Phase II Trial of EVEROLIMUS ± Trastuzumab in Hormone-Refractory Metastatic Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Everolimus; Trastuzumab
Intervention MeSH terms: Trastuzumab; Everolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 70.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Breast Cancer

Summary:

      This phase II trial studies how well everolimus with or without trastuzumab works in treating
      patients with breast cancer that has not responded to hormone therapy and has spread from
      where it started to other places in the body. Everolimus may stop the growth of tumor cells
      by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as
      trastuzumab, may interfere with the ability of tumor cells to grow and spread. Giving
      everolimus and adding trastuzumab at the time of disease progression may be an effective
      treatment for breast cancer.
    

Eligibility criteria:

        Inclusion Criteria:

        Patients will be included in the study based on the following criteria:

          -  Hormone-refractory metastatic breast cancer defined as disease progression within 6
             months from starting most recent hormonal therapy

          -  At least one line of endocrine therapy in the metastatic setting

          -  Candidate for hormonal therapy (ER and/or progestin receptor [PR]-positive at primary
             diagnosis and at metastatic diagnosis where tissue is available)

          -  HER2/neu-negative breast cancer by standard criteria (immunohistochemistry [IHC] < 3+
             or fluorescence in situ hybridization [FISH]-negative if IHC 3+) at primary diagnosis

          -  Must have a biopsy in the metastatic setting with HER2 expression of 1+ or 2+ by IHC

          -  If biopsy of metastatic lesion is performed prior to study entry, HER2 expression by
             IHC must be 1+ or 2+

          -  Histologically confirmed, measurable or evaluable disease; if disease is measurable,
             Response Evaluation Criteria In Solid Tumors (RECIST) criteria should be used

          -  Life expectancy > 6 months

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

          -  Adequate bone marrow function as indicated by the following:

               -  Absolute neutrophil count (ANC) > 1500/µL

               -  Platelets ≥ 100,000/µL

               -  Hemoglobin > 10 g/dL

          -  Adequate renal function, as indicated by creatinine ≤ 1.5x upper limit of normal (ULN)

          -  Adequate liver function, as indicated by bilirubin ≤ 1.5x ULN

          -  International normalized ratio (INR) ≤ 1.3 (or ≤ 3 on anticoagulants)

          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2x ULN unless
             related to primary disease

          -  Signed informed consent

          -  Adequate birth control

          -  Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5
             x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can
             only be included after initiation of appropriate lipid lowering medication.

        Exclusion Criteria:

        Patients will be excluded from the study based on the following criteria:

          -  Prior treatment with trastuzumab or other HER2-directed therapies or with an mammalian
             target of rapamycin (mTOR) inhibitor within 12 months of study entry (when cancer was
             not definitely hormone refractory)

          -  HER2 0 or 3+ by IHC on pre-treatment biopsy of metastatic lesion (if performed)

          -  Active infection

          -  Uncontrolled central nervous system metastases

          -  Life-threatening, visceral metastases

          -  Pregnant or lactating women

          -  Prior chemotherapy within the last 4 weeks

          -  Prior radiation therapy within the last 4 weeks; prior radiation therapy to indicator
             lesion (unless objective disease recurrence or progression within the radiation portal
             has been documented since completion of radiation)

          -  Concomitant malignancies or previous malignancies within the last 5 years, with the
             exception of adequately treated basal or squamous cell carcinoma of the skin or
             carcinoma in situ of the cervix

          -  History of significant cardiac disease, cardiac risk factors or uncontrolled
             arrhythmias

          -  Ejection fraction < 50% or below the lower limit of the institutional normal range,
             whichever is lower

          -  Hypersensitivity to trial medications

          -  Emotional limitations

          -  Prior treatment with any investigational drug within the preceding 4 weeks

          -  Patients receiving chronic, systemic treatment with corticosteroids or another
             immunosuppressive agent

          -  Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN

          -  Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
             hepatitis

          -  A known history of HIV seropositivity

          -  Impairment of gastrointestinal function or gastrointestinal disease that may
             significantly alter the absorption of everolimus (e.g., ulcerative disease,
             uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
             resection)

          -  Patients with an active, bleeding diathesis

          -  Female patients who are pregnant or breast feeding, or adults of reproductive
             potential who are not using effective birth control methods. If barrier contraceptives
             are being used, these must be continued throughout the trial by both sexes. Hormonal
             contraceptives are not acceptable as a sole method of contraception. (Women of
             childbearing potential must have a negative urine or serum pregnancy test within 7
             days prior to administration of everolimus)

          -  Patients who have received prior treatment with an mTOR inhibitor (sirolimus,
             temsirolimus, everolimus)

          -  Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs,
             resulting in dyspnea at rest

          -  Taking any of the following agents:

               -  Chronic treatment with systemic steroids or another immunosuppressive agent

               -  Live vaccines

               -  Drugs or substances known to be inhibitors or inducers of the isoenzyme
                  cytochrome P450, family 3, subfamily A (CYP3A)