Breast Cancer, Hormone Receptor Positive Tumor, Human Epidermal Growth Factor 2 Negative Carcinoma of Breast, Locally Advanced Malignant Neoplasm, Metastatic Breast Cancer
Conditions
Keywords
Breast cancer, HER2Negative, hormone receptor positive (HR+), Metastatic, Locally Advanced, fulvestrant, everolimus, exemestane
Brief summary
This is a multi-center, randomized, open-label, parallel group study designed to evaluate efficacy and safety of fulvestrant followed, at progression, by examestane and everolimus versus examestane and everolimus followed, at progression, by fulvestrant in postmenopausal women with HR+ and HER2- LABC or MBC whose disease has progressed to NSAI in the adjuvant or metastatic setting.
Detailed description
In this study everolimus will be administered in combination with exemestane, which is an irreversible steroidal aromatase inactivator that has demonstrated efficacy in the treatment of postmenopausal patients with ABC. Exemestane is indicated for adjuvant treatment of postmenopausal women with HR+ EBC who have received two to three years of tamoxifen and are switched to exemestane for completion of a total of five consecutive years of adjuvant hormonal therapy. It is also indicated for the treatment of ABC in postmenopausal women whose disease has progressed following tamoxifen therapy (in the USA) or following antiestrogen therapy (in Europe). In 2011, the BOLERO-2 trial reported (5; 33) a significant benefit for HR+ HER2- postmenopausal pretreated women in the ABC setting by combining everolimus with exemestane. In this randomized, double-blind, placebo-controlled trial a statistically significant improvement in 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 QoL data shows positive trend in the everolimus plus exemestane treatment arm.
Interventions
DRUGEverolimus
10 mg daily tablets
DRUGExemestane
25 mg daily tablets
DRUGFulvestrant
500 mg i.m. on Days 1, 15 and 29 and every 28 days thereafter
Sponsors
Clinical Research Technology S.r.l.
Consorzio Oncotech
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult women (≥ 18 years of age) with LABC or MBC not amenable to curative treatment by surgery or radiotherapy, refractory to NSAI 2. Histological or cytological confirmation of ER+ BC and/or PgR+. 3. Postmenopausal women. 4. Radiological or objective evidence of recurrence or progression on or after the last systemic therapy prior to randomization 5. 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 * Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease as defined above. 6. Adequate bone marrow and coagulation according RCP 7. Adequate liver function, according RCP 8. Adequate renal function, according RCP 9. ECOG Performance Status ≤ 2 10. Written informed consent
Exclusion criteria
1. HER2-overexpressing patients by local laboratory testing (IHC3+ staining or in situ hybridization positive). 2. Patients who received chemotherapy for MBC 3. Patients who received more than one NSAI treatment for LABC or MBC 4. Pre-menopausal, pregnant, lactating women. 5. Known hypersensitivity to mTOR inhibitors 6. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose galactose malabsorption. 7. Radiotherapy within four weeks prior to enrollment 8. Currently receiving hormone replacement therapy, unless discontinued prior to enrollment. 9. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at the time of study entry except in some cases 10. Patients with symptomatic visceral disease in need of urgent disease control 11. Symptomatic brain or other CNS metastases. 12. Patients with a known history of HIV seropositivity. 13. Active, bleeding diathesis, or on oral anti-vitamin K medication (except cases). 14. 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 * Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study treatments (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome) * Inability to swallow oral medications * Significant symptomatic deterioration of lung function. 15. Hepatic-related
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS1) | Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months | The number of events required for the other primary endpoint (PFS1), and the expected time needed to achieve it are derived from previous calculations. Assuming an average accrual rate of 31 pts/month (677pts/22 months), a median PFS1 of 6 months in the Fulvestrant arm (control), a Hazard ratio of 0.70 (implying that a median PFS1 of 8,6 months is expected in the experimental arm, a 2-sided significance level of 0.025 and power of 0.90, 391 events are required for PFS1, that will be achieved in about 22 months (East 6 software). |
| Total Progression-free survival (PFST) | Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months | Overall study size is driven by the endpoint less frequent (PFST). Sample size is planned to identify a Hazard ratio of 0.75, assuming an overall study duration of 36 months, an accrual duration of 24 months, a 2-sided significance level of 0.025 and power of 0.80. Assuming a median PFST of 12 months in the Fulvestrant arm (control), the expected PFST in the experimental arm will be equal to 16 months and 677 subjects need to be enrolled (East 6 software) with an average accrual rate equal to 30.8 patients/month (11 months per year have been considered). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate | Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months | Objective Response Rate (ORR), the Clinical Benefit, the overall survival, and the safety profile and the QOLof of the sequence of fulvestrant followed, at progression by exemestane and everolimus versus the sequence of examestane and everolimus followed, at progression, by fulvestrant in postmenopausal women with HR + and HER2- LABC or MBC previously treated with NSAI in the adjuvant or metastatic setting. |
| Clinical Benefit Rate | Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months | Objective Response Rate (ORR), the Clinical Benefit, the overall survival, and the safety profile and the QOLof of the sequence of fulvestrant followed, at progression by exemestane and everolimus versus the sequence of examestane and everolimus followed, at progression, by fulvestrant in postmenopausal women with HR + and HER2- LABC or MBC previously treated with NSAI in the adjuvant or metastatic setting. |
| Overall Survival | Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months | Objective Response Rate (ORR), the Clinical Benefit, the overall survival, and the safety profile and the QOLof of the sequence of fulvestrant followed, at progression by exemestane and everolimus versus the sequence of examestane and everolimus followed, at progression, by fulvestrant in postmenopausal women with HR + and HER2- LABC or MBC previously treated with NSAI in the adjuvant or metastatic setting. |
| Safety - 5D5L questionnaire | up to 31 days since last treatment | The overall observation period will be divided into three mutually exclusive segments per treatment phase: 1. pre-treatment period: from day of patient's informed consent to the day before first dose of study medication (phase 1) on-treatment period: from day of first dose of study medication to 30 days (minimum washout) after last dose of study medication (phase 2) or first dose of second phase treatment after cross-over 2. post-treatment period: starting at day 31 after last dose of study medication (phase 2) |
Countries
Italy
Contacts
Primary ContactClinical Research Technology
Outcome results
None listed