An Open Label Study of Postmenopausal Women With Oestrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Treated With Everolimus (RAD001) With Exemestane, With Exploratory Epigenetic Marker Analysis
Condition: Oestrogen Receptor Positive Advanced Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: RAD001; Exemestane
Intervention description: All postmenopausal women with oestrogen receptor positive locally advanced or metastatic breast cancer were treated with oral tablet RAD001 at a dose of 10mg daily and oral tablet exemestane 25mg daily. The study treatment for an individual patient was to begin on Study Day 1 and continue until the last patient enrolled completed the study at day 336 or until disease progression; unacceptable toxicity, death or early discontinuation from the study for any other reason, whichever occurs first.; All postmenopausal women with oestrogen receptor positive locally advanced or metastatic breast cancer were to be treated with oral tablet RAD001 at a dose of 10mg daily and oral tablet exemestane 25mg daily. The study treatment for an individual patient was to begin on Study Day 1 and continue until the last patient enrolled completed the study at day 336 or until disease progression; unacceptable toxicity, death or early discontinuation from the study for any other reason, whichever occurs first.
Intervention MeSH terms: Everolimus; Exemestane
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 52.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Breast Neoplasms; Neoplasms; Breast diseases; Skin diseases; Exemestane; Antibiotics, Antineoplastic; Everolimus; Antineoplastic Agents; Therapeutic Uses; Pharmacologic Actions; Immunosuppressive Agents; Physiological Effects of Drugs; Aromatase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action

Summary:

      Determine the overall response rate (ORR) at 48 weeks to everolimus (RAD001, 10mg daily p.o.)
      and exemestane (25mg daily p.o.) treatment in postmenopausal women with oestrogen receptor
      positive breast cancer who have previous experienced recurrence or progression on
      non-steroidal aromatase inhibitor (NSAI) therapy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histological or cytological confirmation of oestrogen receptor positive (ER+) and/or
             progesterone receptor positive (PgR+), human epidermal growth factor receptor 2 (HER2)
             negative breast cancer.

          -  Availability of archival tumour tissue (the tissue block or slides will be sent to the
             central laboratory for analysis).

          -  Postmenopausal women. The investigator must confirm postmenopausal status.
             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 and postmenopausal levels of
                  FSH and LH per local institutional standards

               -  Prior hysterectomy and has postmenopausal levels of Follicle stimulating hormone
                  (FSH) and Luteinizing Hormone (LH) per local institutional standards Surgical
                  menopause with bilateral oophorectomy

          -  Disease progression following prior therapy with NSAI, defined as:

               -  Recurrence while on or after completion of an adjuvant treatment including
                  letrozole or anastrozole, or

               -  Progression while on or following the completion of letrozole or anastrozole
                  treatment for locally advanced or metastatic breast cancer

        Note: Non-steroidal aromatase inhibitors (i.e. letrozole or anastrozole) do not have to be
        the last treatment prior to enrollment. Other prior anticancer therapy, e.g. tamoxifen,
        fulvestrant, exemestane are also allowed. Patients must have recovered to grade 1 or better
        from any adverse events (except alopecia) related to previous therapy prior to enrollment.

        - Radiological evidence of recurrence or progression on last systemic therapy prior to
        enrollment.

        Patients must have:

          -  At least one lesion that can be accurately measured or

          -  Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease

             - Adequate bone marrow and coagulation function as shown by:

          -  Absolute neutrophil count (ANC) ≥ 1.5 109/L

          -  Platelets ≥ 100 ×109/L

          -  Hemoglobin (Hb) ≥ 9.0 g/dL

          -  International Normalized Ratio (INR) ≤ 2 .

             - Adequate liver function as shown by:

          -  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)

             - Adequate renal function as shown by:

          -  Serum creatinine ≤ 1.5 × ULN

               -  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

               -  Eastern Cooperative Oncology Group (ECOG) performance status of PS </ 2

               -  Written informed consent obtained before any screening procedure and according to
                  local guidelines.

        Exclusion Criteria:

          -  HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ
             hybridization positive).

          -  Pre-menopausal, pregnant, lactating women.

          -  Known hypersensitivity to mammilian target of Rapamycin (mTOR) inhibitors, e.g.
             sirolimus (rapamycin) or to their excipients.

          -  Known hypersensitivity to exemestane, to the active substance or to any of the
             excipients.

          -  Patients with rare hereditary problems of galactose intolerance, Lapp lactase
             deficiency or glucose galactose malabsorption.

          -  Radiotherapy within four weeks prior to enrollment 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 enrollment. Patients must have recovered
             from radiotherapy toxicities prior to enrollment.

          -  Currently receiving hormone replacement therapy, unless discontinued prior to
             enrollment.

          -  Patients receiving concomitant immunosuppressive agents or chronic corticosteroids
             use, at the time of study entry except in cases outlined below:

        Prolonged systemic corticosteroid treatment during study, except for topical applications
        (e.g. rash),inhaled sprays (e.g. obstructive airways diseases), eye drops or local
        injections (e.g. intra-articular) should not be given. However:

          -  short duration (<2 weeks) of systemic corticosteroids is allowed (e.g. chronic
             obstructive pulmonary disease, anti-emetic)

          -  low doses of corticosteroids for brain metastasis treatment is allowed

          -  Patients with symptomatic visceral metastasis (e.g. significant dyspnoea related to
             pulmonary lymphangitic carcinomatosis and lung metastases or clinically meaningful
             symptomatic liver metastasis)

          -  Symptomatic brain or other Central Nervous system (CNS) metastases.

          -  Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose
             warfarin, low molecular weight heparin (LMWH) and acetylsalicylic acid or equivalent,
             as long as the INR is 2.0)

          -  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 (except for Hep B and Hep C
                  positive patients) 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 gastrointestinal disease that may
                  significantly alter the absorption of study drugs (e.g., ulcerative disease,
                  uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome)

               -  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.

          -  Patients being treated with drugs recognized as being strong inhibitors or inducers of
             the isoenzyme CYP3A (rifabutin, rifampicin, clarithromycin, ketoconazole,
             itraconazole, voriconazole, ritonavir, telithromycin) within the last 5 days prior to
             enrollment

          -  History of non-compliance to medical regimens

          -  Patients unwilling to or unable to comply with the protocol

          -  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