An open-label, phase II, single-arm study of everolimus in combination with letrozole in the treatment of postmenopausal women with estrogen receptor positive metastatic breast cancer (CRAD001Y24135)

Preclinical studies suggest that in breast cancer cells with upregulated AKT
signaling, sensitivity to hormonal therapy may be restored by treatment with
everolimus or other mTOR inhibitors. mTOR inhibitors given in combination with
aromatase inhibitors (AIs) in preclinical models result in synergistic
inhibition of proliferation and induction of apoptosis. This preclinical work
suggests that co-targeting the mTOR pathway and ER signaling may improve the
effectiveness of endocrine therapy. In addition, endocrine-resistant breast
cancer cells demonstrate hyperactivation of the PI3K/mTOR pathway, and
treatment with mTOR inhibitors reverses this resistance.
Results from recent clinical studies support these findings. Combining
everolimus with letrozole in the neoadjuvant setting induced higher response
rates than with letrozole alone in postmenopausal women with ER-positive breast
cancer. The combination of everolimus with tamoxifen was also associated with
prolonged PFS and improved overall survival (OS) in a phase II randomized study
in patients progressing after prior AI treatment compared with tamoxifen alone.
In a recent pivotal phase III, randomized, double-blind, placebo-controlled
trial of everolimus plus exemestane versus exemestane plus placebo in ER
positive postmenopausal women with locally advanced or metastatic disease
refractory to letrozole or anastrozole, the addition of everolimus to
exemestane prolonged median progression free survival from 3.2 to 7.8 months
based on local assessment and 4.1 to 11 months based on central radiology
review.
The above data support the activity of everolimus both in patients progressing
after initial endocrine treatment and in patients who have not received prior
treatment in the neoadjuvant setting. However, to date the efficacy of
everolimus plus endocrine therapy has not been explored for first line therapy
of patients with metastatic disease. Preclinical studies have shown that
inhibition of the PI3K/mTOR pathway can prevent the emergence of
hormone-independent cells, suggesting that early intervention with combined
endocrine therapy and mTOR inhibition may prevent or delay endocrine
resistance. It is also of interest to investigate whether continued mTOR
inhibition with sequential endocrine therapy may provide clinical benefit. The
proposed trial will assess the efficacy of everolimus plus letrozole in the
first line treatment of patients with metastatic breast cancer and explore the
efficacy of continued treatment with everolimus plus exemestane after initial
progression.

Primary: to estimate progression-free survival in patients treated with
everolimus + letrozole in the first line setting.
Secondary: overall response rate, clinical benefit rate, overall survival in
the first line setting, progression free survival and clinical benefit rate in
the second line setting, safety and tolerability. Severity and duration of
stomatitis after therapeutic intervention.

Multicenter open label non-comparative phase II study.
Study treatment: everolimus + letrozole until progression as first line
therapy; option to continue with everolimus + exemestane as second line therapy
until progression.
Follow-up for survival.
Patients developing stomatitis be randomized to take a 5% dexamethasone mouth
rinse (3 times/day) or the best supportive care normally used at each
participating center.
200 patients.

Treatment with everolimus + letrozole and everolimus + exemestane. In case of
stomatitis: treatment with dexamethasone mouth rinse or best supportive care.

Risk: Adverse events of study medication.
Burden: Study duration in principle until disease progression (1st or 2nd
line). Thereafter optional follow-up for survival. Visits every 4 weeks.
Physical examination every visit.
Blood draws every visit, 20-30 mL/occasion (screening 40 mL).
Urine analysis at screening.
ECG at screening.
Tumor evaluations as during regular treatment every 8 weeks
Questionnaire for stomatitis symptoms.