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A Phase IIIB, Multi-Center, Open Label Study For Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Treated With Everolimus (RAD001) in Combination With Exemestane: 4EVER - Efficacy, Safety, Health Economics, Translational Research

Phase 3
18 Years
Open (Enrolling)
Metastatic Breast Cancer

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Trial Information

A Phase IIIB, Multi-Center, Open Label Study For Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Treated With Everolimus (RAD001) in Combination With Exemestane: 4EVER - Efficacy, Safety, Health Economics, Translational Research

In light of the need for new treatment options for postmenopausal, hormone receptor
positive, HER2 negative women after failure of prior non-steroidal aromatase inhibitor
(NSAI) therapy, the BOLERO-2 trial was performed and demonstrated significant efficacy of
the combinatorial treatment of Everolimus and Exemestane compared to an Exemestane
monotherapy in this setting.

In this randomized, double blind, placebo-controlled trial a statistically significant
improvement in progression-free survival (PFS) by adding Everolimus to exemestane versus
Exemestane alone was reported. Adding Everolimus determined a 2.4-fold prolongation in PFS
from 3.2 up to 7.4 months and so lowered the risk of cancer progression by 56% for these
women. These findings were confirmed by an independent assessment (4.1 vs. 11.0 months, risk
reduction: 64%). The quality of life data shows positive trend in the Everolimus plus
Exemestane treatment arm. (Baselga 2011, Hortobagyi 2011). Thus, the benefit of the
combinatorial treatment versus Exemestane monotherapy was shown in a defined patient
population under controlled conditions.

The primary objective of this trial to assess the Overall Response Rate (ORR) in
postmenopausal women with hormone receptor positive breast cancer progressing following
prior therapy with NSAIs treated with the combination of Everolimus and Exemestane. The
secondary objectives include, Progression free survival (PFS), Overall survival (OS),
Safety, Change in Quality of life scores over time, Health resource utilization. The
exploratory objectives reflect scientific interest within the treatment of metastatic breast
cancer and are to be modified, if applicable, according to the current scientific state of
the art at the time of actual analysis. These include: the influence of age, performance
status, cancer activity and inflammation on anxiety and depression; changes in serum
bone-turnover biomarkers; Pharmacogenetics of Everolimus in patients with advanced breast
cancer; presence and molecular characteristics of Circulating Tumor Cells; correlation of
response to Exemestane/Everolimus with Proteomic analysis.

The present national, multi-center, open-label, single-arm study aims to evaluate the
efficacy and safety, quality of life and health resources utilization of the combination of
Everolimus and Exemestane in a broader patient population compared to BOLERO-2, i.e. without
limitations as to the number of previous chemotherapy lines, the time point of progression
after NSAI therapy, and the previous endocrine therapy as patients under Exemestane
monotherapy may be enrolled. Since the combination was shown to significantly improve PFS in
the previous BOLERO-2 trial, for ethical reasons no endocrine comparator drugs will be
investigated in the present study, due to the low efficacy of Exemestane monotherapy (PFS
3.2 months).

Inclusion Criteria

Main Inclusion criteria:

Metastatic or locally advanced breast cancer not amenable to curative treatment by surgery
or radiotherapy or any other non-systemic treatment.

Histological or cytological confirmation of estrogen receptor positive (ER+) and/or
progesterone receptor positive (PgR+), human epidermal growth factor receptor 2 (HER2)
negative breast cancer Postmenopausal women. Disease progression following prior therapy
with non steroidal aromatase inhibitors (NSAI), defined as: Recurrence while on, or
following completion of an adjuvant treatment with Letrozole or Anastrozole, or
Progression while on or following completion of Letrozole or Anastrozole treatment for

Radiological evidence of recurrence or progression on last systemic therapy prior to

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.

Written informed consent obtained before any screening procedure and according to local

Other protocol defined inclusion criteria apply.

Main Exclusion criteria:

HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ
hybridization positive).

Patients with only non-measurable lesions other than bone metastasis (e.g. pleural
effusion, ascites etc.).

Previous treatment with mTOR inhibitors or known hypersensitivity to mTOR inhibitors.

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 enrollment and the dose of corticosteroids is low (i.e. ≤ 10 mg/d
Prednisolone equivalent) and stable for at least two weeks prior to enrollment.

Patients with Hepatitis B or C or with a history of Hepatitis B or C. Patients unwilling
to or unable to comply with the protocol. Other protocol defined exclusion criteria apply.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall Response Rate (ORR) after 24 weeks of treatment

Outcome Description:

The Overall response rate (ORR) is the proportion of patients with a best overall response of confirmed complete (CR) or partial (PR) response by Week 24. The best overall response is determined from the sequence of investigator overall lesion responses according to RECIST 1.1. To be assigned a best overall response of CR at least two determinations of CR at least 4 weeks apart before progression are required. To be assigned a best overall response of PR at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required.

Outcome Time Frame:

24 weeks

Safety Issue:


Principal Investigator

Novartis Pharmaceuticals

Investigator Role:

Study Director

Investigator Affiliation:

Novartis Pharmaceuticals


Germany: Federal Institute for Drugs and Medical Devices

Study ID:




Start Date:

June 2012

Completion Date:

May 2014

Related Keywords:

  • Metastatic Breast Cancer
  • Postmenopausal
  • Estrogen Receptor Positive
  • HER2 negative
  • Locally Advanced
  • Metastatic Breast Cancer
  • Everolimus (RAD001)
  • Exemestane
  • Breast Neoplasms