Simvastatin Plus Dual Anti-HER2 Therapy for Metastatic Breast Cancer

A Phase II Single Arm Trial of Adding Simvastatin to Dual Anti-HER2 Therapy in Patients With HER2-Positive Metastatic Breast Cancer

This study recruits patients with metastatic breast cancer who have progressed on their current regimen of dual anti-HER2 therapy. This study evaluates whether or not the addition of simvastatin to the dual anti-HER2 therapy regimen helps make the tumor respond to the anti-HER2 therapy again. All participants will receive simvastatin in combination with their current anti-HER2 therapy regimen.

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.