable.
- - Focal leptomeningeal disease allowed at investigator discretion.
- - Performance status by Eastern Cooperative Oncology Group (ECOG) 0-2 (appendix 1)
- Written informed consent and HIPAA authorization for release of personal health
information prior to enrollment.
NOTE: HIPAA authorization may be included in the
informed consent or obtained separately.
Exclusion Criteria:
- - No evidence of hemorrhage or impending herniation or need for immediate local
therapy to intracranial disease or escalating dosing of steroids.
- - No grade 2 or greater peripheral neuropathy.
- - Diffuse and symptomatic leptomeningeal carcinomatosis.
- - Prolonged Qtc (QTcF>450), CHF or uncontrolled HTN.
- - Clinically significant cardiopulmonary disease.
- - Acute or chronic pancreatitis within 6 months prior to first day of study treatment.
- - 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
practice),
- hepatitis B (known positive HBV surface antigen (HBsAg) result) ,
- hepatitis C (note: hepatitis C testing at screening will only be performed on
those at high risk or with known history), or.
- - human immunodeficiency virus (positive HIV 1/2 antibodies) (note: HIV testing
at screening will only be performed on those at high risk or with known
history)
- 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)3A4 inhibitor within 5 half-lives of study
treatment.
.. Unable to avoid certain CYP3A4 or CYP2C9 substrates which cannot be
co-administered with study treatment given altered substrate concentrations.
- - 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.
- - 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 5 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 enrollment (Day 1 of
study drug).
