Simvastatin Plus Dual Anti-HER2 Therapy for Metastatic Breast Cancer

This study is recruiting participants with metastatic breast cancer that is HER2 positive.
"Metastatic" means that cancer has spread to areas of the body outside of the breast. "HER2
positive" means that a cancer cell has too many HER2 receptors on its surface. HER2 receptors
act like copy machines, and help tell cancer cells to grow and multiply.

Drugs known as HER2-targeted therapies are often used to treat HER2-positive cancers.
HER2-targeted therapies work by blocking the HER2 protein from telling the cell to grow and
divide. Once the protein stops working, the cancer cells can no longer make copies of
themselves. Once a cancer cell becomes unable to make copies of itself, the tumor will start
to shrink. However, some tumors are able to find other ways to make copies of themselves,
even when the HER2 protein is blocked. When this happens, the cancer will start to grow
again. Researchers believe that adding a drug called simvastatin to an anti-HER2 therapy
regimen may cause the cancer to start responding again to your HER2-medications.

Simvastatin is a drug that is approved by the Food and Drug Administration (FDA) to treat
high cholesterol. Laboratory research has shown that simvastatin together with dual
HER2-targeted therapy slows the growth of breast cancer tumors that had been growing on dual
HER2-targeting therapy alone.

Inclusion Criteria:

- Signed informed consent.

- Patients must have histologically confirmed and documented adenocarcinoma of the
breast with metastatic disease not amenable to curative therapy.

- Cancer must be HER2-positive, according to ASCO-CAP guidelines. Any ER and PR status
is allowed.

- Participants must have documented disease progression while receiving dual anti-HER2
targeted therapy for metastatic breast cancer, as per investigator assessment. Any
combination of biologic therapies is acceptable. Prior chemotherapy is acceptable, but
patients must have been off cytotoxic chemotherapy for at least 1 month. Patients with
ER-/HER2+ disease have must be failed at least 1 line of chemotherapy in the
metastatic setting. Patients with ER+/HER2+ disease who progressed on dual anti-HER2
therapy plus endocrine therapy are eligible. Concomitant endocrine therapy is
acceptable and may be continued at the discretion of the treating physician.

- Patient must be female and at least 18 years of age.

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2

- Patients must have measurable disease, per RECIST criteria v1.1.21

- Participants must not have undergone major surgery or radiation therapy within 28 days
prior to beginning treatment with simvastatin. Any toxicity from prior surgical or
radiation treatment must have sufficiently resolved prior to study entry, as
determined by the treating physician.

- Estimated life expectancy of ≥ 12 weeks.

- Ability to swallow oral medications.

- Participants must have adequate organ function as defined by:

1. ANC ≥1.5 x 109/L, platelet count ≥100 x 109/L, haemoglobin ≥ 10 g/dL.

2. creatinine < 1.5 x UNL (upper normal limit)

3. Total bilirubin < 1.5x UNL

4. ALT & AST < 2.5xUNL; alkaline phosphatase < 2.5xUNL;

5. Creatine phosphokinase (CPK) ≤ 2.5 x UNL

- Baseline left ventricular ejection fraction (LVEF) ≥ 50% as determined by either
echocardiography (ECHO) or multi gated acquisition (MUGA) scan.

- Patients with CNS metastatic disease are allowed if the disease is controlled and
stable for at least 3 months by CT or MRI.

- Negative pregnancy test within 7 days prior to study treatment start, for women of
childbearing potential. Women of childbearing potential must agree to use an adequate
form of contraception for the duration of their study participation

Exclusion Criteria:

- Patients currently treated with a statin or who have been treated with a statin in the
past 2 months are ineligible for this study.

- Known hypersensitivity to statins.

- Prior history of rhabdomyolysis.

- Patients who consume more than 3 alcoholic beverages per day.

- Lack of physical integrity of the upper gastrointestinal tract, clinically significant
malabsorption syndrome, or inability to take oral medications.

- Poorly controlled hypertension at the physician's discretion or clinically significant
(i.e. active) cardiovascular disease: cerebrovascular accident (CVA) / stroke within ≤
6 months prior to the first study treatment, myocardial infarction within ≤ 6 months
prior to the first study treatment, unstable angina, New York Heart Association (NYHA)
grade II or greater congestive heart failure (CHF), or serious cardiac arrhythmia
requiring medication.

- Current severe, uncontrolled systemic disease (e.g. pulmonary, or metabolic disease;
wound healing disorders; ulcers; or bone fractures)

- Current or past infection with Human Immunodeficiency Virus (HIV), Hepatitis B virus
(HBV), or Hepatitis C virus (HCV).

- Receipt of IV antibiotics for infection within 7 days of study enrollment.

- History of other malignancies within the last 2 years, except for carcinoma in situ of
the cervix or basal cell carcinoma

- Participants with bone-only disease are excluded, unless a measureable lesion is
present, as defined by RECIST 1.1.

- Patients who suffer from a medical or psychiatric condition that, in the opinion of
the principal investigator, would impair their ability to participate in the study.

- Concurrent interventional studies.