|E.1 Medical condition or disease under investigation
|E.1.1||Medical condition(s) being investigated ||
|Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer
|E.1.2 Medical condition or disease under investigation
|E.1.2||Classification code ||10006187
|E.1.2||Term ||Breast cancer
|E.1.2||System Organ Class ||10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
|E.1.3||Condition being studied is a rare disease || No
|E.2 Objective of the trial
|E.2.1||Main objective of the trial ||
|To compare the combination treatment of everolimus and exemestane to exemestane alone with respect to progression-free survival in postmenopausal women with estrogen receptor positive breast cancer refractory to NSAIs.
|E.2.2||Secondary objectives of the trial ||
|Key Secondary Objective
▪To compare overall survival (OS) between the 2 treatment arms
Other Secondary Objectives
▪To evaluate the two treatment arms with respect to
▫Overall response rate (ORR)
▫Time to deterioration of ECOG Performance Status
▫Change in QoL scores over time
▫Clinical benefit rate (CBR)
▪To summarize time to response and duration of response in the 2 treatment
▪Both everolimus and exemestane are substrates of CYP3A4 and there is a
potential DDI between the two drugs. The study will therefore,
▫characterize, in a subgroup of patients, the pharmacokinetics of everolimus
(Cmin, C2h) when administered in combination with exemestane.
▫compare the two treatment arms with respect to pre-dose concentration (Cmin)
and concentration at 2 hours post dose (C2h) of exemestane and to compare, in
a subgroup of patients, the 2 treatment arms with respect to estradiol (E2)
changes from baseline.
|E.2.3||Trial contains a sub-study || No
|E.3||Principal inclusion criteria ||
|▪ Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer
not amenable to curative treatment by surgery or radiotherapy.
▪ Histological or cytological confirmation of estrogen-receptor positive (ER+) breast
▪ 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 <
▫ Surgical menopause with bilateral oophorectomy.
▪ Disease refractory to non steroidal aromatase inhibitors (NSAI), defined as:
▫ Recurrence while on, or within 12 months of end of adjuvant treatment with
letrozole or anastrozole, or
▫ Progression while on, or within one month of end of letrozole or anastrozole
treatment for locally Advanced or metastatic Breast Cancer (ABC).
Note: Letrozole or anastrozole do not have to be the last treatment prior to randomization. Patients who received one prior chemotherapy line for ABC are allowed. Other prior anticancer therapy, e.g. tamoxifen, fulvestrant are also allowed. Patients do not need to meet the definition of “refractory to NSAI” within any specified time period prior to randomization. Patients can receive any number of endocrine/hormonal lines of therapy before or after meeting the definition of “refractory to NSAI”. Patients must have recovered to grade 1 or better from any adverse events (except alopecia) related to previous therapy prior to randomization.
▪ Radiological or objective evidence of recurrence or progression on or after the last systemic therapy prior to randomization.
Note: There are no restrictions as to which therapy the patient received as their last line of therapy just prior to randomization. Patients must have recovered to grade 1 or better from any adverse events (except alopecia) related to any previous therapy prior to randomization.
▪ Patients must have:
▫ 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
▫ bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable
disease as defined above.
▪ Adequate bone marrow and coagulation function as shown by:
▫ Absolute neutrophil count (ANC) ≥ 1.5x10 9/L
▫ Platelets ≥ 100 ×10 9/L
▫ Hemoglobin (Hgb) ≥ 9.0 g/dL
▫ 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 x 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
▪ ECOG Performance Status ≤ 2
▪ Written informed consent obtained before any trial related activity and according to local guidelines.
|E.4||Principal exclusion criteria||
|▪ HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ
▪ Patients with only non-measurable lesions other than bone metastasis (e.g. pleural
effusion, ascites etc.).
▪ Patients who received more than one chemotherapy line for ABC.
Note: A chemotherapy line in advanced disease is an anticancer regimen(s) that
contains at least 1 cytotoxic chemotherapy agent and given for 21 days or longer. If a cytotoxic chemotherapy regimen was discontinued for a reason other than disease
progression and lasted less than 21 days, then this regimen does not count as a "prior line of chemotherapy"
▪ Previous treatment with exemestane or mTOR inhibitors.
▪ Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin).
▪ 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.
▪ Radiotherapy within 4 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 2 weeks prior to randomization. Patients must have
recovered from radiotherapy toxicities prior to randomization.
▪ Currently receiving hormone replacement therapy, unless discontinued prior to
▪ Historie of brain or other CNS metastases
• 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 2 weeks before
randomization are allowed.
▪ Bilateral diffuse lymphangitic carcinomatosis
▪ Patients with a known history of HIV seropositivity. Screening for HIV infection at
baseline is not required.
▪ Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose
warfarin, 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 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.
▪ 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 clinically relevant drug interaction listed in tables 6-8 and 6-9)
• History of noncompliance to medical regimens
• Patients unwilling to or unable to comply with the protocol
|E.5 End points
|E.5.1||Primary end point(s)||
|progression-free survival (PFS), defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause.
|E.6 and E.7 Scope of the trial
|E.6||Scope of the trial
|E.6.9||Dose response|| No
|E.7||Trial type and phase
|E.7.1||Human pharmacology (Phase I)|| No
|E.7.1.1||First administration to humans|| No
|E.7.1.2||Bioequivalence study|| No
|E.220.127.116.11||Other trial type description||
|E.7.2||Therapeutic exploratory (Phase II)|| No
|E.7.3||Therapeutic confirmatory (Phase III)|| Yes
|E.7.4||Therapeutic use (Phase IV)|| No
|E.8 Design of the trial
|E.8.1.3||Single blind|| No
|E.8.1.4||Double blind || Yes
|E.8.1.5||Parallel group|| Yes
|E.8.1.6||Cross over || No
|E.8.2|| Comparator of controlled trial
|E.8.2.1||Other medicinal product(s)|| No
|E.8.2.2||Placebo || Yes
The trial involves single site in the Member State concerned
|E.8.4|| The trial involves multiple sites in the Member State concerned || Yes
|E.8.4.1||Number of sites anticipated in Member State concerned||12
|E.8.5||The trial involves multiple Member States|| Yes
|E.8.5.1||Number of sites anticipated in the EEA||81
|E.8.6 Trial involving sites outside the EEA
|E.8.6.1||Trial being conducted both within and outside the EEA|| Yes
|E.8.6.2||Trial being conducted completely outside of the EEA|| Information not present in EudraCT
|E.8.6.3||If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned||
|E.8.7||Trial has a data monitoring committee|| Yes
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|The End of Study visit is the date when no further patient information will be collected, including reasons for death or lost to follow-up. It occurs after the last survival information is collected.
|E.8.9 Initial estimate of the duration of the trial
|E.8.9.1||In the Member State concerned years||4
|E.8.9.1||In the Member State concerned months||6
|E.8.9.1||In the Member State concerned days||3
|E.8.9.2||In all countries concerned by the trial years||4
|E.8.9.2||In all countries concerned by the trial months||6
|E.8.9.2||In all countries concerned by the trial days||3