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 that is refractory to non-steroidal aromatase…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint in this study is progression-free survival (PFS), defined
as the time from date of randomization to the date of first documented
progression or death due to any cause. If a patient has not had an event, PFS
will be censored at the date of last adequate tumor assessment.
Secondary outcome
- To compare the two treatment arms with respect to Overall Survival (OS).
- To evaluate the two treatment arms with respect to
o Overall response rate (ORR)
o Time to deterioration of ECOG performance status
o Safety
o Changes in Quality of Life (QoL) scores over time
o Clinical benefit rate (CBR)
- To summarize time to response and duration of response in the two treatment
arms.
Background summary
Approximately 70% of all invasive breast cancers are positive for ER and/or PgR
expressions at the time of diagnosis. Deprivation of estrogenic signaling with
the anti-estrogen tamoxifen has been the main form of hormonal treatment for
over 30 years. While therapies which interfere with ER functions such as
tamoxifen have significantly contributed to mortality reduction in advanced
breast cancer patients, at best 50-60% of ER-positive patients respond to
anti-estrogen therapy. Consequently, a number of aromatase inhibitors (AIs)
that reduce peripheral estrogen synthesis have been developed for the treatment
of advanced breast cancer (ABC). The third generation AIs can be broadly
classified into two groups: non-steroidal aromatase inhibitors (NSAI), mainly
letrozole (Femara®) and anastrozole (Arimidex®) and the steroidal
aromatase-inactivator, exemestane (Aromasin®).
There are currently no treatments specifically approved for postmenopausal
women with ER positive breast cancer after recurrence or progression on a non
steroidal aromatase inhibitor (letrozole or anastrozole). To date, treatment of
these patients remains an area of unmet medical need.
Activation of the mTOR pathway is a key adaptive change driving endocrine
resistance. Research into the mechanisms of resistance has shown that various
signal transduction pathways are activated to escape the effect of endocrine
therapy. Everolimus is a derivative of rapamycin that acts as a signal
transduction inhibitor. An important aspect of the anti-tumor effect of
everolimus is its potential to act both on tumor cells directly (to inhibit
growth) and indirectly (by inhibiting angiogenesis and displaying anti-vascular
properties). Everolimus and letrozole synergistically inhibit proliferation in
BC cells. mTOR inhibition provides additional efficacy to long term estrogen
deprivation and has an acceptable level of tolerability in the neoadjuvant
setting.
Study objective
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 that is refractory to non-steroidal
aromatase inhibitors.
Study design
This is a multicenter, double-blind, randomized, placebo-controlled,
international phase III study.
Patients will be randomized in 2:1 ratio to receive either everolimus or
matching placebo in a blinded manner in addition to open label exemestane (25
mg daily tablets). Considering the safety of exemestane is already well
established, the 2:1 randomization ratio will allow collection of more data
from the experimental arm to better evaluate the safety of the
everolimus-exemestane combination.
Study treatment will continue until progression, intolerable toxicity or
consent withdrawal. Further treatment after progression will be at the
investigator*s discretion. Subjects on placebo arm will not be allowed to cross
over to study supplied everolimus at the time progression, as everolimus
remains an investigational drug for this patient.
Intervention
Patients will be randomized in 2:1 ratio to receive either everolimus (2
tablets × 5 mg daily) or matching placebo in a blinded manner, in addition to
open label exemestane (25 mg daily tablets).
Study burden and risks
- Every potential side effect of everolimus and/or exemestane.
- Radiation exposure of X-rays and/or CT scans.
- Obtaining blood samples may cause some discomfort, bruising, bleeding from
the site of sampling, formation of a blood clot, and, in rare cases, infection.
Raapopseweg 1
6824 DP Arnhem
NL
Raapopseweg 1
6824 DP Arnhem
NL
Listed location countries
Age
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 cancer.
- Postmenopausal women.
- Disease refractory to non steroidal aromatase inhibitors (NSAI).
- Radiological or clinical evidence of recurrence or progression on last systemic therapy prior to randomization.
- ECOG Performance Status * 2.
-Patients must have:
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.
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.).
- Patients who received more than one chemotherapy regimen for ABC.
- Previous treatment with exemestane or mTOR inhibitors.
- Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin).
- Another malignancy within 5 years prior to randomization.
- Radiotherapy within four weeks prior to randomization.
- Currently receiving hormone replacement therapy, unless discontinued prior to randomization.
- Symptomatic brain or other CNS metastases.
- Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use at the time of study entry.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-008698-69-NL |
| CCMO | NL28031.094.09 |