Study of Fulvestrant +/- Everolimus in Post-Menopausal, Hormone-Receptor + Metastatic Breast Ca Resistant to AI
Condition: Metastatic Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Fulvestrant; Everolimus; Placebo
Intervention description: Fulvestrant 500 mg Day 1 & 15 of Cycle 1, then 500 mg Day 1 of all subsequent cycles (every 28 days for 12 cycles).
If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.; Everolimus 10 mg (2 tablets) daily x 12 cycles.
If no evidence of disease progression after 12 cycles, unblind and continue same dose and schedule until progression or unacceptable toxicity.; Placebo for Everolimus (2 tablets) daily x 12 cycles. Placebo manufactured to mimic everolimus tablet.
Intervention MeSH terms: Everolimus; MTOR Inhibitors; Fulvestrant
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 131.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Post-Menopausal Patients; Hormone-Receptor Positive; Resistant to Aromatase Inhibitor Therapy; Fulvestrant; Faslodex; mTOR Inhibitor; Everolimus; RAD001; Afinitor

Summary:

      Post-menopausal women with hormone-receptor positive (HR+) metastatic breast cancer resistant
      to aromatase inhibitor (AI) therapy will be randomized to receive Fulvestrant (Faslodex) with
      Everolimus or Fulvestrant (Faslodex) with a placebo (no active ingredients).

      Fulvestrant has demonstrated activity when used as first, second, or third line endocrine
      therapy, making it an attractive therapy for combination with other agents. In addition, it
      is commonly reserved for use following disease progression on AI therapy.

      Everolimus is an orally administered drug that blocks a signaling pathway called "mTOR".
      "mTOR" acts as a regulator for many processes in the body, including cell growth. Blocking
      this pathway may have an effect on cell growth.

      The combination of a novel class of agents (mTOR inhibitors) and an established standard
      treatment for metastatic HR+ breast cancer may potentially increase the clinical benefit by
      targeting multiple different biological pathways.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Signed informed consent.

          2. ≥18 years.

          3. ECOG Performance Status 0 or 1.

          4. Histologically or cytologically confirmed adenocarcinoma of the breast.

          5. Stage IV disease or inoperable locally advanced disease.

          6. ER and/or PR-positive disease. Tumors must be HER-2/neu negative or equivocal.

          7. Aromatase Inhibitor (AI) resistant, defined as:

               -  relapsed while receiving adjuvant therapy with an AI or,

               -  progressive disease while receiving an AI for metastatic disease

          8. Received one prior cycle of fulvestrant within 28 days of randomization are eligible.

               -  ≥2 prior doses of fulvestrant are not eligible

          9. Must be female and postmenopausal.

         10. May have received ≤1 prior systemic chemotherapy regimen for metastatic disease.

         11. Adequate organ function:

               -  Whole Blood Cells (WBC) ≥3.0 x 10⁹/L, Absolute neutrophil count (ANC) ≥1.5 x
                  10⁹/L and platelet count ≥100 x 10⁹/L

               -  hemoglobin ≥9 g/dL

               -  serum bilirubin ≤1.5 X ULN (Upper Limit of Normal)

               -  Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≤2.5 X ULN (≤5
                  x ULN in patients with liver metastases)

               -  serum creatinine ≤1.5 X ULN

               -  serum albumin ≥3 g/dL

               -  fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides
                  ≤2.5 x ULN.

               -  Prothrombin time (PT) with international normalized ratio (INR) ≤1.5

         12. May have measurable disease, non-measurable disease, or both.

         13. Basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
             within the past five years treated with curative intent. History of prior malignancy
             are eligible if disease-free for >3 years.

        Exclusion Criteria:

          1. Major surgery or significant traumatic injury within 4 weeks of randomization or
             patients that may require major surgery during the course of the study.

          2. Investigational agents within 4 weeks of randomization.

          3. Anticancer treatment within 4 weeks of randomization, with the following exceptions:

               -  Bisphosphonates or Zometa for bone metastases

               -  a GnRH analog is permitted if the patient had progressive disease on a GnRH
                  (Gonadotropin-Releasing Hormone) analog plus a SERM (Selective Estrogen Receptor
                  Modulators) or an AI; the GnRH analog may continue but the SERM or AI must be
                  discontinued.

          4. Prior treatment with an mTOR inhibitor.

          5. Receiving chronic, systemic treatment with corticosteroids or another
             immunosuppressive agent ≥ 5 mg prednisone or equivalent daily.

          6. Receive immunization with attenuated live vaccines within one week of randomization or
             during the study period.

          7. Current or a prior history of brain metastases or leptomeningeal disease. Must not
             have rapidly progressive, life-threatening metastases.

          8. Known hypersensitivity/history of allergic reactions attributed to compounds of
             similar chemical or biologic composition to everolimus or fulvestrant.

          9. Congenital or acquired immune deficiency at increased risk of infection.

         10. Impairment of gastrointestinal function/disease that may significantly alter the
             absorption of everolimus.

         11. Active, bleeding diathesis.

         12. History of any condition or uncontrolled intercurrent illness that in the opinion of
             the local investigator might interfere with or limit the patient's ability to comply
             with the protocol or pose additional or unacceptable risk to the patient.

         13. Severe and/or uncontrolled medical conditions or other conditions that could affect
             their participation in the study such as:

               -  Symptomatic congestive heart failure of New York Heart Association Class III or
                  IV

               -  Unstable angina pectoris, myocardial infarction within 6 months of randomization,
                  serious uncontrolled cardiac arrhythmia or any other clinically significant
                  cardiac disease

               -  History of symptomatic pulmonary disease or non-malignant pulmonary disease
                  requiring treatment.

               -  Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN

               -  Active (acute or chronic) or uncontrolled severe infections

               -  Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh Class
                  C).

        Note: Detailed assessment of Hepatitis B/C medical history and risk factors must be done at
        screening.