Simvastatin Plus Dual Anti-HER2 Therapy for Metastatic Breast Cancer (SIMPHONY)

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.