Study in Post-menopausal Women With Hormone Receptor Positive, HER2-negative Advanced Breast Cancer

Study Overview
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Brief Summary
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This international, multi-center, open-label, single-arm study evaluated the safety and tolerability profile of everolimus in post-menopausal women with HR positive, HER2 negative locally advanced or metastatic breast cancer after documented recurrence or progression following a non-steroidal aromatase inhibitors (NSAI) therapy in Novartis Oncology emergent growth market (EGM) countries.Data was presented by Asian countries vs Non-Asian countries to confirm no difference in safety and efficacy. Summary statistics were presented.

Official Title
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A Phase IIIb, Multi-center, Open-label Study of RAD001 in Combination With EXemestane in Post-menopausal Women With EStrogen Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative Locally Advanced or Metastatic Breast Cancer

Conditions
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Post Menopausal Breast Cancer

Intervention / Treatment
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* Drug: everolimus
* Drug: exemestane


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal women with metastatic, recurrent or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy. Histological or cytological confirmation of hormone-receptor positive (HR+) breast cancer. Disease refractory to non-steroidal aromatase inhibitors, defined as: Recurrence while on, or within 12 months (365 days) of completion of adjuvant therapy with letrozole or anastrozole, or Progression while on, or within one month (30 days) of completion of letrozole or anastrozole treatment for locally advanced or metastatic breast cancer (ABC). Radiological or objective evidence of recurrence or progression on or after the last systemic therapy prior to enrolment. Patients must have had: At least one lesion that could have been 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 + blastic) in the absence of measurable disease as defined above. Adequate bone marrow, coagulation, liver and renal function. ECOG performance status ≤ 2. Exclusion Criteria: Patients overexpressing HER2 by local laboratory testing (IHC 3+ staining or in situ hybridization positive). Patients with IHC 2+ must have a negative in situ hybridization test. Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites). Patients with more than one prior chemotherapy line for ABC. A chemotherapy line is an anticancer regimen(s) that contained at least 1 cytotoxic chemotherapy agent, given for a minimum of 21 days. Previous treatment with mTOR inhibitors. Known hypersensitivity to mTOR inhibitors, e.g. Sirolimus (rapamycin). Patients with a known history of HIV seropositivity. Screening for HIV infection at baseline was not required. Patient who were being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A History of brain or other CNS metastases, including leptomeningeal metastasis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: everolimus + exemestane<br>Everolimus (10 mg) and exemestane (25 mg) tablets taken orally in combination once daily | Drug: everolimus<br>* one 10 mg tablet or two 5 mg tablets of everolimus were administered orally once daily on a continuous dosing schedule starting on Day 1<br>* Other names: RAD001;Drug: exemestane<br>* 25 mg tablet was administered orally once daily on a continuous dosing schedule starting on Day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of Number of Participants With Treatment Emergent Adverse Events (TEAE) - All Grades | Adverse events (AEs), serious adverse events (SAEs), changes from baseline in vital signs and laboratory results (hematology, blood chemistry, lipid profile) qualifying and reported as AEs. Although a patient might had two or more adverse events the patient is only counted once in a category. The same patient might appear in different categories. AESI: Adverse events of special interest. | Baseline up to approximately 43 weeks for Asian countires and 32 weeks for Non-Asian countries including a 30 day post treatment follow up period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Response Rates (Best Overall and Overall) | The best overall response for each patient is determined from the sequence of investigator overall lesion responses according to RECIST 1.1: Complete Response (CR)=disappearance of target lesions, Partial Response (PR) was >=30% decrease in sum of diameter of lesions, Progressive Disease (PD) was >=20% decrease in sum of diameter of lesions, Stable Disease (SD) does not qualify for PR, CR or PD, Unknown=not documented or assessed. 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. The Overall response rate (ORR) is the percentage of patients with a best overall response of confirmed complete (CR) or partial (PR) response. The 95% confidence intervals (CI) were computed using the Clopper-Pearson method | Baseline up to approximately 43 weeks for Asian countires and 32 weeks for Non-Asian countries | 
| Percentage of Participants Clinical Benefit Rate | Clinical benefit rate: Patients with best overall response rate of CR (any duration), PR (any duration) and SD with duration of 24 weeks or longer according to RECIST 1.1 criteria: Complete Response (CR)=disappearance of target lesions, Partial Response (PR) was >=30% decrease in sum of diameter of lesions, Progressive Disease (PD) was >=20% decrease in sum of diameter of lesions, Stable Disease (SD) does not qualify for PR, CR or PD, Unknown=not documented or assessed. Best overall response of CR = at least two determinations of CR at least 4 weeks apart before progression are required. 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. The Overall response rate (ORR) is the percentage of patients with a best overall response of confirmed complete (CR) or partial (PR) response. The 95% confidence intervals (CI) were computed using the Clopper-Pearson method. | Baseline up to approximately 43 weeks for Asian countires and 32 weeks for Non-Asian countries | 
| Progression Free Survival (PFS) | PFS is time from date of start of treatment to date of disease progression or death due to any cause, whichever occurs first. b Percentiles with 95% CIs are calculated from PROC LIFETEST output using method of Brookmeyer and Crowley (1982) | Baseline up to approximately 43 weeks for Asian countires and 40 weeks for Non-Asian countries | 
| Percent of Participants Event-free Probability Estimates of Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status | Time to deterioration of ECOG performance status, from baseline will be assessed using the ECOG Performance Status Scale (Oken, 1982). Time to deterioration is the time from date of start of treatment to the date of the event defined as deterioration. Deterioration is defined as an increase in performance status from 0 to 2 or greater, an increase in performance status from 1-2 to 3 or greater, or death due to any cause. Event-free probability estimate is the estimated probability that a patient will remain event-free up to the specified time point. Event-free probability estimates were are obtained from the Kaplan-Meier survival estimates. | Baseline up to approximately 50 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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post menopausal, advanced breast cancer, metastatic breast cancer, everolimus, exemestane, mTor inhibitor, endocrine therapy, human epidermal growth factor, estrogen receptor positive, adult, CRAD001