Study of Combined Fulvestrant and RAD001 in Advanced/Metastatic Breast Cancer After Aromatase Inhibitor Failure (BRE-43)

Inclusion:

All subjects must be female. Postmenopausal status, defined as any one of the following criteria: (a) Documented history of bilateral oophorectomy.

(b) Age 60 years or more. (c) Age 45 to 59 and satisfying one or more of the following criteria:

1. Amenorrhea for at least 12 months and intact uterus.

2. Amenorrhea for less than 12 months and a follicle stimulating hormone (FSH) concentration within postmenopausal range including:

   1. Patients who have had a hysterectomy.
   2. Patients who have received hormone replacement. Patients must have histologically confirmed invasive breast cancer. Metastatic or locally advanced disease. Patients must have estrogen receptor and/or progesterone receptor positive disease.

Measurable or evaluable disease. Failure of aromatase inhibitor therapy within the previous 6 months. Patients who received prior tamoxifen are eligible to enroll.

Prior aromatase inhibitor therapy or other endocrine therapy must be discontinued at least 1 week prior to enrollment and any toxicity from such therapy must have reverted to grade I or less at the time of enrollment.

Patients must not have received chemotherapy, radiation therapy, or had surgery within 4 weeks prior to enrollment and any toxicity from such therapy must have recovered to grade 1 or less prior to enrollment.

Patients must not have received either of the study medications previously. WHO performance status of 0, 1, or 2.

Adequate organ function defined as follows:

1. Adequate renal function, defined by a serum creatinine within the upper limits of normal.
2. Adequate liver function, defined by a bilirubin of < 1.5 the upper limit of normal (ULN) and AST, ALT of ≤ 2.5 times the ULN.
3. Adequate bone marrow function, defined as an ANC ≥ 1.5 x 109/L, PLT >100,000/ul, Hb >9 gm/dl.
4. INR <1.3.

Exclusion:

Known severe hypersensitivity to RAD001 (or similar drugs) or any of the excipients of this product.

Premenopausal status. Other coexisting malignancies with the exception of basal cell carcinoma or cervical cancer in situ.

Patients with brain metastasis or leptomeningeal involvement. Patients with malignant pleural effusion or ascites only disease. Rapidly progressive visceral disease. WHO performance status of 3 or 4.

As judged by the investigator, uncontrolled intercurrent illness including, but not limited to:

• Ongoing or active infection
• Symptomatic congestive heart failure
• Unstable angina pectoris or significant cardiac arrhythmia
• Psychiatric illness/social situations that would limit compliance with study requirements.
• Severely impaired lung function such as severe COPD or interstitial lung disease, a known FEV1 of < 1.5 liters, or dyspnea of grade III or greater.
• Uncontrolled diabetes as defined by a FBS of > 1.5 ULM.
• Known liver disease such as cirrhosis or chronic hepatitis.
• Known HIV positivity.
• Known condition causing malabsorption. Chronic treatment with systemic steroids or other immunosuppressive agents. Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period.

Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the subject to participate in the clinical trial.

Prior treatment with an mTOR inhibitor. Treatment with a non-approved or investigational drug within 30 days or 5 half-lives of the drug, whichever is greater, before Day 1 of study treatment.

In the opinion of the investigator, bleeding diathesis or anticoagulation therapy that would preclude intramuscular injections.

History of hypersensitivity to castor oil.