Rad001 (everolimus)

A Randomized Double-Blind, Placebo-Controlled Study of
Everolimus in Combination with Exemestane in the
Treatment of Postmenopausal Women with Estrogen
Receptor Positive Locally Advanced or Metastatic Breast
Cancer who are refractory to Letrozole or Anastrozole.

Population
Postmenopausal women with estrogen receptor positive locally advanced or
metastatic breast cancer whose disease is refractory to non steroidal aromatase inhibitors (NSAI) and has a documented recurrence or progression on last therapy for breast cancer. Refractory disease to NSAI is defined as: 1. Recurrence while on, or within 12 months of end of, adjuvant treatment with letrozole or anastrozole, or 2. Progression while on, or within one month of end of, letrozole or anastrozole treatment for locally advanced or metastatic breast cancer Except for prior use of exemestane and mTOR inhibitors, there are no restrictions as to the last anticancer treatment prior to randomization. Patients must have documented evidence of recurrence or progression on last therapy prior to randomization. No more than one prior chemotherapy for advanced disease is allowed. The investigator or his/her designee must ensure that all patients who meet the following inclusion and exclusion criteria are offered enrollment in the study.

Inclusion criteria
1. Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy. 2. Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer 3. Postmenopausal women. Postmenopausal status is defined either by: • Age ≥ 55 years and one year or more of amenorrhea • Age < 55 years and one year or more of amenorrhea, with an estradiol assay < 20 pg/ml • Surgical menopause with bilateral oophorectomy Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression. 4. Disease refractory to non steroidal aromatase inhibitors (NSAI), defined as: 1. Recurrence while on, or within 12 months of end of adjuvant treatment 2. Progression while on, or within one month of end of letrozole or anastrozole treatment for ABC. • Note: Letrozole or anastrozole do not have to be the last treatment prior to randomization. Patients who received one chemotherapy regimen for ABC are allowed. Other prior anticancer therapy, e.g. tamoxifen, fulvestrant are also allowed. Patients must have recovered to grade 1 or better from any adverse events (except alopecia) related to previous therapy prior to randomization. 5. Radiological or clinical evidence of recurrence or progression on last systemic therapy prior to randomization. Note: There are no restrictions as to the last systemic therapy prior to randomization. Patients must have recovered to grade 1 from any adverse events (except alopecia) related to prior therapy prior to randomization. 1. At least one lesion that can be accurately measured in at least one dimension ≥ 20 mm with conventional imaging techniques or ≥ 10 mm with spiral CT or MRI or 2. bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease as defined above. 7. Adequate bone marrow and coagulation function as shown by: • Absolute neutrophil count (ANC) ≥ 1.5 109/L • Platelets ≥ 100 ×109/L • Hemoglobin (Hgb) ≥ 9.0 g/dL • Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ULN (or ≤ 5 if hepatic metastases are present) • Total serum bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for patients known to have Gilbert Syndrome) 10. Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤ 2.5 ×ULN. In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy and when the above mentioned values have been achieved 11. ECOG Performance Status ≤ 2 12. Written informed consent obtained before any screening procedure and according to local guidelines.

Exclusion criteria
1. HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive). 2. Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites etc.). 3. Patients who received more than one chemotherapy regimen for ABC. 4. Previous treatment with exemestane or mTOR inhibitors. 5. Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin). 6. Another malignancy within 5 years prior to randomization, with the exception of adequately treated in-situ carcinoma of the cervix, uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer. 7. Radiotherapy within four weeks prior to randomization except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture which can then be completed within two weeks prior to randomization. Patients must have recovered from radiotherapy toxicities prior to randomization. 8. Currently receiving hormone replacement therapy, unless discontinued prior to randomization. 9. Symptomatic brain or other CNS metastases Previously treated brain metastases are allowed provided the patient is free of symptoms, prior radiotherapy for brain metastasis was more than four weeks before randomization and the dose of corticosteroids is low and stable for at least two weeks prior to randomization. 10. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at the time of study entry except in cases outlined below: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed. Patients on stable low dose of corticosteroids for at least two weeks before randomization are allowed in case of previously treated brain metastases (as described in exclusion criteria n° 9). 11. Bilateral diffuse lymphangitic carcinomatosis or metastasis of the lung as the only manifestation of disease (>50% of lung involvement), evidence of metastases estimated as more than a third of the liver as defined by sonogram and/or CT scan. 12. Patients with a known history of HIV seropositivity. Screening for HIV infection at baseline is not required. 13. Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose warfarin and acetylsalicylic acid or equivalent, as long as the INR is ≤ 2.0) 14. Any severe and / or uncontrolled medical conditions such as: • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to enrollment, serious uncontrolled cardiac arrhythmia • Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN • Acute and chronic, active infectious disorders and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy • Impairment of gastrointestinal function or who have gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome) • Active skin, mucosa, ocular or GI disorders of Grade > 1 • Significant symptomatic deterioration of lung function. If clinically indicated, pulmonary function tests including measures of predicted lung volumes, DLco, O2 saturation at rest on room air should be considered to exclude restrictive pulmonary disease, pneumonitis or pulmonary infiltrates. 15. Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A (Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itroconazole, Voriconazole, Ritinavir, Telithromycin) within the last 5 days prior to randomization (List of prohibited concomitant medications in Table 6-6) 16. History of non-compliance to medical regimens 17. Patients unwilling to or unable to comply with the protocol

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